Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene
Open accessAbstract
Importance: Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated. Objective: To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4). Design, Setting, and Participants: This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 1010 viral genomes per eye. Interventions: Patients received increasing doses of rAAV2/2-ND4 (9 × 109, 3 × 1010, 9 × 1010, and 1.8 × 1011 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing. Main Outcomes and Measures: A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers). Results: The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers. Conclusions and Relevance: In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.
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Claims the paper makes
7 of 25 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Premisecitation
LHON treatment has been limited to supportive care rather than cure.
“Therapy for LHON has been restricted to supportive measures rather than cure.10”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] 10. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011; 134(Pt 9):2677-2686. doi:10.1093/brain/awr170 source
The Discussion (page unavailable) says that advances had not yet produced treatments of proven efficacy for mitochondrial DNA-associated diseases and that earlier LHON studies were limited. This supports the absence of an established cure, but the paper does not say LHON therapy was restricted to supportive measures; it reports that idebenone appeared to improve visual outcomes. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Interpretationcitation
The results are consistent with prior work in cynomolgus macaques showing that neutralizing antibody detection in the anterior chamber and serum did not correlate with greater exposure to intravitreal AAV vectors.
“Our results are consistent with previous work 38 in cynomolgus macaques showing that detection of NAbs in the anterior chamber and serum did not correlate with increased exposure to intravitreal AAV vectors;”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] 38. Vandamme C, Adjali O, Mingozzi F. Unraveling the complex story of immune responses to AAV vectors trial after trial. Hum Gene Ther. 2017;28(11): 1061-1074. doi:10.1089/hum.2017.150 source
The ‘Impact of neutralizing anti-AAV antibodies’ section discusses subretinal AAV administration, but not intravitreal exposure or antibody detection in the anterior chamber and serum. Searches for ‘cynomolgus macaques anterior chamber,’ ‘anterior chamber,’ and ‘intravitreal’ found no passage reporting the claimed lack of correlation. Page numbers were not available in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Interpretationcitation
The occurrence of intraocular inflammation matched that seen in a preclinical study of rAAV2/2-ND4.
“Occurrence of intraocular inflammation was consistent with a preclinical study 30 using rAAV2/2-ND4.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [30] 30. Matet A, Kostic C, Bemelmans AP, et al. Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates. Transl Res. 2017;188:40-57.e4. doi:10.1016/j.trsl.2017.06.012 source
The Discussion (page unavailable) reports intraocular inflammation in this preclinical study, including a marked but transient reaction in one animal. However, the study used LV-RPE65, and the passages found for rAAV2/2-ND4 do not establish that its inflammation matched findings from a preclinical rAAV2/2-ND4 study. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Findingown data
Thirteen of 15 patients developed intraocular inflammation after receiving rAAV2/2-ND4.
“Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration.”
- Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
“Thirteen of 15 patients experienced intraocular inflammation after rAAV2/2-ND4 administration.”
Quote in the paperSubstantial claim - Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
- Findingown data
No association was found between ocular inflammation intensity and administered dose.
“No association was found between intensity of ocular inflammation and dose administered.”
Quote in the paperNot a substantial claim
- Findingown data
No association was found between OISs and serum neutralizing antibody titers.
“No association was found between OISs and serum NAb titers.”
Quote in the paperNot a substantial claim - Findingown data
Humoral or cellular immune responses were not associated with adverse events of intraocular inflammation.
“Humoral or cellular immune responses were not associated with adverse events of intraocular inflammation.”
Quote in the paperSubstantial claim - Findingown data
Another patient in the 9 × 10 10 vg group received oral prednisone for concomitant severe anterior and intermediate uveitis.
“Another patient in the 9 × 10 10 vg dose group was treated with oral prednisone for concomitant severe anterior and intermediate uveitis.”
Quote in the paperNot a substantial claim - Findingnone given
No association was observed between ocular inflammation and humoral or cellular immune response.
“No association was observed between ocular inflammation and humoral or cellular immune response.”
Quote in the paperSubstantial claim - Findingown data
All IgG levels decreased over time.
“All IgG levels decreased over time.”
Quote in the paperNot a substantial claim - Findingown data
Null ocular inflammation scores (N=138) were associated with neutralizing antibody titers from 0 to 1:6620, with a median of 1:224.
“Null OISs (N = 138) were associated with a range of NAb titers from 0 to 1:6620 (median titer, 1:224).”
Quote in the paperNot a substantial claim - Findingown data
The OIS was not consistently associated with the investigator's CTCAE intensity assessment of ocular inflammation.
“Although all patients with ocular inflammation had an OIS greater than 0, the score was not consistently associated with the intensity of ocular inflammation assessed by the investigator (C.V.C.) using the CTCAE scale (eTable 1 in the Supple- ment).”
Quote in the paperNot a substantial claim - Findingown data
After injection, cellular response increased up to 12 times baseline in a patient with no reported ocular inflammation.
“After in- jection, the cellular response increased up to 12 times the base- line level in a patient for whom no ocular inflammation was reported.”
Quote in the paperNot a substantial claim - Findingown data
Overall, OIS was not associated with the administered viral dose.
“Overall, OIS was not associated with the viral dose administered.”
- Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
“The magnitude of the OIS response did not correlate with the dosage administered.”
Quote in the paperSubstantial claim - Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
- Findingown data
In all 15 patients, no association was apparent between baseline neutralizing antibody levels, the size of the immune response, and the ocular inflammation score.
“No association was evident among NAb levels at baseline, the magnitude of the immune response, and the OIS in all 15 patients (Table 2).”
Quote in the paperSubstantial claim - Findingown data
There were 14 anterior chamber inflammation events in 10 patients at all dose levels except 9 × 10 9 vg, beginning 7 to 93 days after injection.
“A total of 14 events of anterior chamber inflammation occurred in 10 patients at all dose levels except 9 × 10 9 vg starting from 7 to 93 days after injection.”
Quote in the paperSubstantial claim - Findingown data
One patient in the 9 × 10 10 vg group who developed severe uveitis after rAAV2/2-ND4 had a high anti-AAV2 IgG titer at baseline.
“Of note, 1 patient in the 9 × 10 10 vg dose group who experienced severe uveitis after rAAV2/2-ND4 administration presented with a high anti-AAV2 IgG titer at baseline.”
Quote in the paperNot a substantial claim - Findingown data
There were 13 vitreous inflammation events in 11 patients.
“A total of 13 events of vitreous inflammation occurred in 11 patients (Table 1).”
Quote in the paperNot a substantial claim - Findingown data
All OISs returned to baseline by week 78 at the latest (week 96 for a patient in the 1.8 × 10 11 vg group).
“All OISs returned to baseline levels at the latest by week 78 (week 96 for a patient in the 1.8 × 10 11 vg dose group).”
Quote in the paperSubstantial claim - Findingown data
All treated events resolved without sequelae.
“All treated events resolved without sequelae.”
Quote in the paperSubstantial claim - Findingown data
That patient's condition resolved without sequelae after topical and oral corticosteroids.
“The patient's condition resolved without sequelae after treatment with topical and oral corticosteroids (Table 1 and eTable 3 in the Supplement).”
Quote in the paperNot a substantial claim - Findingown data
One patient in the 1.8 × 10 11 vg group received oral prednisone for mild vitritis and small punctate serous detachment, which resolved.
“One patient in the 1.8 × 10 11 vg dose group was treated with oral prednisone for mild vitritis and small punctate serous detachment, which also resolved.”
Quote in the paperNot a substantial claim - Findingown data
Among those responders, neutralizing antibody levels usually fell back to baseline by week 36.
“In these patients, NAb titers typically returned to baseline levels at week 36.”
Quote in the paperNot a substantial claim - Findingown data
One patient in each of the 3 × 10^10 vg, 1.8 × 10^11 vg, and 9 × 10^10 vg dose groups lacked a positive immune response yet had mild ocular inflammation with an ocular inflammation score of 1.5.
