GM1 is a rare neurodegenerative disease with no approved treatment

Disease overview: GM1 pathophysiology

GM1 gangliosidosis (GM1) is a rare inherited neurodegenerative disease caused by loss-of-function mutations in the galactosidase beta 1 (GLB1) gene, which encodes lysosomal beta-galactosidase (β-gal), the enzyme that catalyzes the first step in the degradation of GM1 ganglioside and keratan sulfate.

Patients with GM1 have little to no residual β-gal activity. Consequently, there is progressive accumulation, ultimately to toxic levels, of GM1 gangliosides (primarily in neurons in the brain) and keratan sulfate (primarily in peripheral tissues).

Earlier onset and greater severity of disease generally correlate with lower levels of β-gal activity. Early Onset Infantile (Type 1) GM1, the most common (>60%) and most severe form of the disease, has a symptom onset by 6 months of age and is associated with rapid neurodegeneration. Hypotonia, hepatosplenomegaly, developmental delay or regression, seizures, macula cherry-red spot, skeletal dysplasia, blindness, and deafness are common. Children with Early Onset Infantile GM1 usually do not survive beyond the early childhood years.

Patients with Late Onset Infantile (Type 2a) GM1 exhibit symptom onset generally between 6 months and 2 years of age. Symptomatology is similar to that of Early Onset Infantile GM1, but with a slower rate of disease progression. Life expectancy is 5 to 10 years of age.

Patients with Juvenile Onset (Type 2b) GM1 and Adult Onset (Type 3) GM1, have slower and more heterogeneous rates of decline, with onset as early as 2 to 5 years and > 5 years of age, respectively.

GM1 is an autosomal recessive disease with an estimated global incidence of 1:100,000 to 1:200,000 live births. Currently there are no approved disease-modifying therapies for GM1. Management is limited to supportive care, with a focus on respiratory health, seizure management, and nutrition.

As a monogenic disease, GM1 represents an ideal opportunity for treatment with gene therapy. Additionally, β-gal is a secreted protein that can be taken up by neighboring cells via the mannose-6-phosphate receptor (a process referred to as cross-correction). This provides expansion of potential benefit to cells beyond those directly transduced by PBGM01.


PBGM01: Investigation of an optimized gene therapy for GM1

Our gene therapy product candidate, PBGM01, utilizes an AAVhu68 viral vector to deliver a codon-optimized gene sequence encoding functional β-gal enzyme. The vector will be delivered directly to the cerebrospinal fluid by a single injection to the cisterna magna (ICM injection), with the goal of increasing β-gal enzyme activity levels in the both the central nervous system and periphery.

Preclinical data in a murine knockout model demonstrate that a single-dose, intracerebroventricular injection of PBGM01 restored β-gal activity in the brain and peripheral tissues, reduced brain lesions, prevented onset of neurological signs of GM1, and improved survival. Additional data in non-human primates demonstrated diffuse AAV transduction in the central nervous system from a single ICM injection.

Imagine-1 Logo

Imagine-1 clinical study

Imagine-1 is a multinational Phase 1/2 study designed to examine the safety, tolerability, and efficacy (including developmental and functional measures) of PBGM01 in patients with Early Onset Infantile (Type 1) and Late Onset Infantile (Type 2a) GM1, confirmed by low β-gal enzyme activity and genetic testing.

Imagine-1 is now enrolling patients with GM1

To learn more about the Imagine-1 clinical trial, please visit clinicaltrials.gov.

If you are a health care provider and would like information about the Imagine-1 trial, please email medinfo@passagebio.com.

If you are a caregiver seeking further information for possible referral to a clinical trial site, please visit https://www.PBGM01.com

Additional information for health care providers

To learn more about Passage Bio’s clinical trials, please contact us at medinfo@passagebio.com.

Natural History Study for GM1

Passage Bio has collaborated with the Orphan Disease Center (ODC) at the University of Pennsylvania to conduct a GM1 Natural History Study. This study aims to collect information that will allow a better understanding of the natural course of disease in patients receiving supportive care and to identify demographic, genetic, environmental, and other factors associated with this disease.

The design of the study includes input from patients and their families, foundations, clinical experts in the field, and the FDA. Data from the study may be used to construct natural history patient profiles for use as matched case controls for comparison to the profiles of treated participants in the Imagine-1 trial.

To learn more about enrolling in this Natural History Study, contact the Orphan Disease Center at ODCResearch@uphs.upenn.edu or visit clinicaltrials.gov.