AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness
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Repeat administration of gene therapy to the contralateral retina of three congenitally blind patients was safe and resulted in improved vision.
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Despite a 28-day oral corticosteroid therapy started 2 days before the first IVT, 70.7% of lenadogene nolparvovec-treated eyes developed some degree of intraocular inflammation versus 10.2% of placebo-treated eyes.
“Despite a 28-day oral corticosteroid therapy started 2 days before the first IVT, a regimen similar to that provided in several other clinical studies using IVT or sub-retinal AAV-based gene therapies,41–45 70.7% of lenadogene nolparvovec-treated eyes developed some degree of intraocular inflammation versus 10.2% of placebo-treated eyes.”
From Randomized trial of bilateral gene therapy injection for m.11778G&gt;A <i>MT-ND4</i> Leber optic neuropathy (2023) · cites this paper as [43]
The citation is attached to the comparison with other gene-therapy studies, not to the inflammation percentages. The Discussion (page unavailable) mentions corticosteroids taken around the time of surgery, and the Results identify this as a subretinal AAV study. Our copy does not establish that its corticosteroid regimen was oral or similar in duration and timing to the stated 28-day course begun two days before injection. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSubretinal AAV2 RPE65 trials in LCA showed sustained improvement in subjective and objective vision in over 30 patients.
“during Phase I/II clinical trials for Leber's congenital amaurosis (LCA), over 30 patients who received a subretinal injection of AAV2 encoding RPE65, an enzyme responsible for the isomerohydrolase activity of retinal pigment epithelium, showed sustained improvement in both subjective and objective measurements of vision.8–14”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [13]
The Introduction (page unavailable) reports sustained improvements in retinal and visual function after subretinal AAV2-RPE65 treatment in a phase 1/2 study of 12 patients. The Discussion and Results (pages unavailable) also describe subjective and objective improvements in three of those adults after treatment of their second eyes. Our copy does not substantiate the claim that over 30 patients showed sustained improvement. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNeutralizing antibodies against AAV capsid do not increase (or prevent readministration) when AAV vectors are administered via subretinal injection.
“Although neutralizing antibodies against the AAV capsid do not increase (or prevent readministration) when AAV gene therapy vectors are administered via subretinal injection,13”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [13]
The Results (Safety of subretinal readministration) report that neutralizing antibody responses remained at or close to baseline in all three subjects and that AAV2 readministration was well tolerated. The claim generalizes those findings to subretinal AAV vectors broadly; the Discussion cautions that the safety evidence cannot be extrapolated to higher doses or other vector preparations. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHigher viral doses most commonly result in an increased antibody response, but several studies present contradicting results.
“Higher viral doses most commonly result in an increased antibody response [8, 16, 38], but several studies present contradicting results, with either no effect of viral dose, or a higher immune response to lower doses of AAV [39–41].”
From Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection (2024) · cites this paper as [39]
The Results (Safety of subretinal readministration; page unavailable) report that neutralizing antibody responses remained at or near baseline after readministration. The study design gave all three adults the same readministration dose, although their initial doses differed; the paper does not establish that viral dose had no effect on antibody response or that lower doses produced higher responses. Its Discussion addresses a dose response in visual function, not antibodies. (LLM, conf=0.78)
Experimental — accuracy not yet measuredAAV clinical successes to date have involved delivery either to immune privileged regions or to subjects lacking apparent AAV immunological memory.
“As a result, AAV clinical successes to date have involved delivery either to immune privileged regions or to subjects lacking apparent AAV immunological memory.8–14,30,42”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [13]
AAV has been successful in clinical gene therapy trials for LCA, hemophilia, familial lipoprotein lipase deficiency, and choroideremia.
“Adeno-associated virus has been successful in clinical gene therapy trials for Leber's congenital amaurosis, hemophilia, familial lipoprotein lipase deficiency, and choroideremia.8–15,26,27,60,61”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [13]
In the clinical setting, ocular and intrathecal AAV gene delivery have shown limited transgene-related immune responses, possibly due to their compartmentation and reduced antigen presentation.
“Furthermore, in the clinical setting, ocular and intrathecal AAV gene delivery have shown limited transgene-related immune responses, possibly due to their compartmentation and reduced antigen presentation [16, 132, 133].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [132]
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- Authors
- Bennett, J., Ashtari, M., Wellman, J., Marshall, K. A., Cyckowski, L. L., Chung, D. C., McCague, S., Pierce, E. A., Chen, Y., Bennicelli, J. L., Zhu, X., Ying, G.-S., Sun, J., Wright, J. F., Auricchio, A., Simonelli, F., Shindler, K. S., Mingozzi, F., High, K. A., & Maguire, A. M.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19014, USA.
- University of Pennsylvania (US)
- Federico II University Hospital (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Corresponding author
- Bennett, Jean
- Ashtari, Manzar
- Pierce, Eric A.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2012-02-08
- Volume
- 4
- Issue
- 120
- Pages
- 120ra15-120ra15
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4169122
- OpenAlex
- W2116369307
- Cited by
- 395
- References
- 27
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 9 · 2023: 16 · 2022: 15 · 2021: 21 · 2020: 26 · 2019: 20 · 2018: 35 · 2017: 37 · 2016: 44 · 2015: 45 · 2014: 41 · 2013: 37 · 2012: 18
- FWCI
- 18.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Eye Institute (R21EY020662, R01EY019014, P30EY001583)
- National Center for Research Resources (UL1RR024134)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- Leber congenital amaurosis, congenital blindness, subretinal injection, fellow eye, visual recovery, retinal function
- MeSH terms
- Retinoid Isomerohydrolase, Dependovirus, Adult, Blindness, Genetic Vectors, Humans, Genetic Therapy, cis-trans-Isomerases
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