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
AI snapshot
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.
Integrity signals
Registry
Cites
Statistics
Verification
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.
- Based: passes — The paper gives a reason why it holds.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Based: passes — The paper gives a reason why it holds.
- 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.
- 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.
- 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.
- 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.
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.
- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This suggests that the maximum packaging capacity of members of the Parvoviridae family is approximately 4.5-5.5 kb.”
What the sources say
- Partly supportedcites [8] sourceExperimental — accuracy not yet measured
The Introduction reports that AAV-1 DNA in a particle should not exceed 1.7 × 10⁶ daltons, and the paper describes one DNA strand per AAV virion. These passages support an approximate genome size for AAV, but they do not establish a 4.5–5.5 kb maximum packaging capacity for the Parvoviridae family. No page number is supplied in our copy. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [18] de la Maza LM, 1980, J Biol Chem source
- Partly supportedcites [19] Srivastava A, 1983, J Virol sourceExperimental — accuracy not yet measured
The available passage reports that the adeno-associated virus 2 genome is 4,675 nucleotides long, within the claimed 4.5–5.5 kb range. It does not establish a maximum packaging capacity for AAV2 or for the Parvoviridae family; searches for packaging capacity and encapsidation found no such passage. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [20] source
- Partly supportedcites [21] sourceExperimental — accuracy not yet measured
The Introduction identifies goose parvovirus as a member of Parvoviridae and gives its genome length as approximately 5,106 nt; the Results and Discussion give 5,050 nt for the swan isolate. Those lengths fall within the claimed range, but the paper does not establish a maximum packaging capacity for the family. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [22] Wong FC, 1985, Can J Comp Med
- Not checked — no full text of the sourcecites [23] source
- Not checked — no full text of the sourcecites [24] source
hedged- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Dyka et al. demonstrated that the expression of MYO7A in photoreceptors was stronger with a dual overlapping vector system when compared with a single oversized vector. 47”
What the sources say
- Partly supportedcites [47] sourceExperimental — accuracy not yet measured
The Results section on MYO7A expression in mouse retina reports expression in photoreceptors with both the simple-overlap dual vector and the single oversized fAAV vector. It also reports that simple-overlap MYO7A was detectable by Western blot while fAAV MYO7A was not, but that comparison used whole-retina protein, not a photoreceptor-specific measure of expression strength. No page number is available in our copy. (LLM, conf=0.82)
boosteddirect- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“a study investigating the efficacy of AAV2 and AAV5 vectors to deliver MYO7A, mutations in which cause Usher syndrome 1b, to mouse retinas found the dual overlapping vectors to be less efficacious than a single vector with a genome of * 7.9 kb in size. 48”
What the sources say
- Partly supportedcites [48] sourceExperimental — accuracy not yet measured
The Introduction and Discussion report that overlapping dual AAV2 vectors were substantially less effective than single AAV2 or AAV5 vectors at delivering functional MYO7A to retinas of Myo7a-mutant mice. The Results describe the single vector’s 6.7-kb MYO7A cDNA and say the construct exceeds nominal AAV carrying capacity by about 2 kb, but our copy does not establish the claimed approximately 7.9-kb genome size. (LLM, conf=0.85)
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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Wu et al., 32 who found that packaged vector genomes never exceeded 5.2 kb in length”
What the sources say
- Supportedcites [32] source
The Introduction states that the packaged vector genome DNAs never exceeded 5.2 kb for any plasmid-encoded vector size or capsid type tested. The Results likewise place the upper packaging limit at approximately 5.2 kb. (LLM, conf=0.94)
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.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“plasmid encoded vectors exceeding 5.2 kb existed as a mixture of genomes that were heterogeneous in size.”
