2020 ASGCT Annual Meeting Abstracts
Open accessAbstract
Friedreich’s Ataxia (FRDA) is a genetic disease affecting multiple organ systems, in which an intronic triplet repeat expansion (GAA) suppresses expression of frataxin (FXN). This mitochondrial protein is involved in iron-sulfur clustering, and non-regenerating tissues become especially vulnerable to oxidative stress and cell damage. In FRDA patients, neuronal damage in the CNS and PNS impairs motor coordination, manifesting as progressive gait and limb ataxia. In addition, oxidative stress in the heart leads to hypertrophic cardiomyopathy in early adulthood, which is often lethal. Naturally occurring AAV serotypes are widely used in research settings and clinical trials to deliver genetic cargo throughout the body when administered systemically. However, broad transduction of current systemic vectors (e.g. AAV9) can have deleterious off-target effects[1], underscoring the need for vectors that limit efficient transduction to specific disease targets. In this study, we aimed to develop precision AAV-mediated FXN gene replacement therapy to replace physiologic levels of FXN in the deep cerebellar nuclei, dorsal root ganglia, and the heart in two mouse models of FRDA, while minimizing transduction of organ systems and cell types that are not major contributors to the disease process, including the liver. To this aim, we used a dual-engineering approach to optimize both the delivery system and therapeutic cargo for targeted replacement of physiologic levels of FXN. Three constru…
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Ding and Gradinaru disclosed the generation of engineered 'eXtra Large AAV capsids' (XL-AAVs).
“Suggesting that the T = 1 geometry of AAV capsids could be manipulated by means of rational design, Ding and Gradinaru disclosed the generation of engineered 'eXtra Large AAV capsids' (XL-AAVs) [135].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [135]
These particles were reported to range between 35 nm and 70 nm in size and be able to package genomes from multiple serotypes.
“These particles were reported to range between 35 nm and 70 nm in size and be able to package genomes from multiple serotypes.”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [135]
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- Authors
- Kumar, S. R., Miles, T. F., Chen, X., Brown, D., Dobreva, T., Huang, Q., Ding, X., Luo, Y., Einarsson, P. H., Greenbaum, A., Jang, M. J., Deverman, B. E., & Gradinaru, V.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 28
- Issue
- 4
- Pages
- 1-592
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W4288083446
- Cited by
- 11
- References
- 0
- Citations by year
- 2023: 1 · 2022: 4 · 2021: 5 · 2020: 1
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Friedreich's ataxia, frataxin, AAV gene therapy, targeted gene replacement, deep cerebellar nuclei, dorsal root ganglia, oxidative stress, iron-sulfur proteins
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