Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS073940-01
Application #
8084288
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Tagle, Danilo A
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$579,260
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Green, F; Samaranch, L; Zhang, H S et al. (2016) Axonal transport of AAV9 in nonhuman primate brain. Gene Ther 23:520-6
Samaranch, Lluis; Bringas, John; Pivirotto, Philip et al. (2016) Cerebellomedullary Cistern Delivery for AAV-Based Gene Therapy: A Technical Note for Nonhuman Primates. Hum Gene Ther Methods 27:13-6
Salegio, Ernesto A; Bringas, John; Bankiewicz, Krystof S (2016) MRI-Guided Delivery of Viral Vectors. Methods Mol Biol 1382:217-30
Samaranch, L; Hadaczek, P; Kells, A P et al. (2016) Slow AAV2 clearance from the brain of nonhuman primates and anti-capsid immune response. Gene Ther 23:393-8
Ciesielska, Agnieszka; Sharma, Nitasha; Beyer, Janine et al. (2015) Carbidopa-based modulation of the functional effect of the AAV2-hAADC gene therapy in 6-OHDA lesioned rats. PLoS One 10:e0122708
Forsayeth, John; Bankiewicz, Krystof S (2015) Transduction of antigen-presenting cells in the brain by AAV9 warrants caution in preclinical studies. Mol Ther 23:612
Salegio, Ernesto A; Streeter, Hillary; Dube, Nikhil et al. (2014) Distribution of nanoparticles throughout the cerebral cortex of rodents and non-human primates: Implications for gene and drug therapy. Front Neuroanat 8:9
San Sebastian, Waldy; Kells, Adrian P; Bringas, John et al. (2014) SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE. Mol Ther Methods Clin Dev 3:
Samaranch, Lluis; Sebastian, Waldy San; Kells, Adrian P et al. (2014) AAV9-mediated expression of a non-self protein in nonhuman primate central nervous system triggers widespread neuroinflammation driven by antigen-presenting cell transduction. Mol Ther 22:329-337
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

Showing the most recent 10 out of 16 publications