The DOI matches its Crossref record; 77 of the 78 references it cites were found in a registry or an index; 57 of the 102 sources its claims cite were checked for support.
Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates
Open accessAbstract
Gene delivery vectors based on adeno-associated viruses (AAV) have exhibited promise in both preclinical disease models and human clinical trials for numerous disease targets, including the retinal degenerative disorders Leber's congenital amaurosis and choroideremia. One general challenge for AAV is that preexisting immunity, as well as subsequent development of immunity following vector administration, can severely inhibit systemic AAV vector gene delivery. However, the role of neutralizing antibodies (NABs) in AAV transduction of tissues considered to be immune privileged, such as the eye, is unclear in large animals. Intravitreal AAV administration allows for broad retinal delivery, but is more susceptible to interactions with the immune system than subretinal administration. To assess the effects of systemic anti-AAV antibody levels on intravitreal gene delivery, we quantified the anti-AAV antibodies present in sera from non-human primates before and after intravitreal injections with various AAV capsids. Analysis showed that intravitreal administration resulted in an increase in anti-AAV antibodies regardless of the capsid serotype, transgene or dosage of virus injected. For monkeys injected with wild-type AAV2 and/or an AAV2 mutant, the variable that most significantly affected the production of anti-AAV2 antibodies was the amount of virus delivered. In addition, post-injection antibody titers were highest against the serotype administered, but the antibodies were also cross-reactive against other AAV serotypes. Furthermore, NAB levels in serum correlated with those in vitreal fluid, demonstrating both that this route of administration exposes AAV capsid epitopes to the adaptive immune system and that serum measurements are predictive of vitreous fluid NAB titers. Moreover, the presence of preexisting NAB titers in the serum of monkeys correlated strongly (R=0.76) with weak, decaying or no transgene expression following intravitreal administration of AAV. Investigating anti-AAV antibody development will aid in understanding the interactions between gene therapy vectors and the immune system during ocular administration and can form a basis for future clinical studies applying intravitreal gene delivery.
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Claims the paper makes
57 of 102 cited sources checked · 23 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“In non-human primates (NHPs), high concentrations of anti-AAV antibodies significantly reduced the transduction of hepatocytes,29”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Supportedcites [29] Wang L, Calcedo R, Wang H, Bell P, Grant R, Vandenberghe LH et al. The pleiotropic effects of natural AAV infections on liver-directed gene transfer in macaques. Mol Ther 2010; 18: 126–134. source
The Discussion reports that pre-existing anti-AAV8 neutralizing antibodies significantly interfered with gene transfer in macaques, even at titers as low as 1:5. It also describes diminished hepatocyte transduction in animals with detectable antibodies. The claim captures the effect, although the paper emphasizes that high antibody concentrations were not necessary. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the presence of pre-existing antibodies has been correlated with decreased efficacy of gene therapy in clinical trials where the route of administration exposes vector to serum.26,30,31”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Not checked — no full text of the sourcecites [26] Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342–347. source
- Partly supportedcites [30] Nathwani AC, Tuddenham EGD, Rangarajan S, Rosales C, McIntosh J, Linch DC et al. Adenovirus-associated virus vector–mediated gene transfer in hemophilia B. N Engl J Med 2011; 365: 2357–2365. sourceExperimental — accuracy not yet measured
The Results section (Safety and Efficacy of Peripheral-Vein Infusion of Vector; page unavailable) reports that Participant 3 had higher pre-treatment anti-AAV8 antibody levels and initially low FIX activity, raising the possibility that antibodies blocked transduction. It does not establish a correlation across clinical trials: the authors describe one participant, and his later FIX levels were consistent with successful transgene expression. (LLM, conf=0.84)
- Partly supportedcites [31] Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail 2009; 15: 171–181. sourceExperimental — accuracy not yet measured
The Discussion reports a potential difference in heart-failure progression among the first nine CUPID patients: both patients with pre-existing neutralizing antibodies worsened, and vector sequences were undetectable in both. But it calls the findings too preliminary to draw conclusions. This supports a possible association in one trial, not an established correlation across clinical trials. (LLM, conf=0.85)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“While transient immunosuppression may be a promising approach for reducing cellular immune responses to gene therapy,39–41 it is not effective at mitigating vector neutralization by pre-existing antibodies.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Not checked — no full text of the sourcecites [39] Halbert CL, Standaert TA, Wilson CB, Miller AD . Successful readministration of adeno-associated virus vectors to the mouse lung requires transient immunosuppression during the initial exposure. J Virol 1998; 72: 9795–9805. source
- Partly supportedcites [40] Jiang H, Couto LB, Patarroyo-White S, Liu T, Nagy D, Vargas JA et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood 2006; 108: 3321–3328. sourceExperimental — accuracy not yet measured
The Results section on preexisting AAV8 neutralizing antibodies reports that antibodies at a titer of 1:5 neutralized the vector and prevented detectable FIX expression in rhesus macaques (page unavailable). The Discussion says the transient anti-T-cell regimen did not reliably block the antibody response to AAV capsid (page unavailable). However, the cited passages do not show a direct test of whether that regimen mitigated neutralization by antibodies already present before treatment. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [41] Manning WC, Zhou S, Bland MP, Escobedo JA, Dwarki V . Transient immunosuppression allows transgene expression following readministration of adeno-associated viral vectors. Hum Gene Ther 1998; 9: 477–485. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Furthermore, AAV administration to immune privileged regions can lead to increases in neutralizing antibody titers, including following intravitreal injection in dogs and non-human primates37 and following intracranial injections in several clinical trials.38”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Partly supportedcites [37] Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z, Chen Y et al. Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med 2010; 2: 21ra16. sourceExperimental — accuracy not yet measured
The Results sections on immune responses in dogs and NHPs report increased AAV2 neutralizing-antibody titers after ocular vector administration. But the Results section on bilateral readministration specifies that the vector was injected subretinally, not intravitreally; the intravitreal injection mentioned there was ciprofloxacin. The intracranial-trial clause is attached to a different citation and is not assessed here. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [38] Mingozzi F, High KA . Immune responses to AAV in clinical trials. Curr Gene Ther 2011; 11: 321–330. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“delivery is limited to tissues in contact with the bleb(s),18–20”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Could not verifycites [18] Aleman TS, Cideciyan A V, Sumaroka A, Windsor EAM, Herrera W, White DA et al. Retinal laminar architecture in human retinitis pigmentosa caused by Rhodopsin gene mutations. Invest Ophthalmol Vis Sci 2008; 49: 1580–1590. sourceExperimental — accuracy not yet measured
The Discussion addresses which retinal regions might be treatable in RHO-associated retinitis pigmentosa, but it does not describe a delivery area defined by a subretinal bleb. Searches for “bleb,” “subretinal,” and delivery limited to tissues in contact with a bleb found no passage supporting the claim; the available passages have no page labels. (LLM, conf=0.76)
- Partly supportedcites [19] Jacobson SG, Aleman TS, Cideciyan A V, Roman AJ, Sumaroka A, Windsor EAM et al. Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 2009; 50: 2368–2375. sourceExperimental — accuracy not yet measured
The Discussion describes a subretinal treatment zone and considers different injection sites for focal retinal therapy; the Conclusions likewise refer to selecting retinal sites for delivery. These passages support the idea that treatment is localized, but they do not state that delivery is limited specifically to tissues in contact with a bleb. Page numbers were not provided in our copy. (LLM, conf=0.78)
- Not checked — no full text of the sourcecites [20] Jacobson SG, Aleman TS, Sumaroka A, Cideciyan A V, Roman AJ, Windsor EAM et al. Disease boundaries in the retina of patients with Usher syndrome caused by MYO7A gene mutations. Invest Ophthalmol Vis Sci 2009; 50: 1886–1894. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recent clinical trials for hemophilia have used even more stringent criteria for patient exclusion, removing patients whose neutralizing antibodies were above 1:4.31,43”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Partly supportedcites [31] Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail 2009; 15: 171–181. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says the CUPID heart-failure trial screened for low or absent neutralizing antibodies and later excluded all antibody-positive patients. It does not describe a hemophilia trial or an exclusion threshold of 1:4; the titers it reports are 1:2 and <1:2. (LLM, conf=0.78)
