AAV gene therapy LYS-SAF302 demonstrates widespread sulfamidase distribution in primate brain and correction of disease pathology in MPS IIIA mice

Lysogene completed its program of nonclinical studies for LYS-SAF302, an optimized AAVrh.10 vector carrying the human SGSH gene. LYS-SAF302 achieves 3-fold higher enzyme expression than LYS-SAF301, which was previously tested in a phase 1/2 trial. A dose ranging efficacy study was conducted with LYS-SAF302 in 5-week-old MPS IIIA mice (15/gender/group) at three different doses (8.6E+08, 4.1E+10, and 9.0E+10 vg/animal) injected into the caudate putamen/striatum and thalamus. LYS-SAF302 was able to dose-dependently correct MPS IIIA-related brain pathology at 12-weeks and 25-weeks post-surgery. To study SGSH distribution in the brain of large animals, LYS-SAF302 (7.2E+11vg/animal) was injected into white matter of nonhuman primates (n=22 injections of 50μl per hemisphere), using an optimized injection method. Six weeks following dosing, animals were euthanized, the brain was sliced into 3-4 mm coronal slabs, and each slab was divided into 10 x10 mm sections. Viral DNA and SGSH enzyme activity were determined in each of these punches. In 97% (±2) of punches analysed, we observed a >20% increase in SGSH activity relative to non-injected controls. In parallel, a GLP toxicological and biodistribution study conducted in 12 juvenile NHP did not reveal toxicity following bilateral white matter administration of LYS-SAF302, and confirmed the broad distribution of enzymatically active SGSH throughout the primate brain. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA. An international Phase 2-3 clinical trial in MPS IIIA with LYS-SAF302 is planned.