Design and rationale of the LYS-SAF302 gene therapy study in mucopolysaccharidosis type IIIA (MPS IIIA) children

Mucopolysaccharidosis type IIIA (MPS IIIA) (OMIM 252900) leads to early-onset neurodegeneration and premature death. Though the involvement of multiple organ systems in MPS IIIA is recognized, central nervous system (CNS) manifestations predominate, in particular intellectual disability, progressive loss of acquired skills, behavioral and sleep disturbance. The reduced lifespan is related to progressive neurological deterioration rather than involvement of other organ systems. A direct-to-brain administration is thought best for such diseases because of the profound CNS component and the blood brain barrier, which limits the passage of therapies administered via peripheral routes. Long-term 5-year data in four MPS IIIA patients treated with an intracranial administration of a first-generation adeno-associated viral (AAV) gene therapy (LYS-SAF301) showed that direct to CNS gene therapy was well tolerated. Lysogene’s Phase 2-3 trial (NCT03612869) uses an optimized gene therapy construct (LYS-SAF302). The study is a single-arm, multicenter study of AAV serotype rh.10 carrying the human SGSH (AAVrh.10-SGSH) for the treatment of MPS IIIA. The study will include 20 patients. The primary objective will be to assess the drug efficacy in improving or stabilizing the neurodevelopmental status of patients compared to the expected evolution based on natural history data. Safety, tolerability, effect on behavior, sleep and quality of life are secondary endpoints. Eight clinical sites in the US and Europe are participating in this trial. The principal inclusion criterion is a cognitive developmental quotient (DQ) score  > 50% based on the Bayley Scales of infant and toddler development third edition (BSID-III). Status of the first patients treated in the study will be presented.