David Weinstein, MD, Senior Vice President of Clinical Development at Passage Bio, discusses why the company’s investigational gene therapy (PBGM01) is being administered through the cisterna magna.
GM1 gangliosidosis is an inherited lysosomal storage disorder caused by mutations in the GLB1 gene, which encodes the lysosomal enzyme beta-galactosidase (β-gal). Reduced β-gal activity results in the accumulation of GM1 gangliosides in neurons, causing rapidly progressive neurodegeneration. Progressive damage to other tissues including the heart, liver, and bones, are also observed.The condition may be classified into three major types based on the general age that signs and symptoms first appear: classic infantile (type 1); juvenile (type 2); and adult onset or chronic (type 3). Common signs and symptoms among all three subtypes include hypotonia, progressive CNS dysfunction, seizures, and rapid developmental regression. Currently, there is no targeted treatment approved for GM1 gangliosidosis so management is primarily supportive.
PBGM01 is a gene therapy that utilizes a AAVhu68 capsid to deliver a functional GLB1 gene encoding beta-galactosidase to the brain and peripheral tissues. By increasing beta-galactosidase activity, PBGM01 has the potential to reduce accumulation of toxic GM1 gangliosides and reverse neuronal toxicity, thus restoring developmental potential.
As Dr. Weinstein notes, the gene therapy is being administered via intra cisterna magna (ICM) and there are a number of advantages to ICM administration compared to other delivery methods. Firstly, since PBGM01 does not need to cross the blood-brain-barrier, lower doses of the drug are needed to be effective. This, along with the reduced strain put on the liver by injecting directly into the cerebral spinal fluid, reduces toxicity. Finally, using this approach, the presence of neutralizing antibodies has no effect on the efficacy of PBGM01 – in fact, one patient in the phase 1 clinical trial of PBGM01 tested positive for neutralizing antibodies but was still given the investigational gene therapy.
To learn more about GM1 gangliosidosis and other rare lysosomal storage disorders, visit checkrare.com/diseases/lysosomal-storage-disorders/
