The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index; 53 of the 110 sources its claims cite were checked for support.
Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids
Open accessAbstract
Recombinant adeno-associated virus vectors (rAAV) are being explored as gene delivery vehicles for the treatment of various inherited and acquired disorders. rAAVs are attractive vectors for several reasons: wild-type AAVs are nonpathogenic, and rAAVs can trigger long-term transgene expression even in the absence of genome integration-at least in postmitotic tissues. Moreover, rAAVs have a low immunogenic profile, and the various AAV serotypes and variants display broad but distinct tropisms. One limitation of rAAVs is that their genome-packaging capacity is only ∼5 kb. For most applications this is not of major concern because the median human protein size is 375 amino acids. Excluding the ITRs, for a protein of typical length, this allows the incorporation of ∼3.5 kb of DNA for the promoter, polyadenylation sequence, and other regulatory elements into a single AAV vector. Nonetheless, for certain diseases the packaging limit of AAV does not allow the delivery of a full-length therapeutic protein by a single AAV vector. Hence, approaches to overcome this limitation have become an important area of research for AAV gene therapy. Among the most promising approaches to overcome the limitation imposed by the packaging capacity of AAV is the use of dual-vector approaches, whereby a transgene is split across two separate AAV vectors. Coinfection of a cell with these two rAAVs will then-through a variety of mechanisms-result in the transcription of an assembled mRNA that could not be encoded by a single AAV vector because of the DNA packaging limits of AAV. The main purpose of this review is to assess the current literature with respect to dual-AAV-vector design, to highlight the effectiveness of the different methodologies and to briefly discuss future areas of research to improve the efficiency of dual-AAV-vector transduction.
Overview
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Written from the paper’s full text.
TL;DR
This review assesses strategies for expressing transgenes that exceed the ~5 kb packaging capacity of recombinant AAV vectors, focusing on dual-vector designs (fragmented/oversized, overlapping, trans-splicing, and hybrid). It concludes that hybrid dual-vector systems are currently the most promising in most instances, but that no single system is optimal across all transgenes and tissues.
Key findings
- AAV packaging capacity is limited to roughly 5 kb: wtAAV genomes average ~4.7 kb, Hermonat et al. found ~5.6 kb as the maximum for recovery of significant infectious virus, and Dong et al. reported optimal packaging between 4.1 and 4.9 kb, with vectors >5.2 kb packaged very inefficiently. Claims that AAV5 could package up to 8.9 kb were not supported by later studies, which found such genomes truncated (packaged genomes never exceeded 5.2 kb).
- Because ~6% of human proteins have coding sequences exceeding 4 kb (median human protein is 375 amino acids), some therapeutic cDNAs (e.g., ABCA4 ~7.3 kb, dystrophin, dysferlin, CFTR, MYO7A, factor VIII) cannot fit in a single AAV vector.
- In a direct comparison (Ghosh et al.), hybrid vectors achieved LacZ expression equal to a single intact vector at MOI 20,000 vg/cell, and 71% at 1,000 vg/cell, outperforming overlapping (~25%) and trans-splicing (~50%) variants; in mouse tibialis anterior muscle, hybrid vectors yielded 81% of single-vector β-galactosidase activity versus 34% (overlapping) and 62% (trans-splicing).
- Hybrid systems are not universally superior: Zhang and Duan found a dual overlapping vector system gave ~3-fold higher muscle transduction than three hybrid systems, and Pryadkina et al. obtained similar results for dysferlin. Minimized AP bridging sequences (0.27/0.26 kb vs. 0.87 kb) expand payload by ~1.2 kb; a 77 bp F1 phage-derived homology region has also been used.
Methods
- Narrative literature review; no primary experimental data reported.
- Synthesizes published studies on AAV biology, packaging capacity limits, and dual/triple-vector strategies (fragmented/oversized, overlapping, trans-splicing, hybrid), including in vitro (e.g., HEK293, MO59K, C2C12) and in vivo (mouse models including mdx, mdx4cv, A/J, ABCA4−/−, sh1) comparisons.
- Discusses mechanistic hypotheses (homologous recombination, ITR-mediated concatamerization, Rad51C-dependent repair) and design variables (recombinogenic sequences, splice donor/acceptor sites, ITR heterology).
Limitations
- Stated by the paper: the literature on dual-vector efficacy is "broad and often conflicting"; the mechanism of transduction by fragmented and overlapping vectors is "as yet not fully understood"; efficiency of transgene expression from dual-vector systems has been inconsistent and is currently insufficient for many clinical applications; hybrid systems are not always the most efficient; and optimization must be done empirically per transgene and tissue.
