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Early promise for adeno-associated virus gene therapy in Tay–Sachs disease

By Eleanor McDermid, medwireNews Reporter

Replacement of the enzymes lacking in Tay–Sachs disease (TSD) using adeno-associated virus gene therapy via both the thalamus and cerebrospinal fluid (CSF) is possible and potentially efficacious in humans, shows a study in Nature Medicine.

Patients diagnosed with TSD in infancy usually have mutations in the HEXA and HEXB genes that result in less than 0.1% of normal levels of heterodimeric β-N-acetylhexosaminidase A enzyme (HexA).

Terence Flotte (UMass Chan Medical School, Worcester, Massachusetts, USA) and colleagues used adeno-associated virus gene therapy to replace this enzyme in two infants with TSD. Because the disease affects the entire nervous system, they aimed to deliver the genes intrathecally and also via the thalamus.

The first infant treated showed symptoms from 5–6 months, was diagnosed at 14 months and received gene therapy at 30 months. The researchers did not attempt thalamic delivery, however, “because of severe thalamic degeneration”.

The second patient was diagnosed soon after birth due to having older siblings with the condition, and had no symptoms when treated at 7 months, with bilateral thalamic injections plus intrathecal delivery.

Adverse effects were mild and thought to be related to the injection procedure rather than the gene therapy; they comprised a low-grade fever and brief elevation of transaminases.

Both patients had increases in CSF HexA activity over the 6 months after treatment, from approximately 0.3 nmol/mL at baseline to 0.5–0.6 nmol/mL.

The researchers say that these increases could potentially “alter the trajectory of disease progression in TSD, as patients with 0.5% of normal HexA activity exhibit a late infantile/juvenile phenotype and survival into the second decade of life, and those with 2% HexA activity can have a near-normal life span.”

However, they caution that HexA activity in the CSF may not reflect activity in the brain, “and it must be noted that the intrathalamic route could result in variable levels of enzyme activity in different brain structures.”

Although the second infant was symptom-free at baseline, they had brain magnetic resonance imaging findings “suggestive of mild dysmyelination”, but at 6 months there was evidence of increased myelination and brain volume.

However, this child’s motor function began to deteriorate after 6 months, and by 17 months they had developed seizures. They remained free of further seizures on levetiracetam monotherapy.

The first child had poorer function at baseline, but remained clinically stable and seizure-free on levetiracetam monotherapy at the age of 4.5 years (2 years after therapy).

“By this age, TSD patients are either deceased or at end-stage disease, where they are refractory to antiepileptics, suggesting a positive benefit of the gene therapy intervention”, say Flotte and team.

And they also note that they delivered a much smaller dose of gene therapy to the thalamus than that predicted to be efficacious based on preclinical experiments, to minimise the risk of thalamic injury from the injection of large volumes.

Future trials will need to test higher doses to obtain maximum treatment efficacy, they add, and therefore larger injection volumes.

“Because TSD is fatal, taking the risk associated with injecting larger volumes/doses is warranted and necessary to achieve transformative therapeutic outcomes”, the team concludes.

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

Nat Med 2022; 28: 251–259