- Partly supportedcites [43] Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 2011; 124: 304–313. sourceExperimental — accuracy not yet measured
The Discussion reports that the CUPID heart-failure trial screened patients by neutralizing-antibody titer and later excluded all antibody-positive patients. It does not report an exclusion threshold above 1:4 or an exclusion policy for hemophilia trials; the qualifying titer it gives for CUPID is below 1:2. (LLM, conf=0.86)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“As a result, AAV clinical successes to date have involved delivery either to immune privileged regions or to subjects lacking apparent AAV immunological memory.8–14,30,42”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Partly supportedcites [8] Hauswirth WW, Aleman TS, Kaushal S, Cideciyan A V, Schwartz SB, Wang L et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008; 19: 979–990. sourceExperimental — accuracy not yet measured
The Introduction describes this study as a subretinal AAV gene-therapy trial, and the reported results show improved visual sensitivity in the treated eyes. It therefore provides an example of ocular AAV clinical success. It does not establish that AAV clinical successes generally were confined to immune-privileged regions or to subjects lacking apparent AAV immunological memory; the Materials and Methods describe testing for anti-AAV2 responses but do not establish that broader claim. (LLM, conf=0.82)
- Supportedcites [9] Cideciyan A V, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther 2009; 20: 999–1004. source
The Materials and Methods section identifies this as an AAV gene-therapy trial with administration to the retina. The Results and Discussion section reports that the visual improvements persisted at one year, supporting this paper as an example of a clinical AAV success involving ocular delivery. It does not establish the sentence’s broader claim about all AAV successes, but the citation is supported as an example within the cited group. (LLM, conf=0.87)
- Supportedcites [10] Bainbridge JWB, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2231–2239. source
This paper supports the claim as an example of the immune-privileged-region alternative: the Methods (p. 3) describe subretinal AAV delivery in the eye, and the Discussion (p. 8) reports modest improvements in visual function. It does not need to establish the other alternative or survey all AAV trials to serve as one of the cited clinical successes. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [11] Maguire A, Simonelli F . Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2240–2248. source
- Supportedcites [12] Maguire AM, High K a, Auricchio A, Wright JF, Pierce E a, Testa F et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009; 374: 1597–1605. source
The Methods describe AAV delivery into the subretinal space, and the Discussion reports sustained improvement in retinal function in all 12 treated patients. This paper supports the cited example of an AAV clinical success involving delivery to the eye; it does not need to establish the alternative concerning subjects’ AAV immunological memory. (LLM, conf=0.88)
- Supportedcites [13] Bennett J, Ashtari M, Wellman J, Marshall K a, Cyckowski LL, Chung DC et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 2012; 4: 120ra15. source
The Discussion reports improved retinal and visual function after AAV gene therapy readministration and attributes its strong safety profile partly to the immune-privileged nature of the target tissue. This paper therefore supplies an example of clinical success involving delivery to an immune-privileged region; it need not establish the sentence’s broader claim about all AAV successes on its own. (LLM, conf=0.89)
- Supportedcites [14] Jacobson SG, Cideciyan A V, Ratnakaram R, Heon E, Schwartz SB, Roman AJ et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 2012; 130: 9–24. source
This paper supports the ocular-delivery example in the multiply cited sentence: the Results report improved light sensitivity after subretinal AAV2 treatment, and the immune-response assays report that delivery to the eye did not activate pre-existing peripheral AAV2-specific memory T cells. It does not establish the broader claim about all AAV clinical successes, but that broader survey is not what this individual trial is cited to exemplify. The indexed passages provide section labels but no page numbers. (LLM, conf=0.86)
- Supportedcites [30] Nathwani AC, Tuddenham EGD, Rangarajan S, Rosales C, McIntosh J, Linch DC et al. Adenovirus-associated virus vector–mediated gene transfer in hemophilia B. N Engl J Med 2011; 365: 2357–2365. source
The Methods (Study Design; page not provided) say the trial enrolled patients without neutralizing antibodies to AAV8. The Results (Immune Responses to Vector and Transgene; page not provided) describe their antibody responses as consistent with a primary response to AAV8, and the Discussion reports sustained therapeutic FIX expression. This trial therefore supports the sentence’s example of success in subjects lacking apparent AAV immunological memory, rather than its alternative of delivery to an immune-privileged region. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [42] McPhee SWJ, Janson CG, Li C, Samulski RJ, Camp a S, Francis J et al. Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 2006; 8: 577–588. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The observation that pre-existing antibodies inhibit AAV transduction has been broadly documented following mouse, rabbit, non-human primate, and human gene therapy administrations.31,57–59”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Effect of Pre-Injection Anti-AAV2 Antibodies on Expression
What the sources say
- Partly supportedcites [31] Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail 2009; 15: 171–181. sourceExperimental — accuracy not yet measured
The Discussion (page not provided) says preexisting neutralizing antibodies can block viral-vector entry, and the paper reports suggestive findings in two antibody-positive CUPID patients. Its References include a mouse transduction study, but our copy does not document the claimed rabbit or non-human-primate findings; the Discussion also says its human data are too preliminary for conclusions. (LLM, conf=0.84)
- Partly supportedcites [57] Lin J, Calcedo R, Vandenberghe LH, Figueredo JM, Wilson JM . Impact of preexisting vector immunity on the efficacy of adeno-associated virus-based HIV-1 Gag vaccines. Hum Gene Ther 2008; 19: 663–669. sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) states that even low circulating antibody titers diminish AAV2 transduction in gene-therapy settings. The Results and Discussion (pages unavailable) show that human or macaque antibodies transferred into mice impair AAV vaccine responses. The paper does not document rabbit administrations or demonstrate inhibited transduction following administrations in each of the four named species; its own experiments measured vaccine responses in mice. (LLM, conf=0.85)
- Partly supportedcites [58] Halbert CL, Standaert TA, Aitken ML, Alexander IE, Russell DW, Miller AD . Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration. J Virol 1997; 71: 5932–5941. sourceExperimental — accuracy not yet measured
The indexed passage on rabbit airway transduction (section and page unavailable) reports that AAV readministration produced no additional transduction and that this correlated with the appearance of neutralizing antibodies. It does not establish that pre-existing antibodies caused the inhibition. This paper addresses rabbits; the other species in the multiply cited sentence are not supported by this source. (LLM, conf=0.86)
- Partly supportedcites [59] Wang L, Calcedo R, Bell P, Lin J, Grant RL, Siegel DL et al. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum Gene Ther 2011; 22: 1389–1401. sourceExperimental — accuracy not yet measured
The Results section reports that pre-existing neutralizing antibodies above a 1:10 titer substantially inhibited AAV8 transfer to macaque liver, and the Introduction describes earlier AAV transduction inhibition. But the Introduction’s mouse-and-rabbit example concerns adenovirus, not AAV; this paper therefore does not support the claim of documented AAV inhibition in rabbits. Page numbers were not available in our copy. (LLM, conf=0.85)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“most likely due to the high prevalence of natural AAV8 and AAV9 infections in rhesus macaques.53,54”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Cross-Reactivity of Antibodies to Various AAV Serotypes Pre-Infection vs. Post-Infection
What the sources say
- Partly supportedcites [53] Gao G-P, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM . Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 11854–11859. sourceExperimental — accuracy not yet measured
The Results (page unavailable) report high-titer antibodies to AAV8 in 45% of rhesus monkeys across the colonies studied, supporting evidence of prevalent AAV8 exposure. The paper studies AAV7 and AAV8, not AAV9, and does not link natural infections to the higher initial AAV8/AAV9 titers in the claim. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [54] Nieto K, Stahl-Hennig C, Leuchs B, Müller M, Gissmann L, Kleinschmidt JA . Intranasal vaccination with AAV5 and 9 vectors against human papillomavirus type 16 in rhesus macaques. Hum Gene Ther 2012; 23: 733–741. source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“AAV8 and AAV9 capsids have the highest sequence similarity of any of the four capsids studied (85.7% amino acid sequence identity)55”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Cross-Reactivity of Antibodies to Various AAV Serotypes Pre-Infection vs. Post-Infection
What the sources say
- Partly supportedcites [55] Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol 2004; 78: 6381–6388. sourceExperimental — accuracy not yet measured
