Clinical Trials

Poster Number: 38


Cristina Liberati, MD, Manuela Corti, PT, PhD, Barry Byrne, MD, PhD, Heather Gray, DVM, PhD, Kirsten Coleman, MBA, Samantha Norman, MPH, BS, Melissa Elder, MD, PhD, Maria Escolar, MD. MS, Ibrahim Tuna, MD, Gary Kleiner, MD, PhD, Nathalie Clement, PhD, Brian Cleaver, PhD, Dominic Gessler, PhD, Guangping Gao, PhD


1. University of Florida, 2. University of Florida, 3. University of Florida, 4. University of Massachusetts Medical School, 5. University of Florida, 6. University of Florida, 7. University of Florida, 8. University of Pittsburgh, 9. University of Florida, 10. University of Miami, 11. University of Florida, 12. University of Florida, 13. University of Massachusetts Medical School, 14. University of Massachusetts Medical School

Canavan disease is a rare leukodystrophy due to a mutation in the gene that encodes for aspartoacylase (ASPA). This enzyme converts N-aceytlaspartate (NAA) into acetate and aspartate. When ASPA deficiency occurs, NAA accumulates in several organs including the brain, the kidneys and the liver.
Our team at the University of Florida, conducted an open label, expanded access trial of systemic delivery of ASPA (rAAV9-CB6-AspA) gene vector in a single patient with Canavan Disease. For the first time, a Canavan disease patient was injected with a novel recombinant AAV-vector engineered to carry the human ASPA gene using a double route of administration (systemic and intracerebroventricular). Before and after patient’s exposure to the product, an immunomodulation protocol was adopted to prevent a reaction against ASPA gene and the vector capsids. Transient B-cells ablation and immunomodulation of T-cells response were achieved by the administration of Rituximab and Sirolimus respectively.
Several outcomes were collected to assess product safety and efficacy: blood and cerebrospinal fluid (CSF) clinical pathology and chemistry tests, urinalysis, neurodevelopmental evaluations, brain Magnetic Resonance Imaging (MRI), fractional anisotropy index (measured using Diffusion Tension Imaging) and measurements of NAA level by Magnetic Resonance Spectroscopy (MRS). In addition, total antibody against ASPA and AAV were also collected to monitor patient’s immunological response to the product and the vector capsid.
No adverse events or immunological response related to the product were observed for the entire study. Up to two years post-treatment, improvements in motor development and restoration of vision were associated to sustained improvements in myelination and reduction in brain edema. The NAA level measured in the CSF by MRS, remarkably decreased by 83% compared to baseline.
This approach is relevant to other genetic diseases to reach both peripheral target organs as well as the brain. Further, this study demonstrates that concurrent use of immunomodulation is a safe and successful approach to manage immune responses and allow for future re-exposure to the same study product.