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Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 10

Tay-Sachs Disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Preclinical work demonstrated safety and efficacy of CNS gene therapy using AAVrh8-HEXA/HEXB. Here we describe an expanded access trial in two patients with infantile TSD (IND 18225). Case TSD-001 demonstrated neurodevelopmental regression by 8 months of age and severe seizures by 1 year was treated at 30 months. An equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB (now AXO-AAV-GM2) was administered intrathecally (IT), with 75% of the dose (1x1014vg) delivered to the cisterna magna and 25% at the thoraco-lumbar junction. The second patient (TSD-002) was treated at 7 months of age with 4.2x1013 vg by a combination of bilateral thalamic (0.18 mL; 1.5x1012vg per thalamus), and IT infusion (3.9x1013vg). Both patients underwent immunosuppression with sirolimus, corticosteroids, and rituximab. Injection procedures were well tolerated and have shown no vector-related adverse events to date. CSF HexA activity nearly doubled from baseline and remained stable. In TSD-002 (now 16 months of age), MRI showed stabilization of disease by 3 months post-injection and appeared to temporarily deviate from the natural history of infantile TSD but declined again 6 months post-treatment. TSD-001 (now 4.5 years of age remains seizure-free on the same anti-convulsant therapy as pre-therapy, but TSD-002 developed seizures between 13 and 17 months posttreatment (by 2 years of age). Administration of AXO-AAV-GM2 by IT and thalamic injections was safe, HexA activity increased in CSF and ongoing myelination was apparent in the younger patient treated at an early symptomatic stage. This study provides early safety and proof-of-concept in humans for treatment of TSD patients by AAV gene therapy.