Table 3 (Results and Discussion; page not provided) reports 14.3% cap amino acid differences between AAV8 and AAV9, corresponding to 85.7% identity. The paper compares more than four capsids and does not establish that AAV8 and AAV9 are the most similar of the citing study’s four; its table includes pairs with fewer differences. (LLM, conf=0.85)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
- It may state two separate claims as one. 18
- Probably not a substantial claim. 19
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, another challenge to AAV-mediated gene therapy is humoral, anti-AAV antibody mediated immunity, which results from childhood exposure to one or more serotypes or from prior administration of AAV vectors and poses a significant challenge to AAV gene therapy.26,27”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Not checked — no full text of the sourcecites [26] Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342–347. source
- Partly supportedcites [27] Stroes ES, Nierman MC, Meulenberg JJ, Franssen R, Twisk J, Henny CP et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol 2008; 28: 2303–2304. sourceExperimental — accuracy not yet measured
The trial report (page unavailable in our copy) observed antibodies against AAV1 capsid proteins after intramuscular vector administration and says the later loss of efficacy was potentially related to an immune response. It does not address pre-existing immunity from childhood exposure or prior AAV treatment, nor show severe inhibition of systemic vector delivery. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“during Phase I/II clinical trials for Leber's congenital amaurosis (LCA), over 30 patients who received a subretinal injection of AAV2 encoding RPE65, an enzyme responsible for the isomerohydrolase activity of retinal pigment epithelium, showed sustained improvement in both subjective and objective measurements of vision.8–14”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Partly supportedcites [8] Hauswirth WW, Aleman TS, Kaushal S, Cideciyan A V, Schwartz SB, Wang L et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008; 19: 979–990. sourceExperimental — accuracy not yet measured
The Abstract reports self-reported improvement in visual sensitivity and significant improvement on objective sensitivity testing after subretinal AAV2-RPE65 treatment. But the Results describe only three patients in this trial, and follow-up lasted 90 days; this paper does not establish sustained improvement in over 30 patients. Visual acuity did not improve significantly. (LLM, conf=0.88)
- Partly supportedcites [9] Cideciyan A V, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther 2009; 20: 999–1004. sourceExperimental — accuracy not yet measured
The Introduction reports patient testimonials and measured improvements in light sensitivity, and Results and Discussion reports that the measured gains persisted for one year. But Materials and Methods identifies this as a phase I trial of three subjects, not evidence of sustained subjective and objective improvement in over 30 patients. (LLM, conf=0.88)
- Partly supportedcites [10] Bainbridge JWB, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2231–2239. sourceExperimental — accuracy not yet measured
The Summary (p. 1) describes subretinal AAV2/2-RPE65 treatment in three patients, with objective and subjective visual improvement in only one. The Patients and Study Design section (p. 2) reports follow-up of up to 12 months for one patient, so this paper does not establish sustained improvement in over 30 patients. (LLM, conf=0.89)
- Not checked — no full text of the sourcecites [11] Maguire A, Simonelli F . Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2240–2248. source
- Partly supportedcites [12] Maguire AM, High K a, Auricchio A, Wright JF, Pierce E a, Testa F et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009; 374: 1597–1605. sourceExperimental — accuracy not yet measured
The Abstract (Methods and Findings) describes subretinal AAV2-hRPE65v2 treatment and sustained improvement in subjective and objective vision measures. But this trial enrolled 12 patients, not over 30; this paper alone does not establish the citing sentence’s aggregate patient count across the cited trials. (LLM, conf=0.88)
- Partly supportedcites [13] Bennett J, Ashtari M, Wellman J, Marshall K a, Cyckowski LL, Chung DC et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 2012; 4: 120ra15. sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports sustained improvements in retinal and visual function after subretinal AAV2-RPE65 treatment in a phase 1/2 study of 12 patients. The Discussion and Results (pages unavailable) also describe subjective and objective improvements in three of those adults after treatment of their second eyes. Our copy does not substantiate the claim that over 30 patients showed sustained improvement. (LLM, conf=0.88)
- Partly supportedcites [14] Jacobson SG, Cideciyan A V, Ratnakaram R, Heon E, Schwartz SB, Roman AJ et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 2012; 130: 9–24. sourceExperimental — accuracy not yet measured
The Design passage describes subretinal AAV2-RPE65 treatment in 15 patients, and the Comment reports improved visual function on full-field stimulus testing in all 15, with follow-up extending to three years for the initial cohort. This paper does not establish sustained improvement in both subjective and objective vision measures in over 30 patients; its Results also caution that most visual-acuity changes were not clinically significant. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Several rodent models have reported successful second administrations of AAV gene delivery vectors when different serotypes are used for the first vs. second administrations50–52; however, these observations have not been extended to NHPs.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Cross-Reactivity of Antibodies to Various AAV Serotypes Pre-Infection vs. Post-Infection
What the sources say
- Supportedcites [50] Halbert CL, Rutledge EA, Allen JM, Russell DW, Miller AD . Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J Virol 2000; 74: 1524–1532. source
The paper reports successful second AAV-vector administration in mouse lungs when AAV2 and AAV6 were used in opposite orders. The statement about extension to nonhuman primates is the citing authors’ qualification, not a finding attributed specifically to this source. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [51] Peden CS, Burger C, Muzyczka N, Mandel RJ . Circulating anti-wild-type adeno-associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but not rAAV5-mediated, gene transfer in the brain. J Virol 2004; 78: 6344–6359. source
- Partly supportedcites [52] Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM . Gene Therapy Vectors Based on Adeno-Associated Virus Type 1. J Virol 1999; 73: 3994–4003. sourceExperimental — accuracy not yet measured
The murine readministration experiments (Figs. 7–8) support successful second administration with a different serotype in muscle and, for AAV-1 followed by AAV-2, in liver. The paper reports a roughly 20-fold reduction for the reverse sequence in liver. It tests nonhuman-primate sera for neutralizing antibodies but does not establish the broader claim that these readministration observations had not been extended to nonhuman primates. (LLM, conf=0.85)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although neutralizing antibodies against the AAV capsid do not increase (or prevent readministration) when AAV gene therapy vectors are administered via subretinal injection,13”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Partly supportedcites [13] Bennett J, Ashtari M, Wellman J, Marshall K a, Cyckowski LL, Chung DC et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 2012; 4: 120ra15. sourceExperimental — accuracy not yet measured
The Results (Safety of subretinal readministration) report that neutralizing antibody responses remained at or close to baseline in all three subjects and that AAV2 readministration was well tolerated. The claim generalizes those findings to subretinal AAV vectors broadly; the Discussion cautions that the safety evidence cannot be extrapolated to higher doses or other vector preparations. (LLM, conf=0.86)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recent work has developed AAV variants that are capable of infecting both Muller glia and photoreceptors across the retina following intravitreal administration, making intravitreal injections a promising alternative.24,25”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Partly supportedcites [24] Klimczak RR, Koerber JT, Dalkara D, Flannery JG, Schaffer DV . A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells. PLoS One 2009; 4: e7467. sourceExperimental — accuracy not yet measured
The Results (Figures 2 and 4; page not provided) show that the ShH10 variant transduced Müller cells after intravitreal injection, with expression broadly spread across the rat retina. The paper does not show intravitreal photoreceptor transduction; the Discussion describes targeting photoreceptors as a possibility for future work. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [25] Dalkara D, Byrne LC, Klimczak RR, Visel M, Yin L, Merigan WH et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med 2013; 5: 189ra76. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Subretinal AAV vector injection, used for the LCA and choroideremia trials, enables efficient gene expression in several retinal cell types, including photoreceptors and retinal pigment epithelial cells.16,17”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Supportedcites [16] Koerber JT, Klimczak R, Jang J-H, Dalkara D, Flannery JG, Schaffer DV . Molecular evolution of adeno-associated virus for enhanced glial gene delivery. Mol Ther 2009; 17: 2088–2095. source