What the sources say
- Supportedcites [32] source
The Introduction states that packaged genome DNA from plasmid-encoded vectors exceeding 5.2 kb formed a heterogeneous population with a broad size distribution. The Results section, under “Estimation of the size limit for efficient packaging of intact vector genomes,” reports the same finding. (LLM, conf=0.94)
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.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the authors found high levels of muscle transduction with two overlapping AAV vectors encoding a dysferlin expression cassette ( dysferlin has a cDNA size of 6.5 kb and the overlap between the two vectors was * 1kb). 44”
What the sources say
- Supportedcites [44] source
The Introduction describes an approximately 6.5 kb dysferlin cDNA, and the Results (AAVrh.74.Dysferlin.DV) describe two vectors with a 1 kb overlap. The Results (gene transfer to limb muscles) report dysferlin expression in 74%–90.5% of muscle fibers after intramuscular delivery in dysferlin-deficient mice, supporting the claim of high muscle transduction. (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.
- 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
“One limitation of rAAVs is that their genome-packaging capacity is only * 5kb.”
- Also stated in: § EXPRESSING TRANSGENES THAT EXCEED THE PACKAGING CAPACITY OF AAV CAPSIDS · p. 3 · plain
“In fact, these reports confirmed earlier studies that the packaging capacity of AAV is roughly 5 kb.”
What the sources say
- Not checked — no full text of the sourcecites [30] source
- Supportedcites [31] source
The Discussion states that DNA inside the AAV capsid is less than 5 kb and concludes that an AAV capsid cannot accommodate more than 5,000 nucleotides. This supports the citing sentence’s approximate 5-kb genome-packaging limit. (LLM, conf=0.94)
- Supportedcites [32] source
The Results section estimates the upper limit for packaging intact genomes in AAV2 and AAV5 capsids at approximately 5.2 kb. The Discussion reports that packaged DNA did not exceed approximately 5.2 kb across the AAV2, AAV5, and AAV8 capsids tested, supporting the citing sentence’s approximate 5 kb figure. (LLM, conf=0.94)
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.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § EXPRESSING TRANSGENES THAT EXCEED THE PACKAGING CAPACITY OF AAV CAPSIDS · p. 3 · plain
Every source the paper cites for this claim was checked and supports it.
In the paper
“it has been reported that the nature of the transgene 47 and tissue/cell type (possibly because of differences in DNA repair pathways) 45,46 can influence the efficiency of dual vectors.”
What the sources say
- Supportedcites [45] source
The Discussion (page unavailable in our copy) reports that dual-AAV vector efficiency differed when the overlapping sequence changed, supporting the transgene-sequence portion attributed to this source. It also discusses differences between cell types and tissue-specific DNA-repair factors, although the citing sentence assigns that portion to references 45 and 46. (LLM, conf=0.89)
- Supportedcites [46] Trapani I, 2014, EMBO Mol Med source
The Discussion reports that dual-vector transduction differed between photoreceptors and retinal pigment epithelium, and that an advantage seen with the large ABCA4 and MYO7A transgenes was not seen with the small EGFP transgene. This supports the attributed point that cell type and transgene can influence dual-vector efficiency; the paper does not establish the parenthetical DNA-repair explanation. (LLM, conf=0.90)
- Supportedcites [47] source
The Discussion reports that simple-overlap vectors expressed MYO7A differently from ABCA4 and links their performance to the gene sequence used for overlap. This supports the transgene-related point attributed to this source; the tissue/cell-type point is assigned to other citations. (LLM, conf=0.92)
plainconditional- 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.
- 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 so-called microdystrophin variant can be packaged in a single AAV vector”
What the sources say
- Supportedcites [40] source
The Discussion states that synthetic microgenes can fit into a single AAV virion. The Materials and Methods section also says this study packaged its microdystrophin expression cassette in AAV-9. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [41] source
- Not checked — no full text of the sourcecites [42] 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.
- Based: passes — The paper gives a reason why it holds.
- 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 Discussion (page unavailable) reports that hybrid AK outperformed trans-splicing in mouse photoreceptors but not retinal pigment epithelium, and that small differences in AP recombinogenic sequences may explain differing transduction results. These comparisons support the point that no single dual-vector design works best across the tested conditions. (LLM, conf=0.90)
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.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These results provide further evidence that the choice of the best dual-vector design can depend significantly on the nature of the therapeutic protein.”
