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E - Disease Models and Clinical Applications -> Metabolic, Storage, Endocrine, Liver and Gastrointestinal Diseases

1006: Gene Replacement Therapy with JAG101 Reduces Pathogenic Biomarkers in a Mouse Model of Type 1 Galactosemia

Type: Poster Session

Poster Board Number: W-132
Presentation Details
Session Title: Metabolic, Storage, Endocrine, Liver and Gastrointestinal Diseases II
Location: Hall D
Start Time: 5/18/2022 17:30
End Time: 5/18/2022 18:30

Background: Type 1 galactosemia is a rare genetic disease caused by autosomal recessive mutations in the GALT gene that lead to a severe deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme necessary for conversion of galactose to glucose and UDP-galactose. GALT deficiency leads to a toxic accumulation of multiple metabolites including galactose, galactose-1 phosphate (Gal-1p), and galactitol. The build-up of these metabolites is life-threatening in newborns and although such lethality can be prevented by newborn screening programs and a galactose-restricted diet, endogenous production of galactose persists. As a result, despite continued dietary intervention, most patients develop lifelong cognitive, neurological, and speech complications, as well as primary ovarian insufficiency in females. Therefore, there remains a high unmet need to develop disease-modifying therapies. JAG101 is an investigational AAV9 gene therapy in preclinical development intended as a one-time treatment to restore levels of functional GALT enzyme during the critical postnatal to early childhood period. Here, we present data from a pre-proof-of-concept (POC) study characterizing the effects of JAG101 on key biomarkers in a mouse model of Type 1 galactosemia.
Methods: GALT gene-trapped mouse pups were treated on postnatal day 9 (P9) with high (1.15E14 vg/kg) or low (3.74E13 vg/kg) dose IV JAG101, or vehicle. Animals were sacrificed at either 4 or 12 weeks after treatment, and organs that have the highest degree of damage in galactosemia patients were assessed in the mice. Postmortem tissue analyses included assessment of biomarkers for galactosemia pathophysiology, GALT enzyme activity and immunohistochemistry.
Results: Treatment with JAG101 led to a significant reduction of all three major metabolites associated with Type 1 galactosemia. In the brain at 4 weeks post-treatment, high-dose JAG101 led to a 76% reduction (p=0.0017) and low-dose JAG101 led to a 55% reduction (p=0.009) in galactose levels vs. vehicle. Brain Gal-1p levels were reduced by 59% (p<0.0001) and 48% (p=0.0001), and brain galactitol levels were reduced 48% (p=0.0005) and 27% (p=0.0178) by high and low doses of JAG101, respectively, vs. vehicle. Reductions of all metabolites in the brain were still apparent at 12 weeks following treatment and remained statistically significant in the high-dose JAG101 treatment arm vs. vehicle. In muscle at 4 weeks, galactose was reduced by 51% (p=0.0003) and 33.6% (p=0.0068), and galactitol was reduced 66.8% (p<0.0001) and 57.8% (p<0.0001) by high and low doses of JAG101, respectively, vs. vehicle. These metabolite changes in muscle were even greater at week 12, when galactose was reduced by 52% (p<0.0001) and 45% (p<0.0001) and galactitol by 78% (p<0.0001) and 74% (p<0.0001) by high and low doses of JAG101, respectively. There were no significant changes in Gal-1p in the muscle at week 4 (21% reduction for high-dose JAG101 vs. vehicle, p=0.3609), but there was a significant reduction of the biomarker in the high-dose JAG101 treatment arm at week 12 vs. vehicle (38%, p=0.0185). This delayed change aligns with clinical experience where intracellular Gal-1p is the slowest metabolite to be impacted by dietary changes.
Conclusion: The results of this pre-POC pilot study to assess biomarker changes in relevant tissues of interest suggest that a one-time treatment with JAG101 in patients with Type 1 galactosemia may lead to the reduction of metabolites that are known to contribute to disease pathophysiology. Additional preclinical studies are being conducted to evaluate the effect of JAG101 on measures of behavior and fertility.

Sandeep Dhall1, Bijina Balakrishnan2, Aaron J. Guo2, Michael Hughes1, Kent Lai2, Kevin Foust1

1Jaguar Gene Therapy, Lake Forest, IL,2University of Utah, Salt Lake City, UT
  S. Dhall: 1; Commercial Interest i.e. Company X; Jaguar Gene Therapy. 1; What was received? i.e. Honorarium; Salary. 1; For what role? i.e. Speaker; Employee.

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