The Research Institute at Nationwide Children’s Hospital: Haiyan Fu, PhD
Mucopolysaccharidosis (MPS) III (Sanfilippo Syndrome) are a group of four devastating genetic diseases. These diseases manifest predominantly the central nervous system (CNS), including the brain and spinal cord. The greatest challenge for treating MPS III has been the blood-brain barrier (BBB). The BBB prevent therapeutics from entering the CNS.
MPS IIIB
We have developed an efficient gene therapy procedure to treat MPS IIIB. We have made an AAV9 vector that has the ability to cross the blood-brain-barrier. This AAV9 vector carries the gene for NAGLU, the enzyme missing in MPS IIIB patients. By a singly intravenous injection of this AAV9-NAGLU vector, we were able to restore the NAGLU enzyme activity and correct the lysosomal storage pathology throughout the brain, spinal cord and multiple somatic tissues in adult MPSIIIB mice. Most importantly, the AAV9-vector-treated mice showed significant behavioral improvement and survived to a normal lifespan. In addition, this approach is minimally invasive and the IV injection itself has minimal risk to patients. With the generous support from Sanfilippo families and friends and Ben’s Dream – The Sanfilippo Research Foundation, the experiments of this project are still ongoing.
We believe that we are in a very good position to move our AAV9-gene-therapy approach to clinical trial. We have established a strong team with the goal of obtaining the approval from the FDA for a Phase I/II clinical trial in patients with MPS IIIB. Led by Dr. Kevin Flanigan, MD and professor of neurology, we have submitted a Pre-pre-IND package to the FDA and have a pre-pre-IND meeting scheduled with the FDA. This Pre-pre-IND interaction is for us to get advices from the FDA on specific requirements for the Pre-IND toxicology/safety testing of our approach in animals. This Pre-IND toxicology testing is absolutely required for obtaining the FDA approval for our planned MPS IIIB gene therapy clinical trial.
Additional plans and efforts have been made to prepare for moving this MPS IIIB gene therapy to a clinical trial: 1) We have submitted a translational grant application to the NIH; 2) We are planning to establish a MPS III patient registry; 3) Establish and validate the stable high yield vector producing cell line; and 4) Produce clinical grade AAV9 vectors needed for the planned clinical trial, which is required by the FDA when submitting the IND (Investigational New Drug) application.