“Conversely, 1 patient each in the 3 × 10 10 vg, 1.8 × 10 11 vg, and 9 × 10 10 vg dose groups had no positive immune response but presented with mild ocular inflammation and an OIS of 1.5.”
Quote in the paperNot a substantial claim - Findingown data
No neutralizing antibodies against AAV2 were detected in aqueous humor before treatment.
“No NAbs against AAV2 were detected in aqueous humor before treatment.”
Quote in the paperNot a substantial claim - Findingown data
At baseline, OIS was null in all patients.
“At baseline, the OIS was null in all patients.”
Quote in the paperNot a substantial claim - Findingown data
Four events resolved without treatment.
“Four events resolved without treatment (limited, nonevolving presence of cells in the vitreous)”
Quote in the paperNot a substantial claim - Findingown data
In another patient, cellular immune response increased up to 6 times baseline.
“In another patient, the cellular immune response in- creased up to 6 times the baseline level.”
Quote in the paperNot a substantial claim - Findingown data
Across all doses, mean OIS peaked at 1.1 four weeks after administration.
“All doses considered, the mean OIS peaked at 1.1 four weeks after administration.”
Quote in the paperNot a substantial claim - Findingown data
Twenty-two ocular inflammation adverse events were treated with topical corticosteroids: rimexolone 9 times, dexamethasone 4 times, dexamethasone twice, and fluorometholone once.
“A total of 22 AEs of ocular inflammation were treated with topical corticosteroids: rimexolone (used 9 times), dexamethasone (used 4 times), dexamethasone (used twice), and fluorometholone (used once) (in some cases, concomitant anterior and intermediate inflammation were treated with the same agent).”
Quote in the paperNot a substantial claim - Findingown data
Two of 15 patients tested positive for a cellular immune response against AAV2 capsid at baseline (one in the 9 × 10 9 vg group and one in the 9 × 10 10 vg group).
“Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment.”
- Also stated in: § Immunogenicity of rAAV2/2-ND4 in Patients With LHON · plain
“Two of 15 patients tested positive for cellular response against AAV2 capsid at baseline (one in the 9 × 10 9 vg dose group and the other in the 9 × 10 10 vg dose group) (eFigure 1 in the Supplement).”
Quote in the paperNot a substantial claim - Also stated in: § Immunogenicity of rAAV2/2-ND4 in Patients With LHON · plain
- Findingown data
A maximum OIS of 9.5 occurred in a patient with a history of idiopathic uveitis.
“A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis.”
Quote in the paperNot a substantial claim - Findingown data
No association between cellular response and administered viral dose was evident.
“No association between cellular response and the viral dose administered was evident.”
Quote in the paperNot a substantial claim - Findingown data
One patient in the 9 × 10^10 vg dose group had no detectable neutralizing antibodies after week 48.
“In a patient in the 9 × 10 10 vg dose group, NAbs were undetectable past week 48.”
Quote in the paperNot a substantial claim - Findingown data
A patient in the 9 × 10^9 vg dose group who had positive IgG, neutralizing antibody, and cellular responses after injection did not experience ocular inflammation (score 0).
“In comparison, a patient in the 9 × 10 9 vg dose group who had positive IgG, NAb, and cellular responses after injection did not experience any ocular inflammation (OIS, 0), although this finding could be explained by the lowest dose of vector being injected (9 × 10 9 vg per eye).”
Quote in the paperNot a substantial claim - Findingown data
Null neutralizing antibody titers (N=26) were associated with ocular inflammation scores from 0 to 1.5, with a median score of 0.
“Likewise, null NAb titers (N = 26) were associated with OISs that ranged from 0 to 1.5 (median OIS, 0).”
Quote in the paperNot a substantial claim - Findingown data
Mild anterior chamber inflammation and vitritis occurred at every dose level.
“Mild anterior chamber inflammation and vitritis were reported at all doses”
Quote in the paperNot a substantial claim - Findingown data
Concomitant anterior and intermediate uveitis occurred in 7 patients.
“Concomitant anterior and intermediate uveitis were reported in 7 patients.”
Quote in the paperNot a substantial claim - Findingown data
No sequelae were reported in any patients as a consequence of these adverse events.
“No sequelae were reported in any patients as a consequence of these AEs.”
Quote in the paperNot a substantial claim - Findingown data
A Wilcoxon signed-rank test on individual linear regression slopes found no association between neutralizing antibody titers and ocular inflammation score.
“on individual linear regression slopes and found no association between NAbs titers and OIS.”
Quote in the paperSubstantial claim - Findingown data
Six patients developed a positive neutralizing antibody response, which began two weeks after rAAV2/2-ND4 was given.
“A positive NAb response was found in 6 patients, starting 2 weeks after rAAV2/2-ND4 administration (Figure 2).”
Quote in the paperSubstantial claim - Findingown data
A plot analysis of paired ocular inflammation scores and neutralizing antibody titers at all time points in all patients did not fit any regression model.
“A plot analysis of paired OIS and NAb titers at all time points in all patients did not fit any regression analysis models (Figure 3).”
Quote in the paperSubstantial claim - Findingown data
No neutralizing antibodies were detected in the aqueous humor of patients at baseline, regardless of serum antibody levels.
“As expected, no NAbs were detected in the aqueous humor of the patients at baseline regardless of antibody levels in the serum.”
Quote in the paperNot a substantial claim - Premisecitation
Most people acquire immunity to AAV capsid early in life, mainly humoral, through natural exposure to wild-type AAV.
“Most humans develop immunity against the capsid of AAV early in life (mainly a humoral response) as a consequence of natural exposure to wild-type AAV.17,[23][24][25]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 17,[23][24][25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
These findings suggest that intravitreal rAAV2/2-ND4 in LHON patients is not associated with intraocular inflammatory safety concerns that would preclude further investigations.
“These findings suggest that intravitreal administration of recombinant adeno-associated virus 2 carrying the ND4 gene in patients with Leber hereditary optic neuropathy is not associated with intraocular inflammatory safety concerns that would preclude further investigations.”
Quote in the paperSubstantial claim - Interpretationown data
Investigator assessment considered anterior chamber inflammation probably related to rAAV2/2-ND4 treatment, except in 2 cases involving the untreated eye of a patient with idiopathic uveitis history.
“Anterior chamber inflammation was considered by the investigator (C.V.C.) to be probably associated with treatment with rAAV2/2-ND4 except in 2 cases that involved the untreated eye of a patient with a history of idiopathic uveitis.”
Quote in the paperNot a substantial claim - Premisecitation
LHON is a suitable disease model for genetic intervention because its causative mutation mainly affects retinal ganglion cells.
“Leber hereditary optic neuropathy is an ideal disease model for genetic intervention because the causative point mutation essentially affects the retinal ganglion cells.14”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] 14. Vandenberghe LH, Auricchio A. Novel adeno-associated viral vectors for retinal gene therapy. Gene Ther. 2012;19(2):162-168. doi:10. 1038/gt.2011.151 source
- Premisecitation
Most clinical trials of ocular gene therapy that used peri-injection immunosuppressive agents reported no intraocular inflammation.
“Of note, most clinical trials in ocular gene therapy using peri-injection of immunosuppressive agents reported no intraocular inflammation.18,[34][35][36][37]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 18,[34][35][36][37]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Inflammatory reactions have been reported previously in ocular gene therapy studies regardless of viral vector, serotype, administration route, and prophylactic immunosuppressive therapy.
“Such inflammatory reactions were previously reported in studies 19,21,22,[31][32][33][34] of ocular gene therapy irrespective of the viral vector (adenovirus and lentiviral vectors), serotype (AAV2 and AAV8), route of administration (intravitreal and subretinal), and administration of prophylactic immunosuppressive therapy.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites 19,21,22,[31][32][33][34]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationcitation
This finding suggests that immune responses are not specific to the gene therapy product but are patient driven.