The Results (In vivo gene delivery of selected viral mutants; page unavailable) report GFP expression after subretinal AAV injection in photoreceptors and retinal pigment epithelium, as well as Müller cells with a different vector. The paper describes efficient retinal gene delivery while noting that expression varied by vector. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [17] Petrs-Silva H, Dinculescu A, Li Q, Min S-H, Chiodo V, Pang J-J et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 2009; 17: 463–471. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“NABs are often the most commonly invoked exclusion criterion for patent enrollment.30”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Partly supportedcites [30] Nathwani AC, Tuddenham EGD, Rangarajan S, Rosales C, McIntosh J, Linch DC et al. Adenovirus-associated virus vector–mediated gene transfer in hemophilia B. N Engl J Med 2011; 365: 2357–2365. sourceExperimental — accuracy not yet measured
The Methods > Study Design passage says that patients enrolled in this hemophilia B trial had to lack neutralizing antibodies to AAV8, supporting their use as an enrollment exclusion criterion. It does not establish that this criterion is often used or is the most commonly invoked across trials. No page number is available in our copy. (LLM, conf=0.88)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, a recent phase I trial for choroideremia showed promising signs of efficacy.15”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Supportedcites [15] MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014; 6736: 2117–2120. source
The Results report gains of 21 and 11 letters in visual acuity for two treated patients and an increase in maximal retinal sensitivity. Those initial findings support the cautious phrase “promising signs of efficacy.” The paper describes the trial more precisely as phase 1/2. (LLM, conf=0.92)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In addition, adaptive immune responses, such as T cell responses to vector proteins or transgene encoded factors,62 can pose a risk to transduced cells.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Supportedcites [62] Willett K, Bennett J . Immunology of AAV-Mediated Gene Transfer in the Eye. Front Immunol 2013; 4: 261. source
The Assays for Measuring Immune Response to AAV section says AAV and transgene products can precipitate cellular immune responses, including responses measured in CD4+ and CD8+ cells. The Repeat Administration of AAV section describes selective removal of transduced cells following a cellular response to AAV capsid in a systemic trial; the Immunity in the Eye section also identifies immune responses as a potential threat to tissue safety and gene-transfer efficacy. The systemic example is not presented as an observed outcome of ocular treatment. (LLM, conf=0.88)
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Similar results have been shown for other proteins in rats and rabbits, where intravitreal injection of retinal soluble antigen or human serum albumin resulted in an increase in anti-antigen antibodies in serum.63,64”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Partly supportedcites [63] De Kozak Y, Andrieux K, Villarroya H, Klein C, Thillaye-Goldenberg B, Naud M-C et al. Intraocular injection of tamoxifen-loaded nanoparticles: a new treatment of experimental autoimmune uveoretinitis. Eur J Immunol 2004; 34: 3702–3712. sourceExperimental — accuracy not yet measured
The Results (§2.6.4 Serum antibody isotypes; page unavailable) report increased serum anti-S-Ag IgG1 in rats after intravitreal injection of tamoxifen-loaded nanoparticles. But the Methods (§4.2 Induction of EAU) say S-Ag was administered into the hind footpads, not injected intravitreally. The paper does not report an intravitreal human-serum-albumin experiment in rabbits. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [64] Van der Voet J, Liem A, Otto A, Kijlstra A . Intraocular antibody synthesis during experimental uveitis. Invest Ophthalmol Vis Sci 1989; 30: 316–322.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“This observation is consistent with previous reports that subretinal injections of AAV vectors in dogs and non-human primates,37 as well as some intracranial injections in several clinical trials,38 led to increased serum anti-AAV antibody titers.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Supportedcites [37] Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z, Chen Y et al. Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med 2010; 2: 21ra16. source
The Results sections for dogs and nonhuman primates report increased serum anti-AAV2 antibody titers after subretinal vector injection (page numbers unavailable). The intracranial-injection clause is separately attributed to citation 38, not to this paper. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [38] Mingozzi F, High KA . Immune responses to AAV in clinical trials. Curr Gene Ther 2011; 11: 321–330. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Additionally, in a DP71-null mouse model of retinal degeneration and blood-retinal barrier permeability, gene delivery to Muller cells and photoreceptors via intravitreal injection increased.67”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Partly supportedcites [67] Vacca O, Darche M, Schaffer D V, Flannery JG, Sahel J-A, Rendon A et al. AAV-mediated gene delivery in Dp71-null mouse model with compromised barriers. Glia 2014; 62: 468–476. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports enhanced Müller-cell transduction after intravitreal ShH10 injection, and the photoreceptor Results section reports strong transduction after intravitreal AAV5 injection in Dp71-null mice compared with wild-type mice. The Introduction describes this mouse as a model of permeable blood-retinal barriers that emulates some hallmarks of diseases including age-related macular degeneration, but does not establish it as a model of retinal degeneration itself. (LLM, conf=0.83)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Previous work has shown that AAV-mediated gene therapy is significantly increased following intravitreal injection in the diseased rat retinal compared to the normal rat retinal.66”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Supportedcites [66] Kolstad KD, Dalkara D, Guerin K, Visel M, Hoffmann N, Schaffer DV et al. Changes in adeno-associated virus-mediated gene delivery in retinal degeneration. Hum Gene Ther 2010; 21: 571–578. source
The Abstract reports a significant increase in AAV-mediated gene transfer after intravitreal delivery in diseased versus normal rat retina, while noting that the extent depends on AAV serotype. The Results also report significantly higher vector genome levels in degenerating retinal tissue. Page numbers were not provided in the supplied passages. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Adeno-associated virus has been successful in clinical gene therapy trials for Leber's congenital amaurosis, hemophilia, familial lipoprotein lipase deficiency, and choroideremia.8–15,26,27,60,61”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Supportedcites [8] Hauswirth WW, Aleman TS, Kaushal S, Cideciyan A V, Schwartz SB, Wang L et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008; 19: 979–990. source
This paper supports the LCA portion of the multi-citation sentence: its Abstract describes an AAV2 gene-therapy trial in three adults with RPE65-related LCA and reports significant improvement in visual sensitivity in treated eyes over 30–90 days. It is not being cited here as evidence for the other listed conditions. (LLM, conf=0.90)
- Supportedcites [9] Cideciyan A V, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther 2009; 20: 999–1004. source
This paper supports the LCA portion of the multiply cited sentence. The Introduction describes successful visual improvement in AAV-based LCA trials, and the Results and Discussion report that improvements in this trial persisted at one year. The paper is not offered as evidence for the other listed conditions. (LLM, conf=0.92)
- Partly supportedcites [10] Bainbridge JWB, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2231–2239. sourceExperimental — accuracy not yet measured
The Summary (p. 1) describes an AAV gene-therapy trial in three young adults with RPE65-related Leber’s congenital amaurosis; one patient improved on measures of visual function, while none had a clinically significant change in visual acuity. The cited paper does not address clinical trials for hemophilia, familial lipoprotein lipase deficiency, or choroideremia, so it supports only the LCA part of the sentence. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [11] Maguire A, Simonelli F . Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2240–2248. source
- Supportedcites [12] Maguire AM, High K a, Auricchio A, Wright JF, Pierce E a, Testa F et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009; 374: 1597–1605. source
This paper supports the Leber’s congenital amaurosis portion of the multiply cited sentence. Its Discussion reports improved retinal function in all 12 patients treated with an AAV vector, with the effect stable during follow-up. It is not being cited here as evidence for the other listed conditions. (LLM, conf=0.93)
- Supportedcites [13] Bennett J, Ashtari M, Wellman J, Marshall K a, Cyckowski LL, Chung DC et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 2012; 4: 120ra15. source
This source supports the Leber congenital amaurosis portion of the multi-citation sentence. The Introduction reports improved retinal and visual function in patients treated with an AAV2 vector, and the Discussion reports improvement after readministration. The other conditions are not attributed specifically to this LCA study. (LLM, conf=0.92)
- Supportedcites [14] Jacobson SG, Cideciyan A V, Ratnakaram R, Heon E, Schwartz SB, Roman AJ et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 2012; 130: 9–24. source
This is an LCA trial paper cited within a group of references for several diseases. Its Introduction reports safety and modest efficacy in AAV2-RPE65 clinical trials, and its Results report improved low-light mobility with treated eyes. It supports the LCA portion of the sentence; the other diseases are not attributed specifically to this paper. (LLM, conf=0.89)