What the sources say
- Partly supportedcites [68] sourceExperimental — accuracy not yet measured
The Discussion reports that the best-performing dual-vector set for mini-dystrophin depended on the gene-splitting site and the sequence used for recombination; the Results also show significantly higher transduction with set IV. But the study compares designs for one therapeutic protein, not different proteins, so it does not directly establish that the preferred design depends on the nature of the protein. (LLM, conf=0.82)
plainconditionalSingle case- 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“But, interestingly, they also found that the vectors using the hybrid AP system expressed very poorly when compared with overlapping, trans-splicing, and hybrid-AK vectors. 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 hybrid AP produced the lowest transgene expression in the HEK293-cell comparison of ABCA4 and MYO7A vectors. That comparison included overlapping, trans-splicing, and hybrid-AK vectors. (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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Interestingly, they found that muscle transduction in the mdx4cv mouse model of Duchenne muscular dystrophy was significantly greater when the dual overlapping vector system was used-with an expression level approximately three times higher than with vectors based on the hybrid approach.”
What the sources say
- Partly supportedcites [68] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“When the authors compared three minimal AP HR constructs to the phage F1 HR constructs in HEK293 cells, one of the shortened AP HR vectors (AP1) showed slightly higher expression levels compared with the two other vector systems. 60”
What the sources say
- Partly supportedcites [60] sourceExperimental — accuracy not yet measured
The Results section (page not provided) compares three AP-derived regions (AP, AP1 and AP2) with the F1-phage-derived AK region in HEK293 cells. It reports that both AP1 and AP2 produced slightly higher expression than AK, while all three outperformed AP. It does not establish that AP1 expressed more than AP2, as the claim’s comparison with the other systems implies. (LLM, conf=0.88)
plaincorrelational- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Using this approach, the authors were able to demonstrate that the homologous regions on both vectors could be reduced to 0.27 and 0.26 kb, respectively, without apparent loss of transduction efficiency when compared with the original hybrid vectors (with homology regions of 0.87 kb).”
What the sources say
- Partly supportedcites [67] sourceExperimental — accuracy not yet measured
The results accompanying Figures 3B and 4 report that hybrid-vector sets using 0.27-kb or 0.26-kb bridging sequences performed at least as well as the original 0.87-kb set. But these were separate sets, each using its stated bridging sequence; the paper does not report a pair with 0.27 kb on one vector and 0.26 kb on the other. Page numbers are unavailable in our copy. (LLM, conf=0.85)
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.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Auricchio and colleagues did not observe a significant increase in fulllength ABCA4 production when they compared homologous and heterologous ITR vector pairs in HEK293 cells. 60”
What the sources say
- Partly supportedcites [60] sourceExperimental — accuracy not yet measured
The Results (Figure 3B–D; page unavailable) compare homologous and heterologous ITR vectors in HEK293 cells and report no increase in full-length protein when cells were dosed by transgene titre. But when dosed by ITR2 titre, heterologous vectors produced higher levels of both full-length and truncated protein. The Discussion says there was no significant increase in the ratio of full-length to truncated protein, which is narrower than the claim's unqualified statement about full-length ABCA4 production. (LLM, conf=0.87)
plain- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“On the other hand, in vivo, ABCA4 expression in photoreceptor cells occurred more frequently in mice injected subretinally with F1 HR vectors when compared with mice injected with AP HR vectors. 60”
What the sources say
- Partly supportedcites [60] sourceExperimental — accuracy not yet measured
The Results section on mouse photoreceptor transduction (page unavailable) reports more frequent efficient ABCA4 expression after subretinal injection with AK vectors, whose homology region derives from F1 phage, than with AP1 or AP2 vectors. It does not report an in vivo comparison with the distinct AP vectors named in the claim; those were tested in cells. (LLM, conf=0.86)
plaincorrelational- 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“For instance, Zhang and Duan demonstrated that a simple, dual overlap vector system outperformed three independent hybrid systems, 68 and Pryadkina et al. obtained similar results when they analyzed the efficiency of dysferlin overexpression obtainable with dual overlapping vector or hybrid vector systems. 45”
What the sources say
- Supportedcites [68] source