- Evident from the text: as a narrative review it provides no new experimental data, and several cited comparisons rely on different transgenes, serotypes, cell/tissue types, and titration methods, which the authors note can themselves influence results.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
35 No full text of the sources · 21 Supported · 18 Own interpretation · 14 Partly supported · 6 Supported so far · 3 No basis given · 2 Couldn’t confirm · 1 Not checked yet · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Trapani et al. found the overexpression of MYO7a in HEK293 cells with AAV2 vectors to be more efficient when they used a dual overlapping vector system as opposed to a single oversized vector, 46”
What the sources say
- Supportedcites [46] Trapani I, 2014, EMBO Mol Med source
The Results section, “Dual AAV vectors allow high levels of transduction in vitro,” reports that HEK293 cells were infected with AAV2/2 vectors encoding MYO7A. Its quantification of MYO7A expression found the dual overlapping (OV) approach more efficient than the single oversized (OZ) approach. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“even such seemingly arcane technical details as the method of vector titration appear to be able to influence the results obtained when comparing two different strategies to increase AAV payload. 46”
What the sources say
- Could not verifycites [46] Trapani I, 2014, EMBO Mol Med sourceExperimental — accuracy not yet measured
The Materials and Methods section describes how vector titers were measured, and the Results compare strategies for delivering large genes. Neither passage says that the method of titration influences the comparison. The Discussion suggests other possible reasons for differences between studies, including vector design and purification, but does not identify titration method as one. (LLM, conf=0.76)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Transduction of airway epithelial cells with an rAAV vector containing this expression cassette was sufficient to reverse, at least partially, the cystic fibrosis chloride transport defect in these cells. 35”
What the sources say
- Supportedcites [35] source
The Results and Discussion report that AAV5 vectors carrying the shortened CFTR expression cassette generated chloride current in differentiated primary CF airway epithelia, with correction persisting for at least 28 days. The same section concludes that a single AAV vector corrected the CF chloride-transport defect; the claim’s qualification, ‘at least partially,’ is consistent with this result. (LLM, conf=0.94)
plainconditional- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“the median length of a human protein is only 375 amino acids. 27”
What the sources say
- Could not verifycites [27] sourceExperimental — accuracy not yet measured
The Results section (‘Protein lengths across proteomes’; page unavailable) reports a median of 361 amino acids for the pooled eukaryotic proteins, not a human-specific median. The Methods section (‘Proteomes’; page unavailable) says human proteins were included, but searches for ‘375’ and ‘Homo sapiens Table 2 median’ found no passage in our copy giving the claimed human value. (LLM, conf=0.72)
plain- Asserted: passes — The authors put it forward as true.
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- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Hu and Lipshutz used a similar dual-vector strategy to demonstrate phenotypic correction of FVIII deficiency in a mouse model of hemophilia A. 39”
What the sources say
- Supportedcites [39] source
The Introduction describes co-injecting two AAV vectors, one expressing the FVIII heavy chain and the other the light chain, in a murine model of hemophilia A. The Results report improved FVIII activity and shortened bleeding time in treated knockout mice, demonstrating partial phenotypic correction. (LLM, conf=0.94)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- 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
“in mdx mice (a mouse model of Duchenne muscular dystrophy) gene transfer with AAV vectors encoding microdystrophin provides significant, although not optimal therapeutic benefit. 40-42”
What the sources say
- Supportedcites [40] source
The Results (page not supplied) report significant improvements in cardiac function after AAV-microdystrophin treatment of aged female mdx mice. They also state that some measures did not return to wild-type levels, supporting the qualification that the benefit was not optimal. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [41] source
- Not checked — no full text of the sourcecites [42] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“During transduction, rAAV genomes have been shown to form circular or linear (mostly) head-to-tail arrays of viral genomes, 14,50,51”
What the sources say
- Partly supportedcites [14] Duan D, 1998, J Virol sourceExperimental — accuracy not yet measured
The Results and Discussion report head-to-tail circular rAAV concatemers in infected muscle tissue. The Results say that linear integrated concatemers had previously been hypothesized, whereas this study's data suggest the persistent genomes are circular and episomal. The claim's assertion that linear arrays have been shown to form is therefore not established by this paper. (LLM, conf=0.86)
- Partly supportedcites [50] sourceExperimental — accuracy not yet measured
The Abstract reports circular rAAV intermediates after transduction and describes monomer and multimer head-to-tail conformations. The paper does not establish that linear arrays formed during transduction are mostly head-to-tail; its statement about the most abundant head-to-tail form is limited to a model of circular genomes. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [51] source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“it has been reported that the CMV promoter can be shortened to 173 bp without apparent loss in expression levels-at least in certain cell types. 35”
What the sources say
- Supportedcites [35] source
The Results and Discussion report that the 173CMV promoter produced β-gal activity equivalent to the full-length CMVie enhancer/promoter in A549 cells and primary airway epithelial cultures. It produced less activity in H441 cells, consistent with the claim’s qualification that expression was maintained only in certain cell types. (LLM, conf=0.94)
hedged- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“AAV vectors with two complementary ITRs can form circular concatamers. 13-16”
What the sources say
- Not checked — no full text of the sourcecites [13] source
- Supportedcites [14] Duan D, 1998, J Virol source
The Results describe recombinant AAV circular intermediates with two ITRs in a head-to-tail arrangement and identify larger circular multimers containing approximately three AAV genomes. This supports the claim that AAV vectors with ITRs can form circular concatemers. Page numbers are unavailable in our copy. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [15] source
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says recombinant AAV derivatives can assume circular multimeric structures, supporting the circular-concatamer part of the claim. It also suggests that ITRs contribute to circle formation, but does not establish the specific condition of two complementary ITRs. The concatameric arrays described in the Results were linear products of rolling-circle amplification, not circular vector concatamers. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“overexpression of dysferlin by intramuscular injection of AAV8 encoding dysferlin from either a single oversized vector or from two overlapping vectors showed a * 10-fold higher expression of dysferlin with the dual-vector system. 45”
What the sources say
- Partly supportedcites [45] sourceExperimental — accuracy not yet measured
The Results section on intramuscular injection reports higher dysferlin expression with the overlapping dual-vector Set 3 than with the oversized fAAV vector. It gives the increase as approximately 4–10-fold relative to Batch 2 fAAV, so the citing sentence’s approximately 10-fold figure omits the lower end of the reported range. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Partly supported
- It may state two separate claims as one. 26
- Probably not a substantial claim. 8
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“it is generally believed that rAAV genomes persist episomally as mostly circular concatamers 16 in postmitotic cells, leading to long-term transgene expression.”