“this finding suggests that immune responses are not specific to the gene therapy product but rather are patient driven.”
Quote in the paperSubstantial claim - Premisecitation
GenSight completed a phase 1/2 safety and dose-escalation study of intravitreal rAAV2/2-ND4 in LHON patients with the G11778A mutation.
“GenSight completed a phase 1/2 safety and dose-escalation study that investigated the intravitreal administration of rAAV2/2-ND4 (GS010) in patients with LHON carrying the G11778A mutation.27”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] 27. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10. 1001/jama.2013.281053
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Ocular gene therapy with rAAV2/2-ND4 appeared overall safe and well tolerated in these 15 patients.
“Ocular gene therapy with rAAV2/2-ND4 in these 15 patients appeared to be overall safe and well tolerated with mostly mild, self-limited intraocular inflammation responsive to treatment that might be prevented using prophylactic immunosuppressive therapy in future trials.”
Quote in the paperSubstantial claim- Rests on an assumption: The follow-up period was long enough to detect long-term sequelae of the ocular inflammation.
- May combine two claims. 29
- Classified as probably not a substantial claim. 15
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationThe eye is regarded as immune privileged and therefore a good organ for gene therapy.
“The eye is considered to be immune privileged and thus constitutes an optimal organ for gene therapy.12,13”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [12] 12. Stein-Streilein J. Immune regulation and the eye. Trends Immunol. 2008;29(11):548-554. doi:10. 1016/j.it.2008.08.002
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13] 13. Lam BL, Feuer WJ, Schiffman JC, et al. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol. 2014;132 (4):428-436. doi:10.1001/jamaophthalmol.2013.7971 source
The Discussion describes a planned ocular gene therapy trial for G11778A LHON, but does not say the eye is immune privileged or that immune privilege makes it an optimal organ for gene therapy. Searches for immune privilege and ocular immune responses found no passage addressing that rationale. (LLM, conf=0.73)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationAAVs are currently the most promising retinal gene delivery vectors; they are nonpathogenic, infect retinal cells effectively, and have low intrinsic immunogenicity.
“Adeno-associated viruses (AAVs) are currently the most promising transfer vectors for gene delivery to the retina; they are not pathogenic, can infect the retinal cells effectively, 15,16 and have low intrinsic immunogenicity.17”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [15] 15. Kumar-Singh R. Barriers for retinal gene therapy: separating fact from fiction. Vision Res. 2008;48(16): 1671-1680. doi:10.1016/j.visres.2008.05.005 source
- cites [16] 16. Sun JY, Anand-Jawa V, Chatterjee S, Wong KK. Immune responses to adeno-associated virus and its recombinant vectors. Gene Ther. 2003;10(11): 964-976. doi:10.1038/sj.gt.3302039 source
- cites [17] 17. Yang S, Ma SQ, Wan X, et al. Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy. EBioMedicine. 2016;10:258-268. doi:10.1016/j.ebiom.2016.07.002 source
The Results (Bilateral Gene therapy; page not specified) report sustained retinal ND4 expression after rAAV-ND4 injection and no abnormal AAV2 antibody concentrations, supporting retinal gene delivery and a limited immune-response finding. The paper does not establish that AAVs are the most promising retinal vectors, are nonpathogenic in general, or have low intrinsic immunogenicity. (LLM, conf=0.81)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe G11778A substitution in the ND4 gene explains most LHON cases and the most severe presentations.
“The G to A substitution at nucleotide 11778 (G11778A) in the NADH dehydrogenase subunit 4 (ND4) gene (OMIM 516003) accounts for most cases of LHON and the most severe manifestations.4,7”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [4] 4. Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives. Clin Ophthalmol. 2015;9:1165-1176. source
The Genetics and incomplete penetrance section says the 11778 mutation accounts for 70% of LHON cases, and the Gene therapy section links it to ND4. The Prognosis section says it has the lowest partial visual-recovery rate (4%), but does not establish that it causes the most severe manifestations overall; the LHON plus section links particularly severe syndromes to other mutations. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [7] 7. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol. 2005;140(3):517-523. doi:10.1016/j.ajo. 2005.03.017 source
May combine two claims.
PremisecitationrAAV2/2-ND4 encodes the wild-type ND4 protein and has proof of concept in a rat LHON model.
“The recombinant AAV2 vector carrying the ND4 gene (rAAV2/2-ND4) (GS010) encodes the wild-type ND4 protein and has a proof of concept that was successfully demonstrated in a rat model of LHON.26”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] 26. Vignal C, Uretsky S, Fitoussi S, et al. Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy. Ophthalmology. 2018;125(6): 945-947. doi:10.1016/j.ophtha.2017.12.036 source
May combine two claims.
Findingown dataThe anti-AAV2 neutralizing antibody response overall did not appear linked to baseline levels or to the dose given.
“Overall, the anti-AAV2 NAb response did not seem to be associated with levels at baseline or the dose administered.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAll intraocular inflammation cases responded to treatment, resolving after topical anti-inflammatory therapy.
“and all cases were responsive to treatment.”
- Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
“All events resolved after treatment with topical anti-inflammatory therapy (eTable 3 in the Supplement).”
Quote in the paperSubstantial claim- Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
The quote only partly states this claim.
Findingown dataBaseline anti-AAV2 neutralizing antibody titers varied widely among the 15 patients, spanning from 0 to 1:2850.
“Baseline NAb titers were highly variable among patients, ranging from 0 to 1:2850 (median titer, 1:48) in a patient in the 9 × 10 10 vg dose group (Table 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAt baseline, anti-AAV2 IgG levels varied widely, from 13 to 10 295 × 10 -3 AU/mL (mean 536 × 10 -3 AU/mL), with low levels (<1000 × 10 -3 AU/mL) in 9 of 15 patients.
“At baseline, anti-AAV2 IgG levels were highly variable among patients, ranging from 13 to 10 295 × 10 -3 AU/mL (with a mean at baseline of 536 × 10 -3 AU/mL), with low levels of IgG (<1000 × 10 -3 AU/mL) in 9 of the 15 patients (Table 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNeither ocular inflammation nor immune response could be predicted from the viral dose administered or the patient's baseline immune status.
“Neither ocular inflammation nor immune response could be determined based on the viral dose administered or the patient's immune status at baseline.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBefore administration, one patient in the 9 × 10^10 vg dose group had the highest serum IgG and neutralizing antibody titers and tested positive for cellular response against AAV2.
“Before administration, the patient had the highest IgG and NAb titers in serum and tested positive for cellular response against AAV2;”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAfter unilateral intravitreal rAAV2/2-ND4 injection, a transient mild rise in serum neutralizing antibody titer and treatment-responsive uveitis resolved without long-term sequelae.
“After unilateral intravitreal injection of rAAV2/2-ND4, a transient mild increase in serum NAb titer and treatmentresponsive uveitis resolved without any long-term sequelae.”
Quote in the paperSubstantial claim- Rests on an assumption: The follow-up period was long enough to detect long-term sequelae of the ocular inflammation.
May combine two claims.
Findingown dataOverall humoral immune response against AAV2 peaked between 12 and 24 weeks after administration, with positive IgG responses in 9 of 15 patients.
“The overall humoral immune response against AAV2 peaked between 12 and 24 weeks after administration (eFigure 2 in the Supple- ment), with positive IgG responses in 9 of 15 patients.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEight of 13 vitreous inflammation events were treated with topical anti-inflammatory agents, and 3 events in 2 patients also received oral corticosteroids.
“Eight of 13 events were treated with topical anti-inflammatory agents, and 3 events in 2 patients were also treated with oral corticosteroids (eTable 3 in the Supplement).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn this study, 9 patients received at least 9 × 10^10 vg per eye, and only 1 of them had severe ocular inflammation.
“In our study, 9 patients received a dose of 9 × 10 10 vg per eye or more, and only 1 of these patients presented with severe ocular inflammation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBefore treatment, neutralizing antibodies against AAV2 were absent in six patients, under 1:1000 in seven, and over 1:1000 in two.