The Design and construction section identifies sets I–III as hybrid dual AAV vectors and set IV as an overlapping dual vector. The Results and Discussion report that set IV had significantly higher transduction efficiency than the other sets in mdx4cv mouse muscle. (LLM, conf=0.94)
boosteddirect- 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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Evenshorter, 77bp-long homology regions (HR), derived from the filamentous phage F1, were described by Auricchio and colleagues. 46”
What the sources say
- Supportedcites [46] Trapani I, 2014, EMBO Mol Med source
The Results section (page not supplied) describes a 77 bp sequence from the F1 phage genome used in dual AAV hybrid vectors. Materials and Methods identifies its coordinates as bp 5850–5926, which span 77 bp, and describes it as a recombinogenic sequence. This supports the citing sentence’s description of a short phage-derived homology region. (LLM, conf=0.94)
plain- 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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A potential solution to this challenge was provided by Auricchio and colleagues, who showed that the inclusion of an in-frame degron after the splice-donor site (for the 5 ¢ vector) prevents the accumulation of such fragments. 60”
What the sources say
- Supportedcites [60] source
The Results section (‘Inclusion of the CL1 degron in the 5′-half vector decreases the production of truncated proteins’; page unavailable) places the degron after the splice-donor signal and reports that truncated protein from the 5′ vector fell below detection limits. The Discussion (page unavailable) describes complete degradation of that 5′-half truncated product. (LLM, conf=0.91)
boosteddirect- 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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“It needs to be pointed out, however, that hybrid systems are not always the most efficient vector systems available.”
What the sources say
- Supportedcites [68] source
The Design and construction section identifies sets I–III as hybrid dual AAV vectors. The Results and Discussion report that the non-hybrid set IV had the highest transduction efficiency among the four sets tested in mdx4cv mouse muscle, supporting the claim that hybrid systems are not always the most efficient. (LLM, conf=0.92)
- Supportedcites [45] source
The Results section (‘Comparison of dysferlin expression of different therapeutic strategies in vivo after IM injection’; page not available) reports that Set 2, which combines splicing and overlap, yielded among the lowest dysferlin expression levels, whereas the overlapping Set 3 performed better. The Discussion also states that adding an overlapping region to the splicing strategy did not increase efficiency. This supports the qualified claim that hybrid systems are not always the most efficient. (LLM, conf=0.94)
plain- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In their study, Trapani et al. demonstrated that in vitro transduction with vectors with oversized genomes did not result in efficient transgene expression. 46”
What the sources say
- Partly supportedcites [46] Trapani I, 2014, EMBO Mol Med sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports that oversized AAV vectors produced transgene expression in vitro, but were less efficient than several dual-AAV approaches. It does not establish that expression from oversized vectors was inefficient in absolute terms; one dual-AAV approach produced even lower expression. (LLM, conf=0.85)
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.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Thus, these reduced bridging sequences allow for the expansion of the transgene payload by * 1.2 kb in a dual hybrid AAV vector system. 67”
What the sources say
- Supportedcites [67] source
The Introduction says the original hybrid dual-vector system uses a 0.87-kb bridging sequence in each vector. The study overview reports effective minimized sequences of 0.26 and 0.27 kb. Replacing both original sequences saves approximately 2 × (0.87 − 0.27) = 1.2 kb for the transgene payload. Page numbers are not available in our copy. (LLM, conf=0.91)
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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“For instance, Zhang and Duan demonstrated that a simple, dual overlap vector system outperformed three independent hybrid systems, 68 and Pryadkina et al. obtained similar results when they analyzed the efficiency of dysferlin overexpression obtainable with dual overlapping vector or hybrid vector systems. 45”
What the sources say
- Supportedcites [45] source
The Results (Packaging efficiency of the different strategies) describe Set 2 as combining splicing sequences with a vector overlap and Set 3 as overlapping vectors. The Results (Comparison of dysferlin expression after intramuscular injection) report that Set 2 yielded among the lowest dysferlin protein levels, while Set 3 yielded high expression. This supports the cited comparison of overlapping and hybrid approaches; page numbers are unavailable in our copy. (LLM, conf=0.91)
plain- 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.