What the sources say
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports that naturally acquired wild-type AAV persists mainly as circular episomes in human tissues and says this is consistent with circular episomal forms of recombinant AAV vectors. It does not establish that recombinant genomes are mostly circular concatamers in postmitotic cells or that this form leads to long-term transgene expression. The concatameric forms described in the Results are products of rolling-circle amplification, not evidence that the persisting genomes have that structure. (LLM, conf=0.86)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- 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
“However, the finding that AAV5 capsids could package intact genomes of up to 8.9 kb in length was not supported by further studies, which found that such genomes were truncated and that the packaging capacity of AAV was still limited to genomes substantially smaller than 8.9 kb. 30-32”
What the sources say
- Not checked — no full text of the sourcecites [30] source
- Supportedcites [31] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [32] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Samulski and colleagues reported that transduction by oversized vectors depends on the activity of the strand-annealing protein Rad51C but is independent of the catalytic subunit of DNA-dependent protein kinase. 34”
What the sources say
- Supportedcites [34] source
The Results (p. 2210) report a 50-fold decrease in fragment AAV (fAAV) transduction without Rad51C, while loss of DNA-PKcs did not significantly alter it. The paper distinguishes these oversized-vector fragments from split AAV vectors, which do depend on DNA-PKcs. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“similar to dual overlapping vectors, trans-splicing vector-pair systems do not always outperform single oversized vectors. For instance, Hirsch et al. 34 reported higher expression both in vitro (C2C12 myoblasts and myotubules) and in vivo with a single oversized genome vector when compared with a transsplicing system. 34”
What the sources say
- Supportedcites [34] source
In “Comparison of AAV large-gene transduction strategies” (pp. 2209–2210), the paper reports significantly greater transduction with the oversized fragment AAV vector than with split (trans-splicing) AAV in C2C12 myoblasts and myotubules. In vivo, it reports fourfold higher luciferase activity in mouse muscle at the lower dose and sevenfold greater transduction efficiency in the retina. Muscle activity was similar at the higher dose, consistent with the claim’s qualification that trans-splicing systems do not always outperform oversized vectors. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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
“The trans-splicing method to expand the size of ORFs that can be successfully expressed using AAV vectors was originally developed in the laboratory of John Engelhardt 52,53 and has since been utilized in several studies with varying success (e.g., refs. 53-57 ).”
What the sources say
- Not checked — no full text of the sourcecites [52] source
- Supportedcites [53] source
The Abstract (page not provided) says the authors developed a two-vector trans-splicing approach to deliver transgenes beyond AAV’s packaging limit and demonstrated functional expression. John Engelhardt is among the paper’s authors. The sentence cites other studies for its separate claim about subsequent uses. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [54] source
- Not checked — no full text of the sourcecites [55] source
- Not checked — no full text of the sourcecites [56] source
- Not checked — no full text of the sourcecites [57] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Consistent with their in vitro results, dual trans-splicing and hybrid-AK vectors successfully transduced mouse and pig photoreceptors and were found to improve the phenotype of mouse models of STGD and USH1B. 46”
What the sources say
- Supportedcites [46] Trapani I, 2014, EMBO Mol Med source
The Results section, “Dual AAV TS and hybrid AK but not OV vectors transduce mouse and pig photoreceptors” (page unavailable), reports photoreceptor transduction in both species. The Results section, “Dual AAV vectors improve the retinal phenotype of STGD and USH1B mouse models” (page unavailable), reports improved retinal measures after either vector treatment in the STGD and USH1B models. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, however, both Dyka et al. 47 and Trapani et al. 46 observed the expression of both full-length and smaller fragments (of defined size) of MYO7A and or ABCA4 with the hybrid dual-vector system.”