- Supportedcites [15] MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014; 6736: 2117–2120. source
This paper is the AAV choroideremia clinical trial cited as one example in a sentence with multiple references. Its Discussion reports substantial visual-acuity gains in two patients and improved retinal sensitivity after treatment. The citation supports the choroideremia portion of the sentence; it need not establish the outcomes of the other trials. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [26] Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342–347. source
- Partly supportedcites [27] Stroes ES, Nierman MC, Meulenberg JJ, Franssen R, Twisk J, Henny CP et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol 2008; 28: 2303–2304. sourceExperimental — accuracy not yet measured
The clinical-trial report describes an AAV1 gene-therapy trial in eight lipoprotein lipase–deficient patients and a significant reduction in triglycerides at 12 weeks. But its results passage says only four patients reached the primary efficacy endpoint and efficacy was lost at 18–31 months, so calling the trial simply “successful” overstates its findings. This source addresses the lipoprotein lipase deficiency part of the multi-citation sentence. (LLM, conf=0.84)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Naïve, pre-injection samples from Monkey 013 over a year consistently showed low (or undetectable) antibody titers (data not shown).”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Presence of Anti-AAV2 Antibodies During Long Term Monitoring
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“there was no effect on the level of transduction (measured as GFP positive cells) even in the most concentrated serum dilution (1:10) for a serum sample taken prior to intravitreal administration of 7m8 vector, indicating that this serum did not contain a detectable level of anti-AAV2 antibodies.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Increase of Anti-AAV2 Antibodies Pre-Infection vs. Post-Infection
Strength:hedged· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All injected animals showed consistent antibody titers for the initial months post-injection, though most seemed to experience a slight (2-5 fold) decrease in neutralizing antibody titer as early as 3 months post-injection.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Presence of Anti-AAV2 Antibodies During Long Term Monitoring
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“there was a 50% decrease in transduction with a 1:500 dilution of a serum sample taken from the same monkey after intravitreal administration of 7m8 vector, indicating the presence of anti-AAV2 antibodies. Furthermore, even at a 1:10 dilution transduction was fully inhibited”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Increase of Anti-AAV2 Antibodies Pre-Infection vs. Post-Infection
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“High pre-injection neutralizing titers trended towards a smaller magnitude of change between pre- and post-injection titers (Figure 5d, f, g), but this was not significant.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Cross-Reactivity of Antibodies to Various AAV Serotypes Pre-Infection vs. Post-Infection
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Monkey 109 received an approximately 10-fold higher dose of viral genomes, and developed an antibody response approximately 1-2 orders of magnitude higher towards all serotypes tested compared to Monkey 110.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Cross-Reactivity of Antibodies to Various AAV Serotypes Pre-Infection vs. Post-Infection
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, the initially administered serotype set the antibody response, and small sequence changes to this serotype did not affect or reduce neutralization.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Conversely, a 2-fold increase in anti-AAV5 antibody titer was observed following injection of AAV2, followed by a 100-fold increase in anti-AAV5 antibody titer after injection of AAV5 (Figure 6a).”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Progressive Increase of Anti-AAV Antibodies with Sequential Administrations
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“vectors delivered into the vitreous were more susceptible to neutralizing antibodies than those delivered subretinally in a murine model.36”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Not matchedcites [36] Li Q, Miller R, Han P-Y, Pang J, Dinculescu A, Chiodo V et al. Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Mol Vis 2008; 14: 1760–1769.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These variants, as anticipated, are not sufficiently different from wild-type AAV2 to disrupt the antibody binding sites on the capsid, so antibodies against a mutant will similarly react to the other mutants or the wild-type capsid”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Results > Increase of Anti-AAV2 Antibodies Pre-Infection vs. Post-Infection
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In contrast, intravitreal AAV administration, to the vitreous humor of the eye, offers the potential for pan-retinal delivery without the risk of retinal detachment.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Although NHP studies present inherent challenges for larger scale statistical analysis, the trends observed in this study may lend insights to help understand the interactions between AAV vectors and the immune system during ocular administration, and may therefore aid future clinical studies involving intravitreal gene delivery.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
Strength:plain· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
In the paper
“Recent analysis indicated that the prevalence of anti-AAV IgG antibodies in humans was highest for AAV2 (72%) and AAV1 (67%); however, AAV9 (47%), AAV6 (46%), AAV5 (40%), and AAV8 (38%) antibodies were also present in a large portion of the population studied.28”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Not checked — no full text of the sourcecites [28] Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther 2010; 21: 704–712. source
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Furthermore, the retinal detachment inherent in subretinal injections can lead to reactive gliosis, retinal disorganization, photoreceptor degeneration, and functional losses in vision,21,22”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Introduction
What the sources say
- Not checked — no full text of the sourcecites [21] Nakazawa T, Matsubara A, Noda K, Hisatomi T, She H, Skondra D et al. Characterization of cytokine responses to retinal detachment in rats. Mol Vis 2006; 12: 867–878.
- Not checked — no full text of the sourcecites [22] Nakazawa T, Takeda M, Lewis GP, Cho K-S, Jiao J, Wilhelmsson U et al. Attenuated glial reactions and photoreceptor degeneration after retinal detachment in mice deficient in glial fibrillary acidic protein and vimentin. Invest Ophthalmol Vis Sci 2007; 48: 2760–2768. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the insertion of the 7m8 peptide does not appear to have a significant effect on the neutralizing antibody titer, likely due to the polyclonal nature of antibodies in NHP and human serum.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Although a previous report demonstrated that RGD insertions at amino acid 588 on the AAV2 capsid could disrupt an antibody binding epitope,65”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Not checked — no full text of the sourcecites [65] Huttner NA, Girod A, Perabo L, Edbauer D, Kleinschmidt JA, Büning H et al. Genetic modifications of the adeno-associated virus type 2 capsid reduce the affinity and the neutralizing effects of human serum antibodies. Gene Ther 2003; 10: 2139–2147. source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, directed evolution has been applied to generate AAV variants capable of evading neutralizing antibodies in vitro and in vivo.68–72”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
What the sources say
- Not checked — no full text of the sourcecites [68] Maheshri N, Koerber JT, Kaspar BK, Schaffer DV . Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 2006; 24: 198–204. source
- Not checked — no full text of the sourcecites [69] Koerber JT, Jang J-H, Schaffer DV . DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol Ther 2008; 16: 1703–1709. source
- Not matchedcites [70] Bartel MA, Hwang B-Y, Stone D, Koerber JT, Couto L, Mingozzi F et al. Directed evolution of aav for enhanced evasion of human neutralizing antibodies. American Society of Gene and Cell Therapy’s 15th Annual Meeting 2012: Philadelphia, PA, USA S140.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [71] Perabo L, Endell J, King S, Lux K, Goldnau D, Hallek M et al. Combinatorial engineering of a gene therapy vector: directed evolution of adeno-associated virus. J Gene Med 2006; 8: 155–162. source
- Not checked — no full text of the sourcecites [72] Grimm D, Lee JS, Wang L, Desai T, Akache B, Storm TA et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 2008; 82: 5887–5911. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, if the tissue is already severely degenerated, unfortunately any potential efficacy of gene therapy will likely be substantially decreased.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Severely degenerated retinal tissue cannot support gene therapy efficacy.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, if AAV becomes opsonized by antibodies upon administration to the vitreous fluid, it likely that despite the possibility of increased transduction to degenerated retina, neutralization may well still occur in patients with retinal degeneration.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Opsonization of AAV by antibodies in the vitreous fluid leads to neutralization.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This procedure was conducted according to the ARVO Statement for the Use of Animals and the guidelines of the Office of Laboratory Animal Care at the University of Rochester.”