- Supported
In the paper
“approximately 6% of all human proteins have a coding sequence that exceeds 4 kb, 28”
What the sources say
- Not checked — no full text of the sourcecites [28] 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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“no full-length viral genomes of * 8.2 kb could be detected by alkaline gel Southern blot. 30”
What the sources say
- Not checked — no full text of the sourcecites [30] 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.
- Based: passes — The paper gives a reason why it holds.
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
“for all dual-vector systems (and oversized, i.e., fragmented vectors) to be successful-at a minimuma cell must be co-infected by AAVs encoding the 5 ¢ and 3 ¢ part of the expression cassette, respectively.”
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: unclear — It is unclear why the paper says it holds.
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
“for trans-splicing vector systems, and for hybrid vector systems (in the absence of homologous recombination), coinfection of a cell by AAVs encoding the 5 ¢ and 3 ¢ portion must be followed by appropriate concatamerization of the two vectors.”
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.
In the paper
“In vivo , the best overlapping vector pair yielded almost identical transduction of the airway epithelium when compared with the single-genome virus.”
What the sources say
- Not checked — no full text of the sourcecites [43] source
plain- 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.
In the paper
“Dong et al. 26 reported that rAAVs can package genomes ranging from 2 to 5.2 kb in size.”
What the sources say
- Not checked — no full text of the sourcecites [26] 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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“co-injection of the two vectors into C57/BL6 mice resulted in the production of therapeutic levels of biologically active FVIII.”
What the sources say
- Not checked — no full text of the sourcecites [38] 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.
In the paper
“expression of mini-dystrophin was observed in striated muscled of mdx-mice when rAAV6 was given intravenously.”
What the sources say
- Not checked — no full text of the sourcecites [42] 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.
In the paper
“further molecular characterization found that the oversized virus stock was in fact a mixture of partially packaged viruses.”
What the sources say
- Not checked — no full text of the sourcecites [30] 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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The optimum packaging size for genomes was determined to be between 4.1 and 4.9 kb”
What the sources say
- Not checked — no full text of the sourcecites [26] 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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“in a slot blot with probes directed against the AP and the LacZ open reading frames (ORFs), both probes hybridized to viral DNA from purified rAAV.”
What the sources say
- Not checked — no full text of the sourcecites [30] 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.
- Based: passes — The paper gives a reason why it holds.
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
“For overlapping vector systems, nuclear import and uncoating must then be followed by homologous recombination of the 5 ¢ and 3 ¢ parts of the expression cassette.”
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.
In the paper
“the overlap method was also used successfully with a split mini-dystrophin expression cassette with a combined length of approximately 7.3 kb and a short, 372 bp overlap region. 42”
What the sources say
- Not checked — no full text of the sourcecites [42] source
plain- 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.
In the paper
“they could detect transduction only with vector pairs that shared either 440or 1000-base regions of homology but not with vector pairs without homology. 43”
What the sources say
- Not checked — no full text of the sourcecites [43] source
hedgedcorrelational- 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.
In the paper
“the 32-bp-long polyadenylation of soluble neurophilin 1 is equally efficient in mRNA polyadenylation when compared with the late SV40 polyadenylation signal, 36”
What the sources say
- Not checked — no full text of the sourcecites [36] 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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“simultaneous infection of cells with two vectors containing an overlapping fragment of 440 or 1000 bases of the AP gene could successfully transduce HT-1080 cells, although only at 1-2% efficiency of a vector that expressed AP from a single vector genome. 43”
What the sources say
- Not checked — no full text of the sourcecites [43] source
hedgeddirect- 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.
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
“Taken together, these results provided further evidence that hybrid dual AAV vector systems are a promising platform to express large genes with AAV vectors.”
plainconditional- 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.
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
“Nonetheless, overall-if carefully optimized-the hybrid vector approach, which combines the overlapping sequence and trans-splicing methodologies, appears to be, at least for now, the most promising approach in most instances.”
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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These promising results notwithstanding, it needs to be pointed out that hybrid AAV vectors are not always the best available vector system to overexpress genes that exceed the packaging capacity of a single AAV capsid (see below).”