What the sources say
- Supportedcites [47] source
The Results section (‘Comparison of relative efficiencies and specificity of full-length MYO7A expression,’ Fig. 4; page not supplied) reports full-length MYO7A from the AP hybrid platform and a defined, less-than-full-length peptide detectable on Western blot. This confirms the observation attributed to Dyka et al.; the claim about Trapani et al. is not assessed against this source. (LLM, conf=0.92)
- Supportedcites [46] Trapani I, 2014, EMBO Mol Med source
The Results ('Dual AAV vectors allow high levels of transduction in vitro'; page unavailable) report full-length ABCA4 and MYO7A proteins from hybrid dual vectors. The Results on the mouse models and the Discussion (pages unavailable) also report smaller MYO7A proteins from vector halves in vitro, while specifying that only full-length proteins were detected in the retina in vivo. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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
“Because such a circularization is an intramolecular event, it is probably more efficient than intermolecular concatemerization. 34,49,58”
What the sources say
- Supportedcites [34] source
The Introduction (p. 2205) describes circularization as intramolecular, rapid, and initially the primary persistent form of rAAV DNA, while intermolecular linkages occur to a lesser extent. It also says AAV genomes preferentially form circular monomers, supporting the claim’s qualified comparison. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [49] source
- Not checked — no full text of the sourcecites [58] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“But they also demonstrate that there is no one-fits-all dual-vector system, and that the nature of the artificial recombinogenic regions and the tissue being targeted can drastically influence the efficiency of transduction with such hybrid split AAV vector systems. 46”
What the sources say
- Supportedcites [46] Trapani I, 2014, EMBO Mol Med source
The Results (Dual AAV vectors allow high levels of transduction in vitro; page unavailable) report that hybrid AP produced the lowest transgene-expression levels, while hybrid AK was more efficient. The Discussion (page unavailable) reports that hybrid AK outperformed trans-splicing in mouse photoreceptors but not retinal pigment epithelium, and suggests that differences in AP sequences may explain differing transduction levels across studies. Together, these passages support the claim that recombinogenic-region design and target tissue influence efficiency. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
In the paper
“Nonetheless, AAV5vectorswith the supposedly 8.9kb large viral genomes clearly did result in expression of ABCA4, MYO7A, and CEP290 from genomes whose intact genome length would be 8.9, 8.1, and 8.9 kb in size, respectively.”
What the sources say
- Not checked — no full text of the sourcecites [29] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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 efficiency of reconstituting a genome with a full-length expression cassette is likely dependent on the number of nuclear copies of vector genomes.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“vectors larger than 5.2 kb were found to be packaged very inefficiently, and transduction efficiencies of these oversized vectors were dramatically reduced. 26”
What the sources say
- Not checked — no full text of the sourcecites [26] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Hermonat et al. concluded that the maximum genome size that allowed the recovery of significant amounts of infectious virus was approximately 5.6 kb. 25”
What the sources say
- Not checked — no full text of the sourcecites [25] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
In the paper
“Southern blot hybridization revealed that purportedly oversized packaged genomes were in fact truncated, and the authors suggested that the truncated fragments could assemble thus restoring the full-length expression cassette.”
What the sources say
- Not checked — no full text of the sourcecites [30] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“both AP expression and LacZ expression were detected in mdx muscle of adult mice injected with such AAV vector preparations.”
What the sources say
- Not checked — no full text of the sourcecites [30] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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 combination of AAV serotype and tissue/cell type might have a particularly profound effect on the efficiency of transduction with overlapping systems because for dual -vector approaches to be successful, a high level of co-transduction-preferably with multiple copies of each vector-is essential for efficient transgene overexpression.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Although the overall levels of minidystrophin expression were lower than in wildtype muscles, there was an improvement in limb muscle physiological performance. 42”
What the sources say
- Not checked — no full text of the sourcecites [42] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“They could demonstrate improved expression with vectors containing this artificial intron when compared with trans-splicing vectors that contained a poor splice site; however, expression was not as efficient as with the best trans-splicing vectors using natural dystrophin exon/intron sites. 62”
What the sources say
- Not checked — no full text of the sourcecites [62] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“As expected, successful trans-splicing resulted in the expression of full-length dysferlin, leading to improved membrane repair capacity, muscle histology, and muscle function. 63”
What the sources say
- Not checked — no full text of the sourcecites [63] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Expression from the single vector with a ''regular size genome'' and the hybrid vectors was strong and widespread, whereas expression from the transsplicing, and especially the overlapping vectors, was not as effective.”
What the sources say
- Not checked — no full text of the sourcecites [65] source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Although full-length dystrophin could be detected with this three-vector systemboth in vitro and in vivo -the expression was very weak.”
What the sources say
- Not checked — no full text of the sourcecites [70] source
plain- Asserted: passes — The authors put it forward as true.
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It 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
“Maybe the firmest conclusion that can be drawn from the vast trove of available literature is that there is no one ideal system, and that the choice of what the best vector system is can vary drastically depending on the transgene and the cell type/ tissue targeted by the AAV vectors.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may be too vague to check against evidence.
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
“{ Strictly speaking, trans-splicing and hybrid vector systems do not rely on trans-splicing of pre-mRNAs. Instead, in both systems a full-length mRNA is generated whose manufactured intron is then removed by regular cis -splicing to join the two exons.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“When b -galactosidase activity from muscle tissue was quantified, the hybrid vectors yielded 81% of the activity of the single ''regular size genome'' vector, which was significantly greater than the b -galactosidase activity from overlapping (34%) or trans-splicing vectors (62%).”
What the sources say
- Not checked — no full text of the sourcecites [65] source
plain- Asserted: passes — The authors put it forward as true.