§ Antibody Neutralization Poses a Barrier to Intravitreal Adeno-Associated Viral Vector Gene Delivery to Non-Human Primates > Materials and Methods > Intravitreal Injections
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
The role of neutralizing antibodies in AAV transduction of immune-privileged tissues such as the eye is unclear in large animals.
“However, the role of neutralizing antibodies (NABs) in AAV transduction of tissues considered to be immune privileged, such as the eye, is unclear in large animals.”
The paper relies on this without support.
Findings from non-human primates are informative for understanding and aiding future human intravitreal gene delivery studies.
“Although NHP studies present inherent challenges for larger scale statistical analysis, the trends observed in this study may lend insights to help understand the interactions between AAV vectors and the immune system during ocular administration, and may therefore aid future clinical studies involving intravitreal gene delivery.”
The paper relies on this without support.
The eye is an immune-privileged site.
“pre-existing immunity can challenge transduction of AAV vectors in immune privileged regions, such as the eye and brain.35”
The paper relies on this without support.
Opsonization of AAV by antibodies in the vitreous fluid leads to neutralization.
“if AAV becomes opsonized by antibodies upon administration to the vitreous fluid, it likely that despite the possibility of increased transduction to degenerated retina, neutralization may well still occur in patients with retinal degeneration.”
The paper relies on this without support.
Severely degenerated retinal tissue cannot support gene therapy efficacy.
“if the tissue is already severely degenerated, unfortunately any potential efficacy of gene therapy will likely be substantially decreased.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response.13,21,75,76”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“An important consideration for injections is the pre-existing levels of BABs and NABs.26,27”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, compared to SR delivery, IVT injections may trigger a more robust immune response against the rAAV vector because of its closer proximity to the vascular system, the larger doses required to compensaet for dilution in the vitreous, and the lack of a blood retinal barrier that exists in the SR but not in the IVT space [6].”
From Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection (2024) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A significant titer of anti-AAV antibodies was found in primates and the presence of pre-existing antibodies has been correlated with decreased efficacy of gene augmentation therapy in pre-clinical trials where the route of administration exposes vector to serum [6].”
From Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection (2024) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In line with this, the presence of pre-existing NAb to AAV is strongly correlated with poorly sustained transgene expression following intravitreal gene therapy (Kotterman et al., 2015).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Kotterman et al., 2015
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“However, there is still cross-reactivity of anti-AAV Abs against different serotypes.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“The presence of antiviral Abs has been correlated with minimal or absent gene expression following gene therapy.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“Although this study has shown a positive co-relation (R = 0.3) between the NABs detected in the vitreous fluid and the NABs in the serum, it did not make a comparison of BABs.26”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“Our data, consistent with previous studies,26 reveal that anti-AAV antibodies persist in the serum even after 6 months to 1 year post-injection, which has to be taken into consideration if repeat injections are required.”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“Some studies have shown that there is cross-reactivity across serotypes wherein an injection with one serotype resulted in an increase in NABs against another serotype.26,28”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“When considering the treatment of bilateral nAMD with an AAV gene therapy approach, there is concern that adaptive immunity including NAbs may develop after the initial dose, thereby impacting the potential of administering gene therapy to the second eye.23,24,25”
From Nonclinical study of ixo-vec gene therapy for nAMD supports efficacy for a human dose of 6E10 vg/eye and staggered dosing of fellow eyes (2025) · cites this paper as [23]
In the citing paper
“the limited clinical data88,89 and NHP studies120 utilizing currently available capsids indicate that IVI AAVs contend with many barriers that may reduce gene expression and prevent therapeutic benefit in a majority of patients (i.e., dilution/neutralization in vitreous, inner-limiting membrane).”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [120]
In the citing paper
“In a separate study, AAV-mediated transgene expression was reported to be inversely correlated with the presence of NAbs in both serum and vitreous of macaque, with the latter showing a stronger correlation.120”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [120]
In the citing paper
“These higher doses may trigger a stronger immune response and increase titres of neutralising antibodies [257,258,259], which can spread through the blood and lymphatic tissues [260] and potentially lead to reduced transduction efficacy and a lack of transgene expression with repeated administration [261,262].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [262]
Citations
Cites
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Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802315 · Cited by 2,145
Effect of gene therapy on visual function in Leber’s congenital amaurosis
Bainbridge, J. W. B., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802268 · Cited by 1,924
Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B
Nathwani, A. C., Tuddenham, E. G. D., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D. C., Chowdary, P., Riddell, A., Pie, A. J., Harrington, C., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1108046 · Cited by 1,864
Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy
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Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
Gao, G., Vandenberghe, L. H., Alvira, M. R., Lu, Y., Calcedo, R., Zhou, X., & Wilson, J. M. (2004) · Journal of Virology · doi:10.1128/jvi.78.12.6381-6388.2004 · Cited by 1,070
Boutin, S., Monteilhet, V., Veron, P., Leborgne, C., Benveniste, O., Montus, M. F., & Masurier, C. (2010) · Human Gene Therapy · doi:10.1089/hum.2009.182 · Cited by 970
Adeno-associated Virus Serotypes: Vector Toolkit for Human Gene Therapy
Wu, Z., Asokan, A., & Samulski, R. J. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.05.009 · Cited by 957
Hauswirth, W. W., Aleman, T. S., Kaushal, S., Cideciyan, A. V., Schwartz, S. B., Wang, L., Conlon, T. J., Boye, S. L., Flotte, T. R., Byrne, B. J., et al. (2008) · Human Gene Therapy · doi:10.1089/hum.2008.107 · Cited by 954
Maguire, A. M., High, K. A., Auricchio, A., Wright, J. F., Pierce, E. A., Testa, F., Mingozzi, F., Bennicelli, J. L., Ying, G.-S., Rossi, S., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61836-5 · Cited by 865
Flagged first, then by citations
1 of the 78 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Knipe DM, Howley PM . Fields’ Virology. Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2007.
Cited by
Sorted by citations
Items 101–167 of 167
A Fixed-Depth Microneedle Enhances Reproducibility and Safety for Corneal Gene Therapy
Gilger, B. C., Crabtree, E. E., Song, L., Llanga, T., Cullen, M. A., Blanchard, A., Salmon, J. H., Patel, S. R., Zarnitsyn, V. G., & Hirsch, M. L. (2019) · Cornea · doi:10.1097/ico.0000000000002182 · Cited by 14
Wassmer, S., Repentigny, Y. D., Sheppard, D., Lagali, P. S., Fang, L., Coupland, S. G., Kothary, R., Guy, J. R., Hauswirth, W. W., & Tsilfidis, C. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.8.49 · Cited by 12
“45 To partly mitigate this effect, we increased the viral dose for the second intravitreal injection from 1 × 10 8 to 2 × 10 9 total viral particles.”
