In 2016 the Sanfilippo Children’s Foundation awarded AUD$90,000 towards a project to improve delivery of gene therapy to the brain for Sanfilippo Type C. This project was led by Dr Brian Bigger at the University of Manchester, and the project is now completed.
First the researchers compared three different types of a harmless virus called AAV, which is used to deliver the missing gene in gene therapies. In mice they found that a new AAV called AAV-TT appeared to work better than those currently in gene therapy clinical trials (AAV9 and AAV rh10). This new virus spread more evenly throughout the brain which is very important for any gene therapy for Sanfilippo Type C.
Sanfilippo Type C is more challenging to treat than other subtypes because the enzyme that is missing – HGSNAT – anchors itself inside the cells of the brain and it cannot travel to neighbouring cells and treat them. For this reason, achieving maximum and even distribution of virus throughout the brain is essential.
The next task was to investigate the best method of injection for optimal distribution throughout the brain. They used artificial brain models in the lab and travelled to New Zealand to study the brains of sheep. From this research they have learned how quickly to inject the AAV for the best distribution and what area of the brain to target.
These studies used AAV to deliver a gene that contains the instructions to produce a fluorescent protein. This was useful for visualising exactly what cells of the brain the virus was reaching after it was injected. The next step will be to use the knowledge gained here to complete preclinical testing of AAV delivery of the Sanfilippo Type C gene (HGSNAT), prior to initiating clinical trial, which could start in the next 2 to 5 years. This research could also help improve gene therapy for other types of Sanfilippo and other genetic diseases that affect the brain.