“At baseline, anti-AAV2 NAb titers were undetectable in 6 patients, below 1:1000 in 7 patients, and above 1:1000 in 2 patients (1 each in the 9 × 10 9 vg and 9 × 10 10 vg dose groups).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataFor example, a patient in the 9 × 10 10 vg group had a maximum OIS of 5 from concomitant anterior and intermediate uveitis, both rated mild by the examiner.
“For example, a patient in the 9 × 10 10 vg dose group had a maximum OIS of 5 as the result of concomitant anterior and intermediate uveitis, both of which were considered by the examiner to be of mild intensity.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe humoral immune response was not apparently associated with the administered dose or with patients' baseline immune status.
“Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline.”
- Also stated in: § Immunogenicity of rAAV2/2-ND4 in Patients With LHON · plain
“The anti-AAV2 IgG response did not correlate with levels at baseline or the dose administered.”
Quote in the paperNot a substantial claim- Also stated in: § Immunogenicity of rAAV2/2-ND4 in Patients With LHON · plain
May combine two claims.
Findingown dataSystemic immune responses to rAAV2 were transient and matched previous literature observations.
“systemic immune responses to recombinant adeno-associated virus 2 were transient and consistent with previous observations reported in the literature.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe present analysis included 15 patients (mean age 47.9 years, SD 17.2; 13 men and 2 women) enrolled in 5 cohorts.
“The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial.”
- Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
“Fifteen patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) were enrolled in the 5 cohorts.”
Quote in the paperNot a substantial claim- Also stated in: § Assessment of Ocular Inflammation After rAAV2/2-ND4 Administration · plain
May combine two claims.
Findingown dataA patient in the 9 × 10^9 vg dose group had positive IgG and neutralizing antibody responses but no ocular inflammation.
“A patient in the 9 × 10 9 vg dose group had positive IgG and NAb responses but did not have ocular inflammation.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAll ocular inflammation events were mild by CTCAE except in 1 patient in the 9 × 10 10 vg group who had severe anterior chamber inflammation and vitritis 13 days after injection.
“All events of ocular inflammation were mild in intensity according to the CTCAE except in 1 patient in the 9 × 10 10 vg dose group who experienced concomitant severe anterior chamber inflammation and vitritis 13 days after injection of rAAV2/2-ND4.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe two highest individual OISs were 5 at week 8 and 9.5 at week 4, both in patients in the 9 × 10 10 vg group.
“The 2 highest individual OISs were reported in a patient in the 9 × 10 10 vg with a score of 5 at week 8 and a patient in the 9 × 10 10 vg dose group with a score of 9.5 at week 4.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataTwo weeks after intravitreal injection, that patient had severe ocular inflammation and the highest ocular inflammation score as well as IgG and neutralizing antibody titers.
“2 weeks after intravitreal injection, the patient had severe ocular inflammation and the highest OIS as well as IgG and NAb titers.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIntraocular inflammation in these patients was mostly mild, self-limited, and responsive to treatment.
“Ocular gene therapy with rAAV2/2-ND4 in these 15 patients appeared to be overall safe and well tolerated with mostly mild, self-limited intraocular inflammation responsive to treatment that might be prevented using prophylactic immunosuppressive therapy in future trials.”
Quote in the paperSubstantial claim- Rests on an assumption: The follow-up period was long enough to detect long-term sequelae of the ocular inflammation.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLeber hereditary optic neuropathy is the most frequent inherited mitochondrial disorder.
“L eber hereditary optic neuropathy (LHON) is the most common inherited mitochondrial disease.[1][2][3]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1][2][3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
PremisecitationLHON results from a mitochondrial DNA point mutation affecting a complex I subunit (NADH dehydrogenase), an oxidative phosphorylation enzyme.
“Leber hereditary optic neuropathy is caused by a point mutation in mitochondrial DNA, [4][5][6] affecting a subunit of complex I (NADH dehydrogenase), an enzyme of the oxidative phosphorylation pathway.[6][7][8][9]”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4][5][6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [6][7][8][9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLHON preferentially damages retinal ganglion cells of the papillomacular bundle, leading to optic nerve degeneration and severe bilateral vision loss.
“It is characterized by preferential involvement of the retinal ganglion cells of the papillomacular bundle with ensuing optic nerve degeneration and severe bilateral vision loss.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1][2]2][3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataIn this study, intravitreal rAAV2/2-ND4 in patients with LHON was safe and well tolerated.
“In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo adjustment was made for multiple analyses.
“No adjustment was made for multiple analyses.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCpG-rich viral genomes, such as the rAAV2/2-ND4 vector, can activate Toll-like receptors and trigger an innate immune response.
“It is known that CpG-rich viral genomes, such as that of the rAAV2/2-ND4 vector, can activate Toll-like receptors and trigger an innate immune response.39,40”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [39] 39. Ertl HCJ, High KA. Impact of AAV capsid-specific T-cell responses on design and outcome of clinical gene transfer trials with recombinant adeno- associated viral vectors: an evolving controversy. Hum Gene Ther. 2017;28(4):328-337. doi:10.1089/hum. 2016.172 source
- cites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Study design and conductown dataPatients received no immunomodulatory therapy before intravitreal injection.
“Patients did not receive any immunomodulatory therapy before intravitreal injection.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataVitritis (intermediate uveitis) occurred at all dose levels and was considered probably related to treatment by the investigator.
“Vitritis (intermediate uveitis) was reported at all dose levels and was considered by the investigator (C.V.C.) to be probably related to treatment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningProphylactic corticotherapy should be considered in future rAAV2/2-ND4 trials to reduce inflammatory responses.
“These findings suggest that systematic use of prophylactic corticotherapy should be considered in future trials of rAAV2/2-ND4 to lessen inflammatory responses.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisereasoningThe host immune response is an important factor to monitor after gene therapy because it may affect both safety and efficacy.
“As such, the host immune response is a relevant factor to monitor after gene therapy because it may relate to both the safety and the efficacy of the treatment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIdebenone has been used in the European Union despite uncertain efficacy, because a phase 3 trial did not differ statistically from placebo.
“Idebenone (Raxone), a synthetic analogue of coenzyme Q10, has been used by practitioners in the European Union albeit with controversial efficacy, because results from a phase 3 study were not statistically different from placebo.11”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] 11. Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3(11):879-889. doi:10.1038/nri1224 source
Classified as probably not a substantial claim.
Study design and conductcitationA composite global OIS was calculated from four SUN grades: anterior chamber cells, anterior chamber flare, vitreous cells, and vitreous haze.
“In this post hoc analysis, a composite global ocular inflammation score (OIS) was determined using 4 separate grades according to Standardization of Uveitis Nomenclature classification (eTable 2 in the Supplement): anterior chamber cells, anterior chamber flare, vitreous cells, and vitreous haze.29”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] 29. Thomasson N, Galy A, Fitoussi S, et al. Relevance of NHP safety studies for ocular delivery of AAV-based gene therapy in humans: example of rAAV2/2-ND4 local tolerability, shedding and immunogenicity for the treatment of LHON, after IVT injection in non-human primates and in LHON patients. Poster presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3-7, 2015; Denver, Colorado.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataOne patient with untreated ongoing mild vitritis withdrew consent after 48 weeks and was unavailable for follow-up.
“1 patient with untreated ongoing mild vitritis withdrew consent past 48 weeks and was unavailable for follow-up.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSeveral ongoing trials are assessing safety and efficacy of ocular gene therapies, and no serious treatment- or procedure-related adverse events have been reported.
“Several ongoing trials are evaluating the safety and efficacy of such ocular gene therapies, and as yet no serious adverse events (AEs) related to treatment or procedure have been reported.[18][19][20][21][22]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18][19][20][21][22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductnone givenThe study is limited by the small number of patients and high interpatient variability at baseline.