Haar, J., Blazevic, D., Strobel, B., Kreuz, S., & Michelfelder, S. (2022) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2022.04.008 · Cited by 11
“Thus, pre-screeningofNHPcohorts for their antibody status is required in gene-therapy studies before vector administration.(24,25)”
BackgroundChallenges in AAV-Based Retinal Gene Therapies and the Role of Magnetic Nanoparticle Platforms
Siontas, O., & Ahn, S. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13237385 · Cited by 13
“The proven risks are the disruption of viral vector integrity by neutralizing antibodies (NABs) in the vitreous space through humoral immune responses and volume losses due to dilution of vectors into the vitreous fluid after injection [72,110–112].”
Clerck, K. D., Smedt, S. C. D., Remaut, K., & Peynshaert, K. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113849 · Cited by 11
Current and Future Treatments for Lysosomal Storage Disorders
Rastall, D. P. W., & Amalfitano, A. (2017) · Current Treatment Options in Neurology · doi:10.1007/s11940-017-0481-2 · Cited by 13
Yang, C., Hao, F., He, J., Lu, T., Klein, R. L., Zhao, L., & Duan, W. (2016) · Human Gene Therapy · doi:10.1089/hum.2015.083 · Cited by 12
Day, T. P., Byrne, L. C., Flannery, J. G., & Schaffer, D. V. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7522-8_17 · Cited by 12
Self-citationDeveloping New Vectors for Retinal Gene TherapyPreprint
Zin, E. A., Öztürk, B. E., Dalkara, D., & Byrne, L. C. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041291 · Cited by 13
AAV2-antiVEGFscFv gene therapy for retinal neovascularization
Han, N., Xu, X., Liu, Y., & Luo, G. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.101145 · Cited by 10
Gene therapy for the long term treatment of wet AMD
Rakoczy, E. P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31262-x · Cited by 10
Gyenes, A., István, L., Benyó, F., Papp, A., Resch, M., Sándor, N., Józsi, M., Nagy, Z. Z., Kovács, I., & Kiss, S. (2023) · BMC Ophthalmology · doi:10.1186/s12886-022-02761-9 · Cited by 9
Song, H., Zeng, Y., Sardar Pasha, S. P. B., Bush, R. A., Vijayasarathy, C., Qian, H., Wei, L., Wiley, H. E., Wu, Z., & Sieving, P. A. (2020) · Translational Vision Science & Technology · doi:10.1167/tvst.9.7.28 · Cited by 9
Schwartz, M. K., Likhite, S. B., Vetter, T. A., Baird, M., McGovern, V. L., Sierra-Delgado, J. A., Mendel, T., Burghes, A. H. M., & Meyer, K. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.05.016 · Cited by 10
“30 Septem treal injection.(62,63) While the eye is considered an immune privileged site, it is not absolute.”
BackgroundPoulsen, K., Hanna, K., Nieves, J., Nguyen, N., Sharma, P., Grishanin, R., Corbau, R., & Kiss, S. (2025) · Molecular Therapy Methods & Clinical Development · doi:10.1016/j.omtm.2025.101430 · Cited by 8
A non‐surgical method for subretinal delivery by trans‐scleral microneedle injection
Hejri, A., Chrenek, M. A., Goehring, N. T., Bowland, I. I., Noel, R. K., Yan, J., Nickerson, J. M., & Prausnitz, M. R. (2025) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10755 · Cited by 8
“11 Given these challenges, an ideal method of subretinal delivery should be (1) simple to perform without surgical training (e.g., as an office procedure), (2) targeted without vitreous reflux to enable accurate dosing and minimize systemic exposure, (3) minimally invasive (i.e., avoiding the need…”
Permanent transduction of retinal ganglion cells by rAAV2-retro
Zheng, Y. J., Dilbeck, M. D., Economides, J. R., & Horton, J. C. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.109793 · Cited by 6
“Para-retinal” Vector Administration into the Deep Vitreous Enhances Retinal Transgene Expression
Zeng, Y., Boyd, R. F., Bartoe, J. T., Wiley, H. E., Marangoni, D., Wei, L. L., & Sieving, P. A. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.06.015 · Cited by 7
“The high NAB serum titers are predictive of higher NAB levels in vitreous and correlate with diminished AAV vector expression in NHP eyes following intravitreal injection.(21) Longer transit time of vector through the vitreous to reach the retina following intravitreal administration increases exposure time to vitreou…”
BackgroundFundus imaging of retinal ganglion cells transduced by retrograde transport of rAAV2-retro
Nanjappa, R., Dilbeck, M. D., Economides, J. R., & Horton, J. C. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2022.109084 · Cited by 6
Peynshaert, K., Devoldere, J., Smedt, S. C. D., & Remaut, K. (2023) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2023.2167979 · Cited by 7
“from childhood exposure to one or more serotypes or from previous AAV administration [30,31].”
BackgroundKim, Y., Kim, E., Oh, S., Yoon, Y.-E., & Jang, J. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.034 · Cited by 7
Gene Therapy for Hemophilia and Duchenne Muscular Dystrophy in China
Liu, X., Liu, M., Wu, L., & Liang, D. (2018) · Human Gene Therapy · doi:10.1089/hum.2017.213 · Cited by 7
“7 Therefore, either AAV transduction must be enhanced or NAb activity must be avoided.”
Lentiviral delivered aflibercept OXB-203 for treatment of neovascular AMD
Iqball, S., Beck, D. K., Devarajan, G., Khoo, C. P., O’Connor, D. M., Ellis, S., Guzman, E., Mitrophanous, K. A., & Lad, Y. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.07.001 · Cited by 6
“Additionally, intravitreally administered viral vectors are diluted immediately upon mixing with the vitreous and, situated outside of the immune-privileged retinal compartment, are at increased risk of neutralization.(57,58) On the other hand, delivery of viral vectors directly to the subretinal space, a closed anato…”
BackgroundZhang, H., Sajdak, B. S., Merriman, D. K., Carroll, J., & Lipinski, D. M. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.06.005 · Cited by 6
Gene therapy for age-related macular degeneration
MacLaren, R. E. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00346-3 · Cited by 6
Benefits of gene therapy for both eyes
MacLaren, R. E. (2016) · The Lancet · doi:10.1016/s0140-6736(16)30783-8 · Cited by 6
Gene therapy shines light on congenital stationary night blindness for future cures
Zhang, Y., Lin, S., Yu, L., Lin, X. Y., Qu, S., Ye, Q., Yu, M., Chen, W., & Wu, W. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06392-8 · Cited by 4
“However, in practice, the diffusion of the drug from the vitreous can be affected by various factors, such as the dilution of the vitreous fluid [139], interference from immune response mechanisms [140, 141], barriers posed by the internal limiting membrane [142], and diffusion distance [143].”
Ocular Delivery of Viral Vectors for Retinal and Choroidal Vascular Diseases: A Review
Agrawal, R., Oraskovich, S. V., Francis, P. J., & Schaffer, D. V. (2025) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2025.07.025 · Cited by 6
Self-citationHassan, S., Hsu, Y., Thompson, J. M., Kalmanek, E., VandeLune, J. A., Stanley, S., & Drack, A. V. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1304819 · Cited by 4
Kureshi, R., Zhu, A. Y., Shen, J., Tzeng, S. Y., Astrab, L. R., Sargunas, P. R., Green, J. J., Campochiaro, P. A., & Spangler, J. B. (2020) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-020-00641-0 · Cited by 5
Adeno-associated virus neutralising antibodies in type 1 diabetes mellitus
Andrzejewski, S., Murali, A., Ramlogan‐Steel, C. A., Edwards, K. P., Efron, N., Steel, J. C., & Layton, C. J. (2019) · Gene Therapy · doi:10.1038/s41434-019-0076-5 · Cited by 4
How Advanced are Nanocarriers for Effective Subretinal Injection?
Guan, J.-X., Wang, Y.-L., & Wang, J. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s479327 · Cited by 4
“64 In summary, nanocarriers are invaluable and surpass viral carriers in the widely used route of drug delivery, particularly in subretinal injections.”
