To advance neurological gene therapy applications into the clinic there is an urgent need to improve our understanding of gene delivery vectors, with particular emphasis on distribution and safety after direct brain delivery. While AAV2 currently dominates clinical development, alternative AAV serotypes may be better suited for some applications. The recent game-changing development of image-guided delivery techniques provides opportunity to accurately compare different vectors after direct brain delivery. Accordingly we aim to investigate the distribution and immune responses of 5 AAV serotypes (AAV1, 2, 5, 8 and 9) after confined delivery to grey or white matter structures in the non-human primate (NHP) brain. This in-depth assessment of AAV vectors will provide investigators with scientific rational for selecting a specific vector for a particular neurological application.

Public Health Relevance

Neurological gene delivery is emerging as a viable therapeutic platform with over 200 patients having been treated in clinical trials to date. However, lack of a reliable delivery system has been a major barrier that we have only recently overcome with the development of a complete system for direct image guided brain infusions. This standardized delivery system now enables us to fully investigate alternative gene delivery approaches and will ultimately provide other investigators with the ability to select the best approach for treating a specific neurological disorder.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS073940-04
Application #
8696895
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Samaranch, Lluis; Salegio, Ernesto A; San Sebastian, Waldy et al. (2013) Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the cerebrospinal fluid of nonhuman primates. Hum Gene Ther 24:526-32
Ciesielska, Agnieszka; Hadaczek, Piotr; Mittermeyer, Gabriele et al. (2013) Cerebral infusion of AAV9 vector-encoding non-self proteins can elicit cell-mediated immune responses. Mol Ther 21:158-66
San Sebastian, Waldy; Samaranch, Lluis; Kells, Adrian P et al. (2013) Gene therapy for misfolding protein diseases of the central nervous system. Neurotherapeutics 10:498-510
Samaranch, Lluis; Salegio, Ernesto A; San Sebastian, Waldy et al. (2012) Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum Gene Ther 23:382-9