Dr. Kevin Nash is an Assistant Professor in the College of Medicine, Molecular Pharmacology and Physiology at the University of South Florida. His research focus is targeted toward using recombinant adeno-associated virus (rAAV) in studying neurological disorders. Dr. Nash is a member of the FAST Integrative Research Environment Initiative (FIRE), a consortium of scientists, with precise expertise in Angelman Syndrome (AS), who work collaboratively to identify, characterize and implement new therapeutics for the treatment and ultimate cure of AS. This initiative was launched in 2013, includes five laboratories spanning four universities and is funded in full by donations made to FAST. To date, FAST’s investment in the FIRE Initiative stands at more than $3.4 million.
The results of this collaboration have been remarkable and the FIRE team is now working with more than six pharmaceutical and biotechnology companies to prepare for and test potential therapeutics for human clinical trial. At the last FAST Summit, Dr. Nash presented on his current research in protein replacement therapy using AAV delivery.
Dr. Nash discussed the details of using an adeno-associated virus as a vector in the gene therapy technology being developed by Agilis Biotherapeutics. Gene therapy is the addition of new genes to a patient’s cells to replace missing or mutated genes. Dr. Nash is using a modified virus to carry the UBE3A gene into cells. This is a recombinant virus, meaning it is generated in the lab. This virus was modified to reduce risk to humans and is therefore not dangerous, or “non-pathogenic.” It has many favorable qualities including: low immunogenicity; it infects non-dividing cells (like neurons or brain cells); it does not integrate into the host genome (which could increase the risk of cancer by overproduction of a gene); and it can provide long-term expression of a gene.
The AAV targets the areas of the brain where it is injected. In the study by Daley et al (2011), AAV9 was injected directly into the hippocampus of AS mice, and rescue of some behavior deficits were seen.
The AAV is limited to the injection site, and requires a large number of injections to target the entire brain, therefore, alternative methods are being investigated to figure out the best mode of distribution to gain access into the entire brain (e.g. spinal fluid injection, ventricular system injection, etc).
Two different AAVs (AAV4 and AAV9) have been investigated. AAV4 can infect cells that line the ventricular system enabling them to express proteins, which then would allow the spinal fluid to carry those proteins to the cells of the brain that need it, since much of the brain is bathed in this fluid. The AAV9 can pass out of the spinal fluid and have better expression in neurons and other cells throughout the brain, so intrathecal (spinal tap) injections may be an option. This would ultimately be less invasive than direct brain injections.
