First-in-human AAV Gene Therapy for Tay-Sachs Disease

Abstract

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.

The Translational Benefits of Sheep as Large Animal Models of Human Neurological Disorders

“…Indeed, AAVrh8-mediated gene therapy trials in Tay-Sachs sheep demonstrated safety and efficacy, with widespread vector distribution throughout the brain, as well as near normal levels of Hex A activity and attenuated ganglioside accumulation ( 19 ). This resulted in delayed onset of disease and increased life span in treated sheep and the initiation of a phase I clinical trial of the HEXA gene therapy product in January 2021 [ clinicaltrials.gov NCT04669535, ( 62 )].…”

Gene Therapy for Rare Neurological Disorders

“…In contrast, systemic vector administration might be more susceptible to vector neutralization 34 . To address this problem, human gene therapy trials often include an immune suppression protocol to prevent a humoral and cellular immune response against AAV and the transgene 27,91,94 . Thus, it will remain a critical task to refine our understanding of gene therapy–associated immune response and its modulation while protecting patients from the risk associated with prolonged immune suppression.…”

“…However, vector spread is limited compared with intravenous injection because distribution depends on interstitial, lymphatic, and axonal travel. However, certain conditions such as lysosomal storage diseases, e.g., TSD, undergo a mechanism called “cross‐correction,” which enables the distribution of the transgene from transduced to nontransduced cells and thus can achieve more comprehensive cellular correction than the spread of rAAV itself 27 . Another consideration is that the delivered volume is limited and might be restricted by the target brain region.…”

“…For example, TSD and SD have been evaluated extensively in a preclinical setting, and clinical trials are now underway (NCT04669535). However, an expanded access trial was conducted before the actual trial in two TSD patients 27 . The two participants underwent different administration routes, which was necessary due to neuropathologic findings.…”

“…However, an expanded access trial was conducted before the actual trial in two TSD patients. 27 The two participants underwent different administration routes, which was necessary due to neuropathologic findings. Patient 1 received a mix of rAAVrh.8 expressing the αsubunit or the βsubunit to generate a functional HexA enzyme with a total dose of 1 × 10 14 vg via intrathecal delivery, and patient 2 received the same vector mixture, but a total dose of 4.2 × 10 13 vg, which was divided into bithalamic and intrathecal delivery.…”