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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
“Either pathway results in LacZ expression.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It 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
“Not only are such fragments likely nonfunctional, but they also could be dominant-negative and/or toxic.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
“The two vectors of this hybrid system can lead to the transcription of full-length mRNA by one of two ways: either through AP -mediated homologous recombination or via ITR-mediated head-to-tail concatamerization (Fig. 2).”
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Thus, the hybrid vector outperformed both the overlapping and trans-splicing variants, which only expressed levels of approximately 25% and 50%, respectively, of the original construct.”
What the sources say
- Not checked — no full text of the sourcecites [65] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It 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
“In this context, the most important components of a dual hybrid vector system to be taken into account appear to be the choice of the recombinogenic region and the nature of splice donor and acceptor signals.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
Citations
Cites
Effect of genome size on AAV vector packaging
Wu, Z., Yang, H., & Colosi, P. (2010) · Molecular Therapy · doi:10.1038/mt.2009.255 · Cited by 1,029
Adenovirus-Associated Defective Virus Particles
Atchison, R. W., Casto, B. C., & Hammon, W. M. (1965) · Science · doi:10.1126/science.149.3685.754 · Cited by 1,004
Site-specific integration by adeno-associated virus.
Kotin, R. M., Siniscalco, M., Samulski, R. J., Zhu, X. D., Hunter, L., Laughlin, C. A., McLaughlin, S., Muzyczka, N., Rocchi, M., & Berns, K. I. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.6.2211 · Cited by 906
Site-specific integration by adeno-associated virus.
Linden, R. M., Ward, P., Giraud, C., Winocour, E., & Berns, K. I. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.21.11288 · Cited by 805
Targeted integration of adeno‐associated virus (AAV) into human chromosome 19.
Samulski, R. J., Zhu, X., Xiao, X., Brook, J. D., Housman, D. E., Epstein, N., & Hunter, L. A. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb04964.x · Cited by 783
Nucleotide sequence and organization of the adeno-associated virus 2 genome
Srivastava, A., Lusby, E. W., & Berns, K. I. (1983) · Journal of Virology · doi:10.1128/jvi.45.2.555-564.1983 · Cited by 721
AAV-Mediated Gene Therapy for Research and Therapeutic Purposes
Samulski, R. J., & Muzyczka, N. (2014) · Annual Review of Virology · doi:10.1146/annurev-virology-031413-085355 · Cited by 609
Quantitative analysis of the packaging capacity of recombinant adeno-associated virus
Dong, J.-Y., Fan, P.-D., & Frizzell, R. A. (1996) · Human Gene Therapy · doi:10.1089/hum.1996.7.17-2101 · Cited by 583
HOGGAN, M. D., Blacklow, N. R., & Rowe, W. P. (1966) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.55.6.1467 · Cited by 540
Duan, D., Sharma, P., Yang, J., Yue, Y., Dudus, L., Zhang, Y., Fisher, K. J., & Engelhardt, J. F. (1998) · Journal of Virology · doi:10.1128/jvi.72.11.8568-8577.1998 · Cited by 522
Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas
Nault, J.-C., Datta, S., Imbeaud, S., Franconi, A., Mallet, M., Couchy, G., Letouzé, E., Pilati, C., Verret, B., Blanc, J.-F., et al. (2015) · Nature Genetics · doi:10.1038/ng.3389 · Cited by 489
Nakai, H., Yant, S. R., Storm, T. A., Fuess, S., Meuse, L., & Kay, M. A. (2001) · Journal of Virology · doi:10.1128/jvi.75.15.6969-6976.2001 · Cited by 478
Protein length in eukaryotic and prokaryotic proteomes
Brocchieri, L. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki615 · Cited by 414
Lai, Y., Thomas, G. D., Yue, Y., Yang, H. T., Li, D., Long, C., Judge, L. M., Bostick, B., Chamberlain, J. S., Terjung, R. L., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36612 · Cited by 396
Synthesis, processing, and secretion of recombinant human factor VIII expressed in mammalian cells.