“This study is limited by the small number of patients and the high interpatient variability at baseline.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown datarAAV2/2-ND4 is not highly immunogenic when injected into the vitreous, because not every patient given a medium or high dose developed an immune response.
“In our study, not every patient administered a medium or high dose developed an immune response, indicating that rAAV2/2-ND4 is not highly immunogenic when injected in the vitreous.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThese results support continuing gene therapy in LHON and other families of eye diseases.
“These results support the continuation of gene therapy in LHON and other families of eye diseases.”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
The systemic effects of intravitreal gene therapy still need investigation.
“but its systemic effects remain to be investigated.”
The paper relies on this without support.
An AAV2 vector carrying wild-type ND4 can be easily given intravitreally to LHON patients with the G11778A mutation.
“An AAV2 vector containing the wild-type ND4 gene can easily be administered intravitreally to patients with LHON carrying the G11778A mutation.”
The paper relies on this without support.
The follow-up period was long enough to detect long-term sequelae of the ocular inflammation.
“After unilateral intravitreal injection of rAAV2/2-ND4, a transient mild increase in serum NAb titer and treatmentresponsive uveitis resolved without any long-term sequelae.”
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?
In the Bouquet et al trial, oral steroids were used effectively in 2/11 patients who did not respond to topical therapy.
“Oral steroids were used effectively in 2/11 patients who did not respond to topical therapy.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
The Assessment of Ocular Inflammation section (page unavailable) reports vitreous inflammation in 11 patients and oral corticosteroid treatment for three events in two of them; all treated events resolved. It does not say those two patients had failed to respond to topical therapy before receiving oral steroids. (LLM, conf=0.90)
Experimental — accuracy not yet measuredA first-in-human trial (GS-LHON-CLIN-01) showed that a single intravitreal administration of increasing doses of rAAV2/2-ND4 was safe and well tolerated in LHON subjects.
“Based on these preclinical studies, a first-in-human trial (GS-LHON-CLIN-01) showed that a single intravitreal administration of increasing doses of rAAV2/2-ND4 was safe and well tolerated in LHON subjects.16,17”
From Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset (2021) · cites this paper as [17]
The Phase 1/2 Clinical Study Protocol describes dose escalation and intravitreal injection in 15 patients with LHON, and the Conclusions say treatment appeared overall safe and well tolerated. Our copy identifies the trial as NCT02064569 but does not identify it as GS-LHON-CLIN-01 or explicitly establish that it was first-in-human. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThese features are typically seen within a few weeks of intravitreal injection, particularly with higher vector doses.
“These features are typically seen within a few weeks of intravitreal injection, particularly with higher vector doses (Cukras et al., 2018; Vignal-Clermont et al., 2018; Bouquet et al., 2019).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bouquet et al., 2019
The Assessment of Ocular Inflammation section (p. 402) reports that the mean inflammation score peaked four weeks after injection, supporting the timing in broad terms. But it reports no association between inflammation intensity and dose, and says the score’s magnitude did not correlate with dose; the claim that these features are seen particularly with higher doses is not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredBouquet et al showed that neither baseline antibodies nor the degree of immune response, defined by increased antibody titers, correlated with the degree of intraocular inflammation.
“which is further supported by the work of Bouquet et al79 who showed that neither baseline Abs nor the degree of immune response, defined by increased Ab titers, correlated with the degree of intraocular inflammation.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
Bouquet et al assessed the link between immune response and intraocular inflammation in 15 patients diagnosed with ND4 LHON undergoing ocular gene therapy with rAAV2 vectors.
“In an open-label phase I/II randomized clinical trial, Bouquet et al79 assessed the link between immune response and intraocular inflammation in 15 patients diagnosed with ND4 LHON undergoing ocular gene therapy with rAAV2 vectors.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
In the Bouquet et al study, intensity of inflammation showed no correlation with dosage, and it was also not associated with baseline immune responses and antibody titers.
“Intensity of inflammation showed no correlation with dosage, and it was also not associated with baseline immune responses and antibody titers.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
Few studies did not show an association between inflammatory responses and viral doses.
“Few studies did not show this association between the inflammatory responses and the viral doses.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
In the Bouquet et al study, mild inflammatory reactions were noted in nearly all patients, regardless of the administered dose.
“Following the injections, mild inflammatory reactions were noted in nearly all patients, regardless of the administered dose.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
In the Bouquet et al trial, most patients who developed postoperative vitreal inflammation were controlled by topical steroids.
“Most patients who developed postoperative vitreal inflammation were controlled by topical steroids.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
Experimental — accuracy not yet measuredBouquet et al have not used perioperative steroids in their trial involving an intravitreal injection of AAV vector.
“Bouquet et al have not used perioperative steroids in their trial which involved an intravitreal injection of AAV vector.79”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [79]
The association between the post-treatment serum antibody response and the severity of intraocular inflammation observed in patients is variable.
“However, it must be noted that the association between the post-treatment serum anti body response and the severity of intraocular inflammation observed in patients is variable (Bouquet et al., 2019; Pennesi et al., 2022).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Bouquet et al., 2019
High rAAV doses lead to a higher incidence of intraocular inflammation.
“It has been reported that a higher rAAV dose leads to a higher incidence of intraocular inflammation29.”
From An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species (2024) · cites this paper as [29]
Both cellular and humoral factors have been implicated in the immune response.
“Both cellular and humoral factors have been implicated (45–47).”
From Subretinal therapy: technological solutions to surgical and immunological challenges (2022) · cites this paper as [46]
Bouquet et al. reported inflammation according to the Standardization of Uveitis Nomenclature classification.
“For instance, Bouquet et al. reported inflammation according to the Standardization of Uveitis Nomenclature classification [138,139].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [138]
A high vector dose needed because of the large human vitreous volume could substantially raise the risk of intraocular inflammation.
“In addition, the large volume of vitreous in humans means a high dose of vector is generally required to achieve therapeutic concentrations at the retinal surface. This could significantly increase the risk of intraocular inflammation [Bouquet 2019].”
From Correcting visual loss by genetics and prosthetics (2020) · cites this paper as Bouquet 2019
In LHON, eyes treated with gene therapy have shown little or no improvement in visual acuity.
“So far, eyes treated with gene therapy for LHON have exhibited little to no improvement in visual acuity.”
From Correcting visual loss by genetics and prosthetics (2020) · cites this paper as Bouquet 2019
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Current clinical applications of in vivo gene therapy with AAVs
Mendell, J. R., Al-Zaidy, S. A., Rodino-Klapac, L. R., Goodspeed, K., Gray, S. J., Kay, C. N., Boye, S. L., Boye, S. E., George, L. A., Salabarria, S., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2020.12.007 · Cited by 743 · see citing works
AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer
Costa Verdera, H., Kuranda, K., & Mingozzi, F. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2019.12.010 · Cited by 641 · see citing works
“Levels of anti-capsid antibodies increased after injection in most patients enrolled in the trial.(164,165) Follow-up of LHON patients enrolled in a phase III trial is currently ongoing.”
