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

1008: Gene Replacement with JAG101 Leads to GALT Transgene Expression in Target Organs and Reduces Toxic Metabolites in a Rat Model of Type 1 Galactosemia

Type: Poster Session

Poster Board Number: W-134
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 an autosomal recessive disease caused by mutations in the GALT gene that lead to profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), an enzyme required to break down galactose. GALT deficiency results in an accumulation of galactose metabolites that can be life-threatening in newborns exposed to galactose from breast milk or dairy milk formula. Immediate restriction of dietary galactose can address acute symptoms of the disease. However, despite continued dietary intervention, most patients develop lifelong cognitive, neurological, and speech complications, ostensibly due to the endogenous production of galactose. Thus, there remains a high unmet need to develop disease-modifying therapies. JAG101 is an investigational AAV9 gene therapy in preclinical testing intended as a one-time treatment to restore metabolically effective levels of GALT activity during the postnatal to early childhood period considered most vulnerable. Here, we present data from a pre-proof-of-concept study characterizing the biodistribution of JAG101 transgene expression and its effects on key biomarkers and cataracts in a rat model of Type 1 galactosemia.
Methods: GALT-null rats were treated on postnatal day 2 (P2) with high (1.16E14 vg/kg) or low (3.82E13 vg/kg) dose IV JAG101, or vehicle. All rats were euthanized at either 2 or 5 weeks after treatment, and blood and key organs were assessed for GALT transgene expression, activity, and metabolic efficacy.
Results: GALT activity in liver and brain was undetectable in vehicle-treated rats but was strikingly elevated in JAG101-treated animals. Both enzyme activity assays and immunohistochemistry (IHC) staining showed that these increases were significant, dose-dependent, and present through 5 weeks. Further, brain samples showed robust GALT IHC signal in neurons and glia in both cortex and cerebellum following high-dose JAG101. Finally, strong GALT enzyme activity and IHC signals were observed in skeletal muscle at 5 weeks post-dosing in rats treated with JAG101.
Consistent with the role of GALT in the Leloir pathway, JAG101 not only restored GALT activity but also significantly reduced all three major metabolites associated with galactosemia: galactose, galactitol, and galactose 1-phosphate (Gal-1p). In plasma, JAG101 reduced galactose by up to 96% and 97% and galactitol by up to 92% and 50% at 2 and 5 weeks, respectively. In the brain, JAG101 reduced galactose by up to 96% and 95%; galactitol by up to 93% and 86.5%; and Gal-1p by up to 30% and 89% at 2 and 5 weeks, respectively. In the liver, JAG101 reduced galactose by up to 99% and 95%; galactitol by up to 88% and 35%; and Gal-1p by 95% and 97% at 2 and 5 weeks, respectively. Finally, compared to vehicle-treated rats, JAG101 reduced the incidence and severity of cataracts at both timepoints.
Conclusion: These data provide evidence that JAG101 increases GALT enzyme expression and function in both liver and brain; tissues relevant to long-term outcomes in galactosemia. Further, detection in muscle, a relatively stable population of cells, may predict extended durability of transgene expression following a single early dose. In sum, the results reported here documenting GALT restoration, metabolic efficacy, and representative phenotypic efficacy in a rat model of GALT deficiency support the continued development of JAG101, and suggest that lowering of toxic metabolites associated with Type 1 galactosemia correlates with prevention of disease progression in a target organ.

Michael Hughes1, Shauna Rasmussen2, Jennifer Daenzer2, Josephine Rudd2, Nathan Paull2, Sandeep Dhall1, Judith Fridovich-Keil2, Kevin Foust1

1Jaguar Gene Therapy, Lake Forest, IL,2Department of Human Genetics, Emory University School of Medicine, Atlanta, GA
  M. Hughes: 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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