Kaufman, R. J., Wasley, L. C., & Dorner, A. J. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68793-9 · Cited by 388
Trans-splicing vectors expand the utility of adeno-associated virus for gene therapy
Yan, Z., Zhang, Y., Duan, D., & Engelhardt, J. F. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.12.6716 · Cited by 305
Allocca, M., Doria, M., Petrillo, M., Colella, P., Garcia-Hoyos, M., Gibbs, D., Kim, S. R., Maguire, A., Rex, T. S., Di Vicino, U., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34316 · Cited by 292
Tratschin, J.-D., Miller, I. L., & Carter, B. J. (1984) · Journal of Virology · doi:10.1128/jvi.51.3.611-619.1984 · Cited by 272
Effective delivery of large genes to the retina by dual AAV vectors
Trapani, I., Colella, P., Sommella, A., Iodice, C., Cesi, G., de Simone, S., Marrocco, E., Rossi, S., Giunti, M., Palfi, A., et al. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201302948 · Cited by 269
Overcoming adeno-associated virus vector size limitation through viral DNA heterodimerization
Sun, L., Li, J., & Xiao, X. (2000) · Nature Medicine · doi:10.1038/75087 · Cited by 267
Duan, D., Yue, Y., & Engelhardt, J. F. (2001) · Molecular Therapy · doi:10.1006/mthe.2001.0456 · Cited by 262
Intracellular transport of recombinant adeno-associated virus vectors
Nonnenmacher, M., & Weber, T. (2012) · Gene Therapy · doi:10.1038/gt.2012.6 · Cited by 258
Self-citationCharacterization of Adeno-Associated Virus Genomes Isolated from Human Tissues
Schnepp, B. C., Jensen, R. L., Chen, C.-L., Johnson, P. R., & Clark, K. R. (2005) · Journal of Virology · doi:10.1128/jvi.79.23.14793-14803.2005 · Cited by 231
Characterization of Genome Integrity for Oversized Recombinant AAV Vector
Dong, B., Nakai, H., & Xiao, W. (2010) · Molecular Therapy · doi:10.1038/mt.2009.258 · Cited by 230
Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors
Lai, Y., Yue, Y., Liu, M., Ghosh, A., Engelhardt, J. F., Chamberlain, J. S., & Duan, D. (2005) · Nature Biotechnology · doi:10.1038/nbt1153 · Cited by 224
Ho, M. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh212 · Cited by 201
Duan, D., Yue, Y., Yan, Z., & Engelhardt, J. F. (2000) · Nature Medicine · doi:10.1038/75080 · Cited by 200
Nakai, H., Storm, T. A., & Kay, M. A. (2000) · Journal of Virology · doi:10.1128/jvi.74.20.9451-9463.2000 · Cited by 194
Straus, S. E., Sebring, E. D., & Rose, J. A. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.3.742 · Cited by 194
Rose, J. A., Berns, K. I., Hoggan, M. D., & Koczot, F. J. (1969) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.64.3.863 · Cited by 179
Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer
Lostal, W., Bartoli, M., Bourg, N., Roudaut, C., Bentaïb, A., Miyake, K., Guerchet, N., Fougerousse, F., McNeil, P., & Richard, I. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq065 · Cited by 173
Evidence for the Failure of Adeno-associated Virus Serotype 5 to Package a Viral Genome ≥8.2 kb
Lai, Y., Yue, Y., & Duan, D. (2010) · Molecular Therapy · doi:10.1038/mt.2009.256 · Cited by 166
Ghosh, A., Yue, Y., Lai, Y., & Duan, D. (2008) · Molecular Therapy · doi:10.1038/sj.mt.6300322 · Cited by 161
Recombinant Adeno-Associated Viral Vectors Mediate Long-Term Transgene Expression in Muscle
Clark, K. R., Sferra, T. J., & Johnson, P. R. (1997) · Human Gene Therapy · doi:10.1089/hum.1997.8.6-659 · Cited by 153
Host Cell DNA Repair Pathways in Adeno-Associated Viral Genome Processing
Choi, V. W., McCarty, D. M., & Samulski, R. J. (2006) · Journal of Virology · doi:10.1128/jvi.00841-06 · Cited by 144
Dyka, F. M., Boye, S. L., Chiodo, V. A., Hauswirth, W. W., & Boye, S. E. (2014) · Human Gene Therapy Methods · doi:10.1089/hgtb.2013.212 · Cited by 128
Halbert, C. L., Allen, J. M., & Miller, A. D. (2002) · Nature Biotechnology · doi:10.1038/nbt0702-697 · Cited by 121
Gene therapy enters the pharma market: The short story of a long journey
Büning, H. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201202291 · Cited by 120
Gregorevic, P., Blankinship, M. J., Allen, J. M., & Chamberlain, J. S. (2008) · Molecular Therapy · doi:10.1038/mt.2008.28 · Cited by 120
Retinal gene therapy with a large MYO7A cDNA using adeno-associated virus
Lopes, V. S., Boye, S. E., Louie, C. M., Boye, S., Dyka, F., Chiodo, V, Fofo, H., Hauswirth, W. W., & Williams, D. S. (2013) · Gene Therapy · doi:10.1038/gt.2013.3 · Cited by 112
Yan, Z., Zak, R., Zhang, Y., & Engelhardt, J. F. (2005) · Journal of Virology · doi:10.1128/jvi.79.1.364-379.2005 · Cited by 107
Ostedgaard, L. S., Rokhlina, T., Karp, P. H., Lashmit, P., Afione, S., Schmidt, M., Zabner, J., Stinski, M. F., Chiorini, J. A., & Welsh, M. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409845102 · Cited by 105
Koo, T., Popplewell, L., Athanasopoulos, T., & Dickson, G. (2014) · Human Gene Therapy · doi:10.1089/hum.2013.164 · Cited by 104
