Bradbury AM, Bagel JH, Nyugen D,et al. Krabbe disease successfully treated via monotherapy of intrathecal gene therapy. J Clin Invest. 2020.
Although effective therapies for central nervous system (CNS) disorders, like infantile-onset Krabbe disease (GLD) are being developed, the current inability to treat peripheral neuropathies continues to impact the outcomes for patients. While cognitive function is improved in infants with Krabbe disease who receive hematopoietic stem cell transplantation (HSCT), motor deficits and peripheral nerve dysfunction often decline. Exciting work reported in the canine GLD model, shows early delivery of high-dose, but not low-dose, intrathecal gene therapy resulted in a significant increase in GALC enzyme activity and significant reduction of psychosine to below normal levels in both presymptomatic and post symptomatic dogs. These results reiterate findings from other AAV9 gene therapy clinical trials that high-dose and early intervention are necessary for AAV9 to provide the greatest benefit.
- In the GLD dog, the efficacy of intrathecal administration of gene therapy (AAV9-cGALC) was evaluated in both presymptomatic and symptomatic dogs.
- Intrathecal delivery means the therapy is injected into the fluid surrounding the brain and spinal cord or directly into the ventricles of the brain.
- AAV-mediated therapy successfully prevented clinical neurological decline, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs.
- A 5-fold lower dose resulted in a milder (attenuated) form of disease, indicating that sufficient dosing is critical.
- In contrast to HSCT, which only treats CNS disease, intracisternal administration of gene therapy (AAV-GALC) improved both CNS and peripheral nervous system (PNS) myelination.
- CSF psychosine increased early and steadily in untreated GLD and strongly correlated with disease progression. In the 2Wk-Low cohort, detection of psychosine in the CSF was delayed until 12 weeks of age. In the 2Wk-High cohort, CSF psychosine remained undetectable up to 24 weeks, and from 24 to 52 weeks psychosine was detected in the CSF of only 1 dog, which currently remains without symptoms.
The results in the dog far exceed expectations based on the findings in the twitcher mouse model. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or post-symptomatically. In light of safety data of intrathecal delivery of AAV9 emerging from clinical trials for other diseases, we believe that this positive finding in a large-animal model of Krabbe disease warrants timely translation to the clinic.