PHILADELPHIA—Passage Bio Inc. recently published data in a murine model of gangliosidosis (GM1) demonstrating that a single injection of an adeno-associated virus (AAV) into the cerebral spinal fluid (CSF) resulted in significant expression in the brain, demonstrating dose-related reductions in neurological impairment and improvement in survival. These data were published online in the November issue of Human Gene Therapy.
GM1 is a rare and often life-threatening monogenic lysosomal storage disease caused by mutations in the GLB1 gene, which encodes lysosomal acid β-gal. Reduced β-gal activity results in the accumulation of toxic levels of GM1 in neurons throughout the brain, causing rapidly progressing neurodegeneration. The disease mostly affects infants.
“This study suggests that delivery of an AAV vector optimized to express β-gal directly into the CSF restored β-gal activity in the brain and, if further developed and tested in human clinical trials, may be effective in modifying and preventing the devastating effects of the genetic disease GM1,” says Dr. James Wilson, director of the Gene Therapy Program at the University of Pennsylvania and chief scientific advisor of Passage Bio. “The AAV vector used in the study is the same as Passage Bio’s PBGM01 gene therapy, which is designed to deliver a functional human GLB1 gene into the brain and optimized to express β-gal. These preclinical study data support the further development of PBGM01 as a potential therapy for patients suffering from GM1.”
This research evaluated the impact of single intracerebroventricular administration of the human β-gal containing AAV on β-galactosidase enzyme activity in the murine brain and peripheral tissues, lysosomal storage lesions, neurological function (including neurological exams and gait analysis) and survival in mice lacking the β-galactosidase gene. The mice received the single administration at age one month and were evaluated over 300 days. β-gal activity was increased significantly in the cerebral spinal fluid and serum of the vector-treated mice compared to vehicle control-treated mice.
Significant improvements in gait assessments and significant preservation of neurological function—as measured by stride length and hind paw print length, and by neurological exam scores, respectively—were observed throughout the study period in the human β-gal vector-treated mice.
There were significant decreases in lysosomal storage lesions of vector-treated animals, and by day 300 all animals that received the two highest doses were still alive, whereas none of the vehicle control-treated animals had survived. In preclinical models, PBGM01 has demonstrated broad brain distribution and wide uptake of the β-gal enzyme in both the central nervous system (CNS) and critical peripheral organs.
It was Wilson who chose to conduct studies and preclinical trials on GM1.
“Dr. Wilson is a pioneer in gene therapy, with years of experience working with communities of physicians and families in rare pediatric diseases,” says Bruce Goldsmith, CEO of Passage Bio.
“Dr. Wilson’s experience working with communities of physicians and families in rare pediatric diseases, combined with our company’s scientific approach of considering patient and family need, product differentiation and the ability to execute a successful clinical program informed by preclinical studies, led to our decision to move forward a clinical program to address GM1.”
While the published results are in mice, human testing is on the horizon. According to Goldsmith, “We are planning to initiate a Phase 1/2 clinical trial in humans in the first quarter of next year. A single dose of PBGM01 will be administered to patients via injection into the cisterna magna, which provides the greatest brain biodistribution.”
The first cohort in the clinical trial will be patients with late-onset infantile GM1, he reports, and the company intends to report initial 30-day safety and biomarker data by mid-2021.
“We are currently on clinical hold for the Investigational New Drug (IND) application for PBGM01 because of biocompatibility questions that the FDA asked us to address regarding the ICM delivery device we’re using to administer PBGM01,” Goldsmith explains. “Based on discussions with the FDA, we’ve conducted biocompatibility risk assessments and testing of the device in an effort to submit the most robust possible response to FDA. We have confidence that we will receive clearance for the GM1 ICM device. So, the next step is for us to receive FDA clearance of the IND.”
In the meantime, Goldsmith says Passage Bio is activating clinical sites in preparation for the clinical trial.
The incidence rate for GM1 is approximately 0.5 to 1 in 100,000 live births, which translates into approximately 40 children born with this disease in the U.S. each year, according to Goldsmith.
“We think, based on external benchmarks and other analyses, that this is probably an underestimate because there are no approved disease-modifying therapies, and there is currently no newborn screening for this disease,” he remarks, adding that “There have been reports of GM1 being detected in unborn babies who are siblings of children who were already born with this disease. Detecting GM1 in unborn babies is not likely to be a widespread diagnostic.”
GM1 manifests as a continuum of disease and is most severe in the infantile form, which is characterized by onset in the first six months of life with hypotonia (reduced muscle tone), progressive CNS dysfunction, and rapid developmental regression. Life expectancy for infants with GM1 is two to four years, and infantile GM1 represents approximately 60 percent of the incidence of 0.5 to 1 in 100,000 live births.