BackgroundHigh, K. A., & Roncarolo, M. G. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1706910 · Cited by 555 · see citing works
Various AAV Serotypes and Their Applications in Gene Therapy: An Overview
Issa, S. S., Shaimardanova, A. A., Solovyeva, V. V., & Rizvanov, A. A. (2023) · Cells · doi:10.3390/cells12050785 · Cited by 319 · see citing works
Bucher, K., Rodríguez-Bocanegra, E., Dauletbekov, D., & Fischer, M. D. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100915 · Cited by 242 · see citing works
Yu-Wai-Man, P., Newman, N. J., Carelli, V., Moster, M. L., Biousse, V., Sadun, A. A., Klopstock, T., Vignal-Clermont, C., Sergott, R. C., Rudolph, G., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz7423 · Cited by 232 · see citing works
Self-citationImmunogenicity of Cas9 Protein
Mehta, A., & Merkel, O. M. (2019) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2019.10.003 · Cited by 186 · see citing works
Newman, N. J., Yu-Wai-Man, P., Carelli, V., Moster, M. L., Biousse, V., Vignal-Clermont, C., Sergott, R. C., Klopstock, T., Sadun, A. A., Barboni, P., et al. (2021) · Ophthalmology · doi:10.1016/j.ophtha.2020.12.012 · Cited by 168 · see citing works
“Based on these preclinical studies, a first-in-human trial (GS-LHON-CLIN-01) showed that a single intravitreal administration of increasing doses of rAAV2/2-ND4 was safe and well tolerated in LHON subjects.(16,17) Two phase 3 clinical trials with a follow-up of 96 weeks postadministration of the gene therapy vector an…”
BackgroundSelf-citationImmunogenicity of CRISPR therapeutics—Critical considerations for clinical translation
Ewaisha, R., & Anderson, K. S. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1138596 · Cited by 145 · see citing works
Gene therapy for inherited retinal diseases: Progress and possibilities
Hu, M. L., Edwards, T. L., O’Hare, F., Hickey, D. G., Wang, J.-H., Liu, Z., & Ayton, L. N. (2021) · Clinical and Experimental Optometry · doi:10.1080/08164622.2021.1880863 · Cited by 118 · see citing works
Newman, N. J., Yu-Wai-Man, P., Biousse, V., & Carelli, V. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00174-0 · Cited by 97 · see citing works
Drug Development for the Therapy of Mitochondrial Diseases
Weissig, V. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.09.002 · Cited by 92 · see citing works
Understanding AAV vector immunogenicity: from particle to patient
Dhungel, B. P., Winburn, I. C., Pereira, C. D. F., Huang, K., Chhabra, A., & Rasko, J. E. J. (2024) · Theranostics · doi:10.7150/thno.89380 · Cited by 90 · see citing works
Pennesi, M. E., Yang, P., Birch, D. G., Weng, C. Y., Moore, A. T., Iannaccone, A., Comander, J. I., Jayasundera, T., Chulay, J., Chulay, J., et al. (2022) · Ophthalmology Retina · doi:10.1016/j.oret.2022.06.013 · Cited by 71 · see citing works
Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses
Ghoraba, H. H., Akhavanrezayat, A., Karaca, I., Yavari, N., Lajevardi, S., Hwang, J., Regenold, J., Matsumiya, W., Pham, B., Zaidi, M., et al. (2022) · Clinical Ophthalmology · doi:10.2147/opth.s364200 · Cited by 76 · see citing works
Britten‐Jones, A. C., Jin, R., Gocuk, S. A., Cichello, E., O’Hare, F., Hickey, D. G., Edwards, T. L., & Ayton, L. N. (2021) · Genetics in Medicine · doi:10.1016/j.gim.2021.10.013 · Cited by 67 · see citing works
Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine
Khatib, T. Z., & Martin, K. R. G. (2019) · Current Eye Research · doi:10.1080/02713683.2019.1663385 · Cited by 61 · see citing works
Seven-year follow-up of gene therapy for Leber’s hereditary optic neuropathy
Yuan, J., Zhang, Y., Liu, H., Wang, D., Du, Y., Tian, Z., Li, X., Yang, S., Pei, H., Wan, X., et al. (2020) · Ophthalmology · doi:10.1016/j.ophtha.2020.02.023 · Cited by 59 · see citing works
Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies
Chu, W. S., & Ng, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.658038 · Cited by 59 · see citing works
Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective
Donfrancesco, A. D., Massaro, G., Meo, I. D., Tiranti, V., Bottani, E., & Brunetti, D. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061287 · Cited by 60 · see citing works
Humoral immune responses to <scp>AAV</scp> gene therapy in the ocular compartment
Whitehead, M., Osborne, A., Yu‐Wai‐Man, P., & Martin, K. (2021) · Biological Reviews · doi:10.1111/brv.12718 · Cited by 52 · see citing works
Subretinal therapy: technological solutions to surgical and immunological challenges
Ladha, R., Caspers, L. E., Willermain, F., & de Smet, M. D. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.846782 · Cited by 54 · see citing works
Vignal-Clermont, C., Girmens, J.-F., Audo, I., Said, S. M., Errera, M.-H., Plaine, L., O’Shaughnessy, D., Taiel, M., & Sahel, J.-A. (2021) · BioDrugs · doi:10.1007/s40259-021-00468-9 · Cited by 51 · see citing works
“Importantly, no association was observed between intraocular inflammation and humoral or cellular immune response [41].”
BackgroundSelf-citationUpdate on viral gene therapy clinical trials for retinal diseases
Cheng, S.-Y., & Punzo, C. (2022) · Human Gene Therapy · doi:10.1089/hum.2022.159 · Cited by 49 · see citing works
“Mild adverse events were reported including intraocular inflammation as well as anterior chamber inflammation.(107,108) Following this trial, two phase III clinical studies, RESCUE and REVERSE, evaluated the efficacy and safety of unilateral intravitreal injection of rAAV2ND4 into ND4-LHON patients who had vision loss…”
BackgroundDelivering AAV to the Central Nervous and Sensory Systems
Peters, C. W., Maguire, C. A., & Hanlon, K. S. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.03.004 · Cited by 44 · see citing works
Wang, J.-H., Zhan, W., Gallagher, T. L., & Gao, G. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.10.017 · Cited by 48 · see citing works
Towards optogenetic vision restoration with high resolution
Ferrari, U., Deny, S., Sengupta, A., Caplette, R., Trapani, F., Sahel, J., Dalkara, D., Picaud, S. A., Duebel, J., & Marre, O. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007857 · Cited by 41 · see citing works
Self-citationThe curious case of AAV immunology
Keeler, A. M., Zhan, W., Ram, S., Fitzgerald, K. A., & Gao, G. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.03.037 · Cited by 46 · see citing works
Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I/IIa gene therapy trial
Mishra, A., Vijayasarathy, C., Cukras, C. A., Wiley, H. E., Sen, H. N., Zeng, Y., Wei, L. L., & Sieving, P. A. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.02.013 · Cited by 38 · see citing works
An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species
Luo, S., Jiang, H., Li, Q., Qin, Y., Yang, S., Li, J., Xu, L., Gou, Y., Zhang, Y., Liu, F., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48221-4 · Cited by 39 · see citing works
Focused Update on AAV-Based Gene Therapy Clinical Trials for Inherited Retinal Degeneration
Fuller-Carter, P. I., Basiri, H., Harvey, A. R., & Carvalho, L. S. (2020) · BioDrugs · doi:10.1007/s40259-020-00453-8 · Cited by 41 · see citing works
Tummala, G., Crain, A., Rowlan, J., & Pepple, K. L. (2021) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.62.2.41 · Cited by 36 · see citing works
“6,15,16 To address these possibilities, we used serial OCT imaging as a sensitive method for detecting anterior chamber cell and vitritis in murine eyes.”