Burton, M., Nakai, H., Colosi, P., Cunningham, J., Mitchell, R., & Couto, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12725 · Cited by 104
Berns, K. I., & Adler, S. (1972) · Journal of Virology · doi:10.1128/jvi.9.2.394-396.1972 · Cited by 101
Structural Analysis of Adeno-Associated Virus Transduction Circular Intermediates
Duan, D., Yan, Z., Yue, Y., & Engelhardt, J. F. (1999) · Virology · doi:10.1006/viro.1999.9821 · Cited by 100
AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models
Sondergaard, P. C., Griffin, D. A., Pozsgai, E. R., Johnson, R. W., Grose, W. E., Heller, K. N., Shontz, K. M., Montgomery, C. L., Liu, J., Clark, K. R., et al. (2015) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.172 · Cited by 99 · cited 2×
“provided another example of the successful use of an overlapping vector system to overexpress genes that exceed the packaging capacity of a single AAV vector.(44) In this study, the authors found high levels of muscle transduction with two overlapping AAV vectors encoding a dysferlin expression cassette (dysferlin has…”
BackgroundMethodHermonat, P. L., Quirk, J. G., Bishop, B. M., & Han, L. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00311-6 · Cited by 98
Reich, S. J., Auricchio, A., Hildinger, M., Glover, E., Maguire, A. M., Wilson, J. M., & Bennett, J. (2003) · Human Gene Therapy · doi:10.1089/10430340360464697 · Cited by 96
Zhang, Y., & Duan, D. (2012) · Human Gene Therapy · doi:10.1089/hum.2011.131 · Cited by 95
Ghosh, A., Yue, Y., & Duan, D. (2011) · Human Gene Therapy · doi:10.1089/hum.2010.122 · Cited by 95
Gene Therapy of mdx Mice With Large Truncated Dystrophins Generated by Recombination Using rAAV6
Odom, G. L., Gregorevic, P., Allen, J. M., & Chamberlain, J. S. (2011) · Molecular Therapy · doi:10.1038/mt.2010.205 · Cited by 95
Trapani, I., Toriello, E., de Simone, S., Colella, P., Iodice, C., Polishchuk, E. V., Sommella, A., Colecchi, L., Rossi, S., Simonelli, F., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv386 · Cited by 94
Little Vector, Big Gene Transduction: Fragmented Genome Reassembly of Adeno-associated Virus
Hirsch, M. L., Agbandje‐McKenna, M., & Samulski, R. J. (2010) · Molecular Therapy · doi:10.1038/mt.2009.280 · Cited by 86
AAV-microdystrophin Therapy Improves Cardiac Performance in Aged Female mdx Mice
Bostick, B., Shin, J.-H., Yue, Y., & Duan, D. (2011) · Molecular Therapy · doi:10.1038/mt.2011.154 · Cited by 85
Expression of Human Factor VIII by Splicing between Dimerized AAV Vectors
Chao, H., Sun, L., Bruce, A., Xiao, X., & Walsh, C. E. (2002) · Molecular Therapy · doi:10.1006/mthe.2002.0607 · Cited by 75
Arrangement of nucleotide sequences in adeno-associated virus DNA
Gerry, H. W., Kelly, T. J., & Berns, K. I. (1973) · Journal of Molecular Biology · doi:10.1016/0022-2836(73)90001-6 · Cited by 69
Ghosh, A., Yue, Y., & Duan, D. (2006) · The Journal of Gene Medicine · doi:10.1002/jgm.835 · Cited by 69
Oversized AAV Transductifon Is Mediated via a DNA-PKcs-independent, Rad51C-dependent Repair Pathway
Hirsch, M. L., Li, C., Bellon, I., Yin, C., Chavala, S., Pryadkina, M., Richard, I., & Samulski, R. J. (2013) · Molecular Therapy · doi:10.1038/mt.2013.184 · Cited by 62
Molecular structure of adeno-associated virus variant DNA.
de la Maza, L. M., & Carter, B. J. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)85870-2 · Cited by 61
Spliceosome-Mediated RNA Trans-splicing
Yang, Y., & Walsh, C. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.09.006 · Cited by 59
Pryadkina, M., Lostal, W., Bourg, N., Charton, K., Roudaut, C., Hirsch, M. L., & Richard, I. (2015) · Molecular Therapy - Methods & Clinical Development · doi:10.1038/mtm.2015.9 · Cited by 53
Hu, C., & Lipshutz, G. S. (2012) · Gene Therapy · doi:10.1038/gt.2011.200 · Cited by 48 · cited 1×
“More recently, Hu and Lipshutz used a similar dual-vector strategy to demonstrate phenotypic correction of FVIII deficiency in a mouse model of hemophilia A.(39) An example of successfully truncating a gene was reported by Ostedgaard et al.”
BackgroundEfficacy of Codelivery of Dual AAV2/5 Vectors in the Murine Retina and Hippocampus
Palfi, A., Chadderton, N., McKee, A. G., Blanco Fernandez, A., Humphries, P., Kenna, P. F., & Farrar, G. J. (2012) · Human Gene Therapy · doi:10.1089/hum.2011.142 · Cited by 42
Yan, Z., Lei-Butters, D. C. M., Zhang, Y., Zak, R., & Engelhardt, J. F. (2007) · Human Gene Therapy · doi:10.1089/hum.2006.128 · Cited by 41
Synthetic Intron Improves Transduction Efficiency of Trans -Splicing Adeno-Associated Viral Vectors
Lai, Y., Yue, Y., Liu, M., & Duan, D. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.1036 · Cited by 37
McFarland, T. J., Zhang, Y., Atchaneeyaskul, L.-O., Francis, P., Stout, J. T., & Appukuttan, B. (2006) · Plasmid · doi:10.1016/j.plasmid.2005.11.005 · Cited by 26
Adenovirus associated viruses.