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.
- Based: unclear — It is unclear why the paper says it holds.
In the paper
“A/J mice, which do not express functional dysferlin, 64 were injected intramuscularly with dual rAAV vectors, encoding the 5 ¢ and 3 ¢ parts of the dysferlin expression cassette, respectively.”
What the sources say
- Not checked — no full text of the sourcecites [64] 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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, the size of the AP sequence (0.87 kb within each vector) was a burden on the packaging capacity of the two vectors, effectively reducing the combined genome capacity of the dual-vector system from 10 to 8.2 kb. 65”
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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The choice of the 872 bp AP fragment was based on earlier work that showed that this AP fragment is highly recombinogenic in the overlapping vector system. 66”
What the sources say
- Not checked — no full text of the sourcecites [66] 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.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“intramuscular injection of a vector pair with heterologous ITRs resulted in a 3-6-fold higher expression level when compared with a homologous vector pair. 49,59”
What the sources say
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.
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.
- 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.
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.”
hedgedcorrelational- 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.
In the paper
“For example, Koo et al. 70 created a triple-vector system based on the trans-splicing approach that was capableofdeliveringthefull-length11.1kb dystrophin genome via three vectors.”
What the sources say
- Not checked — no full text of the sourcecites [70] source
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.
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
“So far, however, the efficiency of transgene expression from dual-vector systems has been inconsistent.”
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.
- Based: passes — The paper gives a reason why it holds.
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
“At present, for many clinical gene therapy applications, the efficiency of expression from the available dual-vector systems is insufficient.”
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.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Even when only 1,000 vector genomes per cell were used, the transduction efficiency reached 71% of the single vector with a genome size fitting into a single AAV capsid. 65”
What the sources say
- Not checked — no full text of the sourcecites [65] 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.
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
“it is likely that the formation of ''correct'' concatamers of two, or more, AAV genomes increases as the copy number of AAV genomes in the nucleus rises.”
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.
In the paper
“When MO59K cells were transduced with the hybrid vectors at a multiplicity of infection of 20,000 viral genomes per cell (10,000 vector genomes of each vector), the LacZ expression from the hybrid vectors was equal to that of the single intact vector.”
What the sources say
- Not checked — no full text of the sourcecites [65] 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.
- Based: passes — The paper gives a reason why it holds.
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
“of the 10 possible two-vector linear concatamers, only one has the correct tail to head orientation.”
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.
- Based: passes — The paper gives a reason why it holds.
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
“A mandatory step for the successful expression of proteins from two trans-splicing AAV vectors is that splicing of the pre-mRNA must occur across the ITR junction (Fig. 1B).”
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.
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
“Moreover, the homologous recombination efficiency of particular artificial recombinogenic sequences can vary drastically depending on the specific applications.”
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.
In the paper
“with the optimal exon/intron/exon combination approximately 80% of myofibers expressed mini-dystrophin. 61”
What the sources say
- Not checked — no full text of the sourcecites [61] 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Confirming these results, recent publications have shown greater success when the researchers identified the optimal exon-splitting site in the design of dual trans-splicing vectors with other transgenes.”
boostedcorrelational- 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.
In the paper
“Intramuscular injection of AAV6 vectors with different exon/intron/ exon splitting sites demonstrated that the nature of the splice site substantially influences transduction efficiencies”
What the sources say
- Not checked — no full text of the sourcecites [61] 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. 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.
- 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.
- 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.
- Based: passes — The paper gives a reason why it holds.
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.
- 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.
- 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.
- 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
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.
- 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
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.
- Load-bearing: passes — The paper’s conclusions depend on it.
- 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.
- 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
“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.
- Based: passes — The paper gives a reason why it holds.
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.
- 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
“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.
- 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.
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.
- 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
“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.
- 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
“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.
- 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
“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.
- Based: passes — The paper gives a reason why it holds.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
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.
- 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.
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.
- 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.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.
- 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
“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.
- 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
“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.
- Load-bearing: passes — The paper’s conclusions depend on it.
- 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. 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
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 ›
Are you an author, or do you see a problem with this page? Request a review