Kiss, S., Oresic Bender, K., Grishanin, R. N., Hanna, K. M., Nieves, J. D., Sharma, P., Nguyen, A. T., Rosario, R. J., Greengard, J. S., Gelfman, C. M., et al. (2021) · Translational Vision Science & Technology · doi:10.1167/tvst.10.1.34 · Cited by 36 · see citing works
Kachanov, A., Kostyusheva, A., Brezgin, S., Karandashov, I., Ponomareva, N. I., Tikhonov, A., Lukashev, A. N., Pokrovsky, V. S., Zamyatnin, A. A., Parodi, A., et al. (2024) · Medicinal Research Reviews · doi:10.1002/med.22036 · Cited by 38 · see citing works
Sobh, M., Lagali, P. S., Ghiasi, M., Montroy, J. R., Dollin, M. L., Hurley, B. R., Leonard, B. C., Dimopoulos, I. S., Lafreniere, M., Fergusson, D. A., et al. (2023) · Translational Vision Science & Technology · doi:10.1167/tvst.12.11.24 · Cited by 35 · see citing works
ICG-mediated photodisruption of the inner limiting membrane enhances retinal drug delivery
Peynshaert, K., Vanluchene, H., Clerck, K. D., Minnaert, A., Verhoeven, M., Gouspillou, N., Bostan, N., Hisatomi, T., Accou, G., Sauvage, F., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.07.002 · Cited by 33 · see citing works
Wiley, L. A., Boyce, T. M., Meyering, E. E., Ochoa, D., Sheehan, K. M., Stone, E. M., Mullins, R. F., Tucker, B. A., & Han, I. C. (2023) · Human Gene Therapy · doi:10.1089/hum.2022.222 · Cited by 30 · see citing works
Ocular Inflammation and Treatment Emergent Adverse Events in Retinal Gene Therapy
Mehta, N., Robbins, D. A., & Yiu, G. (2021) · International Ophthalmology Clinics · doi:10.1097/iio.0000000000000366 · Cited by 33 · see citing works
Nuzbrokh, Y., Kassotis, A. S., Ragi, S. D., Jauregui, R., & Tsang, S. H. (2020) · Ophthalmology and Therapy · doi:10.1007/s40123-020-00287-1 · Cited by 31 · see citing works
Investigation of Cas9 Antibodies in the Human Eye
Toral, M. A., Charlesworth, C. T., Ng, B., Chemudupati, T., Homma, S., Nakauchi, H., Bassuk, A. G., Porteus, M. H., & Mahajan, V. B. (2022) · Nature Communications · doi:10.1038/s41467-022-28674-1 · Cited by 28 · see citing works
Bennett, J., & Maguire, A. M. (2022) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041307 · Cited by 25 · see citing works
Gene Therapies for the Treatment of Leber Hereditary Optic Neuropathy
Sahel, J., Newman, N. J., Yu‐Wai‐Man, P., Vignal‐Clermont, C., Carelli, V., Biousse, V., Moster, M. L., Sergott, R. C., Klopstock, T., Sadun, A. A., et al. (2021) · International Ophthalmology Clinics · doi:10.1097/iio.0000000000000364 · Cited by 28 · see citing works
Self-citationVIGNAL-CLERMONT, C., YU-WAI-MAN, P., NEWMAN, N. J., CARELLI, V., MOSTER, M. L., BIOUSSE, V., SUBRAMANIAN, P. S., WANG, A.-G., DONAHUE, S. P., LEROY, B. P., et al. (2023) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2022.11.026 · Cited by 25 · see citing works
Self-citationA comparison between SARS-CoV-1 and SARS-CoV2: an update on current COVID-19 vaccines
Abdolmaleki, G., Taheri, M. A., Paridehpour, S., Mohammadi, N. M., Tabatabaei, Y. A., Mousavi, T., & Amin, M. (2022) · DARU Journal of Pharmaceutical Sciences · doi:10.1007/s40199-022-00446-8 · Cited by 25 · see citing works
Purdy, R., John, M., Bray, A., Clare, A. J., Copland, D. A., Chan, Y. K., Henderson, R. H., Nerinckx, F., Leroy, B. P., Yang, P., et al. (2025) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2025.101354 · Cited by 24 · see citing works
“However, it must be noted that the association between the post-treatment serum antibody response and the severity of intraocular inflammation observed in patients is variable (Bouquet et al., 2019; Pennesi et al., 2022).”
Ford, J. L., Karatza, E., Mody, H. R., Shastri, P. N., Khajehpour, S., Yang, T., Swanson, M., Chao, D. L., & Devineni, D. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3230 · Cited by 21 · see citing works
“Another study of IVT administered rAAV2-ND4 in patients with Leber hereditary optic neuropathy 51 measured pre-existing neutralizing antibodies to AAV2 in aqueous humor and, while most patients tested positive for pre-existing AAV2 antibodies in serum, levels in aqueous humor were undetectable.”
BackgroundImmunology of Retinitis Pigmentosa and Gene Therapy–Associated UveitisPreprint
Yang, P. G., Mustafi, D., & Pepple, K. L. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041305 · Cited by 20 · see citing works
MacDonald, I. M., Moen, C., Duncan, J. L., Tsang, S. H., Cehajic-Kapetanovic, J., & Aleman, T. S. (2020) · Translational Vision Science & Technology · doi:10.1167/tvst.9.3.17 · Cited by 20 · see citing works
Risk mitigation of immunogenicity: a key to personalized retinal gene therapy
Varin, J., Morival, C., Maillard, N., Adjali, O., & Cronin, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222312818 · Cited by 19 · see citing works
Corydon, T. J., & Bek, T. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101323 · Cited by 19 · see citing works
Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy
Crabtree, E. E., Uribe, K., Smith, S. M., Roberts, D. M., Salmon, J. H., Bower, J. J., Song, L., Bastola, P., Hirsch, M. L., & Gilger, B. C. (2022) · PLoS ONE · doi:10.1371/journal.pone.0270972 · Cited by 19 · see citing works
“More recent published reports suggest growing evidence that intraocular gene therapy can cause uveitis following IVT or subretinal administration [53, 55].”
BackgroundAdvancing precision medicines for ocular disorders: Diagnostic genomics to tailored therapies
Panikker, P., Roy, S., Ghosh, A., Poornachandra, B., & Ghosh, A. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.906482 · Cited by 16 · see citing works
“An AAV2 vector carrying the ND4 gene (GS010) for LHON patients showed good safety and efficacy results in a number of 1/2 trials and several phase three clinical trials are currently being done (93).”
BackgroundDevi, S. M., Abishek Kumar, B., Iyer, M., & Vellingiri, B. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.08.013 · Cited by 18 · see citing works
Advances in viral vector-based delivery systems for gene therapy: a comprehensive review
Singh, K., Jain, D., Sethi, P., Gupta, J. K., Dubey, A., Noman, A. A., lal, S., Sharma, P., & Abdallah, E. M. (2025) · 3 Biotech · doi:10.1007/s13205-025-04366-7 · Cited by 19 · see citing works
Neutralizing Antibodies: Role in Immune Response and Viral Vector Based Gene Therapy
Tsaregorodtseva, T. S., Gubaidullina, A. A., Kayumova, B. R., Shaimardanova, A. A., Issa, S. S., Solovyeva, V. V., Sufianov, A. A., Суфианова, Г. З., & Rizvanov, A. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115224 · Cited by 19 · see citing works
“Research conducted in the past five years highlights the importance of thoroughly evaluating the immune response to selected viral vectors for successful gene therapy outcomes [66–68].”
Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials
Michalakis, S., Gerhardt, M. J., Rudolph, G., Priglinger, S. G., & Priglinger, C. (2021) · Klinische Monatsblätter für Augenheilkunde · doi:10.1055/a-1384-0818 · Cited by 15 · see citing works
“Also, in the clinical phase I/II trial for LHON, anterior chamber inflammation was reported in 10 of 15 patients 7–93 days after injection, and vitritis occurred in 11 of 15 patients [45].”
BackgroundLiu, Y.-F., Huang, S., Ng, T. K., Liang, J.-J., Xu, Y., Chen, S.-L., Xu, C., Zhang, M., Pang, C. P., & Cen, L.-P. (2020) · Experimental Eye Research · doi:10.1016/j.exer.2020.107955 · Cited by 15 · see citing works
Kurimoto, T., Ueda, K., Mori, S., Kamada, S., Sakamoto, M., Yamada‐Nakanishi, Y., Matsumiya, W., & Nakamura, M. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9051359 · Cited by 13 · see citing works
“implemented gene therapy for cases of LHON with the 11,778 mtDNA mutation [26].”
