According to a recent press release from Passage Bio, their investigational gene therapy for Krabbe disease, PBKR03, may be ready to move into the clinical trial stage of drug development. Preclinical data supports this transition, as it demonstrated improvements in key biomarkers alongside disease progression. You can read the full paper at Human Gene Therapy.
About Krabbe Disease
Firstly, let’s gain an understanding of what this rare condition is. Krabbe disease, also called globoid cell leukodystrophy, is a rare disorder that causes the destruction of myelin in the brain and nervous system. It can range in severity between affected individuals, but it is typically fatal by age two. Symptoms include fever, difficulties feeding, vomiting, loss of head control, developmental delays, irritability, unexplained crying, muscle spasms, and declines in alertness. These effects are all the result of a mutated gene that is inherited in an autosomal recessive pattern. This gene is responsible for an enzyme called galactocerebrosidase (GALC), and when there is not enough of it, it allows fats to accumulate. This buildup then results in the destruction of myelin. Unfortunately, there is no cure for this condition. Treatment is symptomatic.
PBKR03 for Krabbe Disease
Currently being developed by Passage Bio, PBKR03 is utilizes an AAV capsid and ICM administration to deliver a working version of the GALC gene to patients’ cerebral spinal fluid (CSF). Already, this drug has been granted the Orphan Drug, Rare Pediatric Disease, and Fast Track designations within the US, along with the Orphan designation from the European Commission (EC).
These designations were based off of preclinical research that utilized animal models of specific Krabbe disease characteristics (e.g., toxic psychosine accumulation, little to no GALC enzyme activity, rapid neurological deterioration). In the first stage, researchers used mice models of the rare disease and dosed them with PBKR03. Upon evaluation, they found that the gene therapy led to dose-dependent improvements in clinical disease, biochemical, and histopathological signs.
The next step was to move to canine models of Krabbe disease. Researchers observed the following after PBKR03 treatment:
- Decreased accumulation of psychosine
- Preservation of central and peripheral nerve myelination
- Increased GALC enzyme activity in the CSF, brain, and spinal cord
- Improvements in the following:
- Nerve conduction function
With these extremely positive preclinical data in hand, Passage Bio is now moving into clinical trials. In fact, the Phase I/II GALax-C trial has already began to dose infantile Krabbe disease patients. Hopefully, clinical data continues to be positive, as this gene therapy could fill a large unmet need for this patient population.