BackgroundDelivery of Genetic Information: Viral Vector and Nonviral Vector Gene Therapies
Gemayel, M. C., Byrne, L. C., Ciulla, T. A., & Sahel, J. (2021) · International Ophthalmology Clinics · doi:10.1097/iio.0000000000000360 · Cited by 5
Gene and Cell Therapy for Inherited Retinal Dystrophies
Garita‐Hernandez, M., Goureau, O., & Dalkara, D. (2016) · Wiley eBooks · doi:10.1002/9780470015902.a0026565 · Cited by 4
Gene Therapy for Rhodopsin MutationsPreprint
Lewin, A. S., & Smith, W. C. (2022) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041283 · Cited by 6
Ross, M., Sade, K., Obolensky, A., Averbukh, E., Desrosiers, M., Rosov, A., Dvir, H., Gootwine, E., Banin, E., Dalkara, D., et al. (2024) · Gene Therapy · doi:10.1038/s41434-024-00495-5 · Cited by 3
AAV-based gene therapies for neovascular AMD
Kim, T. H., Kwon, C. Y., Song, J. Y., & Yoo, H. C. (2026) · Gene Therapy · doi:10.1038/s41434-026-00595-4 · Cited by 6
“However, long-term expression raises concerns about overexpression toxicity [117], and re-administration remains challenging due to neutralizing antibodies (NAbs) [118].”
Tropism of the Novel AAVBR1 Capsid Following Subretinal Delivery
Carroll, L. S., Uehara, H., Zhang, X., & Ambati, B. K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147738 · Cited by 4
CoreTIA: a modular, statistically robust transduction inhibition assay for AAV neutralization
Kovács, B., Somogyi, F., Szabó, V., Nagy, Z. Z., Hernádi, I., Mátyás, F., Vanduffel, W., Szemlaky, Z., Rózsa, B. J., Ulbert, I., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1623848 · Cited by 3
“Additionally, patients previously treated with AAV-based gene therapy can develop robust anti-AAV immunity, leading to rapid vector clearance upon re-administration (11, 12).”
Gene Therapy for Retinal Diseases
Gopinath, C., Sarkar, S., & Ghosh, A. (2021) · Essentials in ophthalmology/Essentials ophthalmology · doi:10.1007/978-981-15-9184-6_30 · Cited by 3
Intravitreal AAV2 gene delivery to feline retinal ganglion cells
Oikawa, K., Eaton, J. S., Kiland, J. A., Torné, O., Mathu, V., Nickells, R. W., & McLellan, G. J. (2024) · Vision Research · doi:10.1016/j.visres.2024.108519 · Cited by 3
“…interventions to induce ocular hypertension and/or model glaucomatous RGC damage may cause inflammatory responses and therefore dampen transduction efficiency by viral vectors delivered to retinal cells, as previous studies suggested (Ail et al., 2022; Kotterman et al., 2015; Muhuri et al., 2021).”
InfluentialDNA- and RNA-based Gene Therapies in Ophthalmology
Ciulla, T. A., Pennesi, M. E., Kiss, S., & Cunningham, E. T. (2021) · International Ophthalmology Clinics · doi:10.1097/iio.0000000000000359 · Cited by 4
Challenges to Gene Editing Approaches in the Retina
Bonillo, M., Pfromm, J. K., & Fischer, M. D. (2022) · Klinische Monatsblätter für Augenheilkunde · doi:10.1055/a-1757-9810 · Cited by 4
“In regards to retinal gene editing, AAVs have become the vector of choice, as higher levels of immunogenicity in response to AV were observed than in response to AAVs [92].”
BackgroundInfluentialOptogenetik – eine Chance für fortgeschrittene retinale Dystrophien
Swiersy, A., Klapper, S. D., & Busskamp, V. (2017) · Klinische Monatsblätter für Augenheilkunde · doi:10.1055/s-0043-101820 · Cited by 3
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“While AAVs are known to elicit neutralizing antibodies, especially in patients with prior viral exposure, non-viral nano-delivery systems are increasingly favored for their lower immunogenic profiles and greater biocompatibility, particularly in the context of brain-targeted therapies [93].”
Clinical and Ocular Inflammatory Inhibitors of Viral-Based Gene Therapy of the Retina
Ohlhausen, M. E., & Conrady, C. D. (2024) · Acta Microbiologica Hellenica · doi:10.3390/amh69030018 · Cited by 2
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Virus Vectors for Optogenetic Prosthetization of the Retina
Rotov, A. Y., Nikolaeva, D. A., Astakhova, L. A., & Firsov, M. L. (2020) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-020-00911-4 · Cited by 2
Overcoming matrix effects in AAV neutralization assays with a constant serum concentration approach
Kovács, B., Szabó, V., Horváth, D., Dobos, A. B., Nagy, Z. Z., Vanduffel, W., Szemlaky, Z., Szepesi, Á., Ulbert, I., Rózsa, B. J., et al. (2025) · Gene Therapy · doi:10.1038/s41434-025-00567-0 · Cited by 2
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Ren, D., Chauveau, G. A., Cabon, E., Vendomèle, J., Vignal‐Clermont, C., Saliba, H., Ail, D., Dalkara, D., & Fisson, S. (2026) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2026.101443 · Cited by 1
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“38 While most conditions are manageable, the necessity for close patient monitoring diminishes the convenience advantage offered by gene therapy.”
AAV9-mediated engineering of autotransplanted kidney of non-human primates
Tomasoni, S., Trionfini, P., Azzollini, N., Zentilin, L., Giacca, M., Aiello, S., Longaretti, L., Cozzi, E., Baldan, N., Remuzzi, G., et al. (2017) · Gene Therapy · doi:10.1038/gt.2017.21 · Cited by 2
Administration of Ocular Gene Therapy
Xu, D. N., Khan, M., Klufas, M. A., & Ho, A. C. (2021) · International Ophthalmology Clinics · doi:10.1097/iio.0000000000000365 · Cited by 1
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Suprachoroidal Delivery of Subretinal Gene and Cell Therapy
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Goats with low levels of AAV antibody may serve as candidates for large animal gene therapy
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Bypassing pre-existing antibodies extends the applicability of AAV-based retinal therapies
Hu, H. F., & Tsang, S. H. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.11.005
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AAV2 serotype demonstrates the highest transduction efficiency in porcine lung-derived cells
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Development of safe and efficient aav vectors for retinal gene therapy
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“Preexisting anti-AAV immunity can reduce efficacy and exacerbate adverse effects of AAV-based therapies and thereby affect the overall validity of nonclinical evaluations (4–6).”
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Metadata
- Authors
- Kotterman, M. A., Yin, L., Strazzeri, J. M., Flannery, J. G., Merigan, W. H., & Schaffer, D. V.
- Affiliations
- University of California, Berkeley (US)
- University of Rochester Medicine (US)
- Corresponding author
- Schaffer, D V
- Venue
- Gene Therapy
- Published
- 2014-12-11
- Volume
- 22
- Issue
- 2
- Pages
- 116-126
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC4393652
- OpenAlex
- W1997582178
- Cited by
- 169
- References
- 78
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 13 · 2023: 14 · 2022: 14 · 2021: 27 · 2020: 22 · 2019: 11 · 2018: 11 · 2017: 19 · 2016: 9 · 2015: 7
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Eye Institute (R01EY021166, R01EY022975)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- adeno-associated virus vectors, neutralizing antibodies, intravitreal gene delivery, AAV2, cross-reactive antibodies, retinal gene therapy, non-human primates, transgene expression, ocular immune privilege, Leber congenital amaurosis, choroideremia
- MeSH terms
- Dependovirus, Animals, Antibodies, Viral, Genetic Vectors, Humans, Macaca mulatta, Retinal Degeneration, Transduction, Genetic, Genetic Therapy, Antibodies, Neutralizing, HEK293 Cells, Intravitreal Injections
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