HOGGAN, M. D. (1970) · PubMed · Cited by 25
Diffoot, N., Chen, K. C., Bates, R. C., & Lederman, M. (1993) · Virology · doi:10.1006/viro.1993.1040 · Cited by 23
Physicochemical characteristics of the DNA of parvovirus Lu III
Siegl, G. (1973) · Archiv für die gesamte Virusforschung · doi:10.1007/bf01556150 · Cited by 22
Isolation of a goose parvovirus from swan and its molecular characteristics
SHAO, H., LV, Y., YE, J., QIAN, K., JIN, W., & QIN, A. (2014) · Acta virologica · doi:10.4149/av_2014_02_194 · Cited by 18
(1985) · Europe PMC (PubMed Central) · Cited by 14
Protein trans- splicing as a protein ligation tool to study protein structure and function
Aranko, A. S., & Volkmann, G. (2011) · BioMolecular Concepts · doi:10.1515/bmc.2011.014 · Cited by 10
Lai, Y., Yue, Y., Liu, M., & Duan, D. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.ft-246 · Cited by 1
Yan, Z., Lei-Butters, D. C. M., Zhang, Y., Žák, R., & Engelhardt, J. F. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.ft-274 · Cited by 1
Lostal, W., Bartoli, M., Bourg, N., Roudaut, C., Bentaib, A., Guerchet, N., Fougerousse, F., McNeil, P. L., & Richard, I. (2009) · Neuromuscular Disorders · doi:10.1016/j.nmd.2009.06.357
Duan, D., Sharma, P., Yang, J., et al. (1999) · Journal of Virology · doi:10.1128/jvi.73.1.861-861.1999
Research works printed but not linked: 2
- Hoggan MD, 1970, Prog Med Virol, 12, 211
- Wong FC, 1985, Can J Comp Med, 49, 50
Cited by
Sorted by citations
Adeno-Associated Virus (AAV) as a Vector for Gene Therapy
Naso, M. F., Tomkowicz, B., Perry, W. L., & Strohl, W. R. (2017) · BioDrugs · doi:10.1007/s40259-017-0234-5 · Cited by 1,362
“) [12], should be considered in these cases.”
BackgroundCRISPR-Cas9 DNA Base-Editing and Prime-Editing
Kantor, A., McClements, M., & MacLaren, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176240 · Cited by 462
“For many diseases, vector-mediated gene delivery is not feasible due to the cargo limit of viral vectors as well as the expression of multiple heterogeneous variants of the target gene [97,98].”
BackgroundSystemic AAV vectors for widespread and targeted gene delivery in rodents
Challis, R. C., Kumar, S. R., Chan, K. Y., Challis, C., Beadle, K., Jang, M. J., Kim, H. M., Rajendran, P. S., Tompkins, J. D., Shivkumar, K., et al. (2019) · Nature Protocols · doi:10.1038/s41596-018-0097-3 · Cited by 449
Al‐Moyed, H., Cepeda, A. P., Jung, S., Moser, T., Kügler, S., & Reisinger, E. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809396 · Cited by 230
“The correct reassembly of the full-length expression cassette in the nuclei of target cells results in the production of full-length mRNA and protein (Yan et al, 2000; Duan et al, 2001; Chamberlain et al, 2016).”
BackgroundStrategies for nonviral nanoparticle‐based delivery of CRISPR/Cas9 therapeutics
Chen, F., Alphonse, M., & Liu, Q. (2020) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1609 · Cited by 197
Metadata
- Authors
- Chamberlain, K., Riyad, J. M., & Weber, T.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Weber, Thomas
- Venue
- Human Gene Therapy Methods
- Publisher
- SAGE Publications
- Published
- 2016-02
- Volume
- 27
- Issue
- 1
- Pages
- 1-12
- ISSN
- 1946-6536 (ISSN-L)
- 1946-6544
- PMC
- PMC4761816
- OpenAlex
- W2280525353
- Semantic Scholar
- 2025d56e2cca1328dc2aed3bfe2dab7881704456
- Cited by
- 141
- References
- 74
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 8 · 2023: 13 · 2022: 17 · 2021: 22 · 2020: 20 · 2019: 12 · 2018: 13 · 2017: 12 · 2016: 4
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Gene Therapy Methods (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation Leducq (14CVD03)
- National Institutes of Health (HL112324)
- National Heart, Lung, and Blood Institute (P50HL 112324, HL117505, R01HL117505, HL112324)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Keywords
- recombinant adeno-associated virus vectors, co-infection, transgene expression, gene therapy vectors, transduction efficiency
- MeSH terms
- Dependovirus, Animals, DNA, Viral, Genetic Vectors, Humans, Genetic Therapy, Gene Expression, Genome, Viral, Gene Transfer Techniques, Virus Assembly, Transgenes, Capsid Proteins, Genome Size
About these checks
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.
A language model drew the claims from the paper on 2026-10-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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