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 (1x10 14 vg) 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•2x10 13 vg by a combination of bilateral thalamic (0•18 mL; 1•5x10 12 vg per thalamus), and IT infusion (3•9x10 13 vg). 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; there now 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 anticonvulsant therapy as pre-therapy, but TSD-002 developed seizures between 13 and 17 months post-treatment (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.

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

“…66,67 Despite the promising pre-clinical data sustained the development of AAV GT, there are still several drawbacks associated with IC and systemic AAV delivery, including failure to correct early pathological hallmarks (e.g., myelin defects), 22,56 the neurotoxicity associated with transgene overexpression in brain cells, 28 and the potential liver and heart toxicity associated with off-target transgene expression. [66][67][68][69] These considerations, together with the known immunogenicity of AAVs, 70 dictate the need to accurately monitor individuals enrolled in first in-human AAV GT trials for GM2 gangliosidosis 27 (ClinicalTrials.gov: NCT04798235 and NCT04669535) and provide a rationale for exploring alternative/ complementary therapeutic strategies.…”

“…20,21 Gene therapy (GT) holds promise as a means to address TSD and SD pathology. In vivo intracerebral (IC) GT, delivering functional Hex enzymes by means of adeno-associated viral vectors (AAVs), has benefited SD mice and cats [22][23][24][25][26] and is currently under clinical testing for infantile individuals 27 (ClinicalTrials.gov: NCT04798235 and NCT04669535). Despite this, pre-clinical studies and clinical observations have highlighted several major issues associated with this strategy; i.e., the necessity to co-deliver the a and b subunits at the appropriate ratio to achieve a fully functional enzyme, toxicity associated with Hex overexpression in brain cells upon IC GT, 28 immunogenicity of AAVs that require some immunosuppressive treatment to support durable transgene expression, 29,30 and potential off-target toxicity because of AAV leakiness, 31 which requires longterm efficacy and safety evaluations.…”

Compound Heterozygote Reason for Juvenile Form of Tay-Sachis Disease -Case Report

“…In February 2022 the first gene therapy for Tay Sachs diseases is published. Two patients with infantile form of Tay-Sachs received adeno-associated gene therapy (AAVrh8-HEXA and AAVrh8-HEXB), with signs of improvement in the clinical course of the disease 3 months after the application of the therapy and with no vector associated side effects [12].…”

Adeno-Associated Virus Toolkit to Target Diverse Brain Cells

“…The initial success rates of clinical programs as measured by translation from investigational new drug to new drug application have been higher than for other modalities (Kuzmin et al 2021). Notably, trial outcomes for neurological (Flotte et al 2022) and ophthalmological (Sahel et al 2021) indications have been similarly favorable. AAV-based optogenetic therapy, for example, recently achieved partial visual restoration in a blind patient (Sahel et al 2021) and could pave the way for adopting other improved opsins (Bedbrook et al 2019, Gong et al 2020, Marshel et al 2019) for circuit therapies.…”