LAKE FOREST, Ill.--(BUSINESS WIRE)--Jaguar Gene Therapy, a biotechnology company accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases, including those that affect sizeable patient populations, today announced results of two preclinical studies of JAG101 in two different animal models of Type 1 galactosemia. Results showed that low and high doses of intravenous JAG101 given as a one-time gene replacement therapy reduced levels of toxic metabolites in brain and liver tissues and increased GALT enzyme expression and activity in tissues relevant to long-term outcomes in Type 1 galactosemia. The data are available online and will be presented later this week in poster sessions at the American Society of Gene and Cell Therapy (ASGCT) 25^th Annual Meeting in Washington, D.C.

Type 1 galactosemia is a rare genetic disease caused by mutations in the GALT gene that can lead to a severe deficiency in functional GALT enzyme. This in turn leads to a toxic accumulation of multiple metabolites, including galactose, galactose-1 phosphate (Gal-1P) and galactitol, which can be life-threatening in newborns exposed to galactose from breast milk or formula and can contribute to lifelong cognitive, neurological and speech complications. JAG101, an investigational gene therapy currently in preclinical development, is intended as a one-time treatment for Type 1 galactosemia.

“These preclinical data across two different animal models and in partnership with two different institutions demonstrate the potential of JAG101, intended as a one-time gene replacement therapy to deliver the functional GALT gene via the AAV9 vector, to address the root cause of Type 1 galactosemia by restoring levels of functional GALT enzyme and reducing toxic metabolites thought to contribute to the disease process,” said Suku Nagendran, M.D., President of R&D and Chief Medical Officer at Jaguar Gene Therapy. “In collaboration with researchers at Emory University and the University of Utah, we are conducting additional preclinical studies to evaluate JAG101 on measures of behavior and fertility. Pending the results of these IND-enabling studies, we plan to advance JAG101 into clinical development.”

Gene replacement therapy with JAG101 reduces pathogenic biomarkers in a mouse model of Type 1 galactosemia (abstract #1006)
In a mouse model of Type 1 galactosemia, a one-time low or high intravenous dose of JAG101 significantly reduced all three major metabolites associated with galactosemia (galactose, Gal-1P and galactitol) in the brain compared with vehicle. Both doses of JAG101also led to significant reductions in all three metabolites in the liver at 12 weeks compared with vehicle. Additionally, significant reductions in galactose and galactitol in muscle were observed at four weeks, with even greater reductions at 12 weeks. A significant reduction in Gal-1P in muscle was observed at 12 weeks with the high dose, which aligns with clinical experience in which intracellular Gal-1P is the slowest metabolite to be impacted by dietary changes. Both doses of JAG101 also resulted in increases in GALT enzyme activity in the liver, skeletal muscle and brain at 12 weeks, with activity levels approaching or surpassing wild-type levels in the liver and skeletal muscle.

Gene replacement with JAG101 leads to GALT transgene expression in target organs and reduces toxic metabolites in a rat model of Type 1 galactosemia (abstract #1008)
In a GALT-null rat model of Type 1 galactosemia, a one-time low or high intravenous dose of JAG101 demonstrated significant, dose-dependent increases in GALT expression and enzyme activity in tissues affected by galactosemia, including liver and brain, compared with vehicle, with robust GALT levels detected in neurons and glia in both the cortex and cerebellum with high-dose JAG101. GALT expression and enzyme activity were also significantly increased in skeletal muscle at five weeks compared with vehicle with both low and high doses. As skeletal muscle has a relatively stable population of cells and low cell turnover, these findings suggest that a single early dose of JAG101 results in extended durability of GALT activity. Administration of JAG101 also led to significant reductions in galactose and galactitol in the plasma, brain and liver, and significant reduction in Gal-1P in the liver and brain. Furthermore, JAG101 reduced the incidence and severity of cataracts, suggesting that lowering toxic metabolites associated with Type 1 galactosemia correlates with prevention of disease progression in a target organ.

About Type 1 Galactosemia
Type 1 galactosemia is a rare genetic disease that can be life-threatening for newborns and cause severe lifelong complications starting as early as the first year of life.^1,2,3 Galactosemia affects the body’s ability to make the enzyme that breaks down galactose, a simple sugar the body endogenously produces and is also found in dairy and other foods, including breast milk.^1,4,5 Type 1 galactosemia is caused by mutations in the GALT gene, which lead to a severe deficiency in functional galactose-1-phosphate uridylyltransferase (GALT) enzyme, which causes a toxic buildup of galactose and its metabolites including Gal-1P and galactitol. This buildup of toxic metabolites is a life-threatening medical emergency in newborns and can contribute to lifelong cognitive, neurological and speech complications, as well as primary ovarian insufficiency in girls and women.^1,2,4,5 Because of its severity, galactosemia is part of newborn screening in all 50 states of the United States and in several other countries.^1,2,5 No treatments are currently approved for galactosemia, and there is significant unmet medical need. The current standard of care – a galactose-restricted diet – is insufficient because the body endogenously produces galactose, causing patients to experience chronic complications.²

To learn more about Type 1 galactosemia, view the Roundtable Discussion Understanding Type 1 Galactosemia.

About JAG101
JAG101 aims to deliver a gene replacement solution to address the root cause of Type 1 galactosemia by delivering the functional GALT gene via an AAV9 vector. Gene therapy offers the opportunity to have immediate impact to reduce multiple toxic metabolites simultaneously, notably galactose, Gal-1P and galactitol, bringing them closer to a normal level to positively change the clinical course of the disease and mitigate longer-term complications. Jaguar has research agreements in place for the program with Emory University and the University of Utah, which produced encouraging preclinical proof-of-concept data in animals.

About Jaguar Gene Therapy
Jaguar Gene Therapy, LLC is dedicated to accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases including those that impact sizeable patient populations. The company is made up of a proven team of experts with unparalleled CMC (Chemistry, Manufacturing and Controls), regulatory, clinical and commercial acumen who have first-hand experience in bringing novel gene therapy treatments to patients and their families. Committed to patient safety and product purity, Jaguar is rapidly advancing an initial pipeline of three programs targeting: 1) Type 1 galactosemia; 2) a genetic cause of autism spectrum disorder and Phelan-McDermid syndrome and other severe neurodevelopmental disorders with a SHANK3 mutation or deletion; and 3) Type 1 diabetes. The company continues to evaluate opportunities to expand its pipeline using the strength of the team and close relationships with numerous academic institutions. For more information, please visit www.jaguargenetherapy.com and follow Jaguar Gene Therapy on LinkedIn.

References
¹Galactosemia. National Organization for Rare Disorders (NORD) Rare Disease Database. 2019. Accessed October 27, 2021. https://rarediseases.org/rare-diseases/galactosemia/
²Berry GT. Classic galactosemia and clinical variant galactosemia. February 4, 2000. Updated March 11, 2021. Accessed October 27, 2021. https://www.ncbi.nlm.nih.gov/books/NBK1518/
³Rubio-Gozalbo ME, Gubbels CS, Bakker JA, Menheere PPCA, Wodzig WKWH, Land JA. Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update. 2010;16(2):177-188. https://doi.org/10.1093/humupd/dmp038
⁴GALT gene. MedlinePlus. August 18, 2020. Accessed October 27, 2021. https://medlineplus.gov/genetics/gene/galt/
⁵Galactosemia. Genetic and Rare Diseases (GARD) Information Center. 2021. Accessed October 27, 2021. https://rarediseases.info.nih.gov/diseases/2424/galactosemia

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