Optimization and validation of gene therapy using a patient-specific mouse model of SLC6A1-related disorders

  • Awarded: 2021
  • Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
  • Award #: 891323

Solute carrier family 6 membrane 1 (SLC6A1) protein is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane and removes GABA from the synaptic cleft. Autosomal dominant mutations in the SLC6A1 gene result in a form of pediatric epileptic encephalopathy, intellectual challenges and autism spectrum disorder (ASD). The condition has not been well characterized to date; however, primary symptoms comprise various forms of seizures, altered cognitive development and ataxia. Treatment options for affected individuals are currently limited to antiepileptic drugs.

Gene therapy with adeno-associated virus serotype 9 (AAV9) is a promising strategy of intervention for SLC6A1-related pathology. AAV9 is already widely used for neurological indications and shows a favorable safety profile in clinic. Intrathecal administration of AAV9 permits dissemination of transgenes throughout the nervous system and is currently used in trials for the treatment of inherited neurological disorders, including neuronal ceroid lipofuscinosis 3 (CLN3), CLN6, CLN7, spinal muscular atrophy (SMA), GM2 gangliosidosis (Tay–Sachs and Sandhoff diseases) and giant axonal neuropathy.

In an ongoing pilot study, Allison Bradbury in collaboration with Kathrin Meyer, is evaluating AAV9-mediated gene replacement as a treatment for SLC6A1-related disorders using delivery directly to the cerebrospinal fluid (CSF). SLC6A1 is primarily expressed in the brain, specifically in GABAergic neurons and astrocytes. Bradbury’s approach includes multiple versions of AAV vectors in order to achieve expression in both neurons and astrocytes or to restrict it to either neurons or astrocytes.

Her team is evaluating the safety and efficacy of gene replacement strategies in a novel mouse model carrying a point mutation equivalent to an affected individual. Treated mice have now been followed for more than 90 days and a vector construct targeting both neurons and astrocytes has outperformed the other vectors on several behavioral tests and expression analyses in the brain. With a candidate vector showing great promise for this disorder, the therapeutic dose needs to be determined and clinically-relevant readouts assessed for timely translation to patients.

Herein, Bradbury and colleges plan to perform a dose response study on their candidate vector and determine efficacy with additional clinically relevant readouts of seizure monitoring and electrophysiology. The dose escalation study will allow the team to determine the minimal efficacious dose in which a clear benefit is quantifiable without unnecessary risk of off target or toxic effects. As seizures and nerve conduction deficits are hallmarks of disease in patients, they will evaluate the effect of treatment utilizing these clinically relevant readouts to enhance translatability.

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