BackgroundLooking to the Future of Viral Vectors in Ocular Gene Therapy: Clinical Review
Kharisova, C. B., Kitaeva, K. V., Solovyeva, V. V., Sufianov, A. A., Суфианова, Г. З., Фаисович, А. Р., Bulgar, S. N., & Rizvanov, A. A. (2025) · Biomedicines · doi:10.3390/biomedicines13020365 · Cited by 15 · see citing works
The clinical safety landscape for ocular AAV gene therapies: A systematic review and meta-analysis
Liu, Z., Zhang, H., Jia, H., Wang, H., Huang, Z., Tang, Y., Wang, Z., Hu, J., Zhao, X., Li, T., et al. (2025) · iScience · doi:10.1016/j.isci.2025.112265 · Cited by 15 · see citing works
Tang, Y., Fakhari, S., Huntemann, E. D., Feng, Z., Wu, P., Feng, W. Y., Lei, J., Yuan, F., Excoffon, K. J. D. A., Wang, K., et al. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.02.015 · Cited by 12 · see citing works
“In another AAV gene therapy clinical trial for Leber’s hereditary optic neuropathy, corticosteroids were used to manage the ocular inflammation after intravitreal administration of rAAV2/2-ND4.(27)”
BackgroundCurrent progress in the therapeutic options for mitochondrial disorders.
Koňaříková, E., Markovic, A., Korandová, Z., Houštěk, J., & Mráček, T. (2020) · Physiological Research · doi:10.33549/physiolres.934529 · Cited by 13 · see citing works
“As reported in the clinical trials, patients’ visual acuity improved and visual field was enlarged without observation of any undesirable side-effects (Wan et al., 2016, GenSight, 2019, Yang et al., 2016, Bouquet et al., 2019, Feuer et al., 2016).”
BackgroundWassmer, 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 · see citing works
“52–56 It remains to be seen whether this therapy will have long-term effects in protecting RGCs, or if the retina will continue to degenerate, similar to the clinical trials (and now marketed therapy) in Leber congenital amaurosis, which showed functional improvements following gene replacement…”
International expert consensus on gene therapy for hereditary hearing loss: Based on clinical trials
Fan, X., Gao, Z., Zhong, J., Chen, Y., Chen, X., Landegger, L. D., Moser, T., Zeng, F., Sun, Y., Jin, X., et al. (2025) · Med · doi:10.1016/j.medj.2025.100886 · Cited by 12 · see citing works
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 · see citing works
New avenues for therapy in mitochondrial optic neuropathies
Ng, V., Trigano, M., Freeman, T. J., Varricchio, C., Kandaswamy, S., Newland, B., Brancale, A., Rôżanowska, M., & Votruba, M. (2021) · Therapeutic Advances in Rare Disease · doi:10.1177/26330040211029037 · Cited by 8 · see citing works
Retinal gene therapy using epiretinal AAV-containing fibrin hydrogel implants
Scruggs, B. A., Berger, A., Knudsen, T., Kopp, F. N., Hill, M., Trncic, E., Anderson, K., Iezzi, R., & Marmorstein, A. D. (2025) · Science Advances · doi:10.1126/sciadv.adv7922 · Cited by 10 · see citing works
Sin, T.-N., Tng, N., Dragoli, J., Kumar, S. R., Villafuerte-Trisolini, C., Chung, S. H., Tu, L., Le, S. M., Shim, J. H., Pepple, K. L., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.09.027 · Cited by 7 · see citing works
Gene therapy for age-related macular degeneration: potential, feasibility, and pitfalls
Berkowitz, S. T., & Finn, A. P. (2024) · Current Opinion in Ophthalmology · doi:10.1097/icu.0000000000001043 · Cited by 7 · see citing works
Leber Hereditary Optic Neuropathy: Molecular Pathophysiology and Updates on Gene Therapy
Chi, S.-C., Cheng, H., & Wang, A.-G. (2022) · Biomedicines · doi:10.3390/biomedicines10081930 · Cited by 7 · see citing works
“These two trials were randomized, doublemasked, sham-controlled studies with a single unilateral intravitreal injection of rAAV2/2ND4 (GS010, LUMEVOQ).”
MethodInfluentialChiale, C., Marchese, A., Furuya, Y., & Robek, M. D. (2021) · npj Vaccines · doi:10.1038/s41541-021-00400-w · Cited by 6 · see citing works
Correcting visual loss by genetics and prosthetics
Xue, K., & MacLaren, R. E. (2020) · Current Opinion in Physiology · doi:10.1016/j.cophys.2020.03.003 · Cited by 5 · see citing works
“Both approaches are currently being tested in clinical trials [Guy 2017, Bouquet 2019].”
BackgroundMethodEmerging Gene Manipulation Strategies for the Treatment of Monogenic Eye Disease
Burgess, F. R., Hall, H. N., & Megaw, R. D. (2022) · Asia-Pacific Journal of Ophthalmology · doi:10.1097/apo.0000000000000545 · Cited by 4 · see citing works
Genes and Gene Therapy in Inherited Retinal Disease
Shughoury, A., Ciulla, T. A., Bakall, B., Pennesi, M. E., Kiss, S., & Cunningham, E. T. (2021) · International Ophthalmology Clinics · doi:10.1097/iio.0000000000000377 · Cited by 4 · see citing works
Les anti-TNF-α pour le traitement des uvéites non infectieuses
Hoogewoud, F., Kowalczuk, L., Bousquet, E., Brézin, A. P., Touchard, E., Buggage, R. R., Bordet, T., & Béhar‐Cohen, F. (2020) · médecine/sciences · doi:10.1051/medsci/2020160 · Cited by 5 · see citing works
Cai, Y., Gu, Y., Zhang, J., Zhu, Y. Y., Ma, Z., He, Q., Sun, Y. J., Yuan, M., Li, X., Zhu, K., et al. (2025) · Research · doi:10.34133/research.0717 · Cited by 5 · see citing works
“Low specificity determines higher doses of AAV, indicating a higher incidence of health problems such as ocular inflammation [ 31 , 32 ].”
Amante, J. J., Twombly, B., Thotathil, N., & Kearney, C. J. (2025) · Biomaterials Science · doi:10.1039/d5bm00623f · Cited by 6 · see citing works
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 · see citing works
“…vector for gene delivery to retinal tissues, accumulating evidence suggests that both intravitreal and sub-retinal AAV injection can induce ocular immune responses /inflammation in pre-clinical animal models, including non-human primates (Reichel et al., 2017), and in humans (Bouquet et al., 2019).”
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 · see citing works
Gene and cell-based therapies for retinal and optic nerve disease
Esposito, E. P., Han, I. C., & Johnson, T. V. (2024) · Handbook of clinical neurology · doi:10.1016/b978-0-323-90120-8.00016-2 · Cited by 4 · see citing works
Clinical and Ocular Inflammatory Inhibitors of Viral-Based Gene Therapy of the Retina
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- Authors
- Bouquet, C., Vignal Clermont, C., Galy, A., Fitoussi, S., Blouin, L., Munk, M. R., Valero, S., Meunier, S., Katz, B., Sahel, J. A., & Thomasson, N.
- Affiliations
- GenSight Biologics (France) (FR)
- Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France
- University Hospital of Bern (CH)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Katz, Barrett
- Venue
- JAMA Ophthalmology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-04-01
- Volume
- 137
- Issue
- 4
- Pages
- 399
- ISSN
- 2168-6165 (ISSN-L)
- PMC
- PMC6459107
- OpenAlex
- W2914705959
- Cited by
- 102
- References
- 45
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 13 · 2023: 12 · 2022: 15 · 2021: 19 · 2020: 16 · 2019: 6
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Ophthalmology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- HAL (Le Centre pour la Communication Scientifique Directe) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Leber's hereditary optic neuropathy, intravitreal gene therapy, recombinant adeno-associated virus 2, ND4 gene, ocular inflammation, immune response, vitritis, anterior chamber inflammation
- MeSH terms
- Dependovirus, Electroretinography, Female, Fluorescein Angiography, Follow-Up Studies, Fundus Oculi, Genetic Vectors, Humans, Male
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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