Stoke Therapeutics Presents New Data That Demonstrate Tango Antisense Oligonucleotides (ASOs) Increase OPA1 Protein Production and Improve Mitochondrial Function in Cells Derived From Patients With Autosomal Dominant Optic Atrophy (ADOA)

Rhea-AI Summary

Stoke Therapeutics (Nasdaq: STOK) announced new preclinical data showing successful in-vitro protein upregulation and enhanced mitochondrial function in fibroblasts from ADOA patients. This data highlights the effectiveness of their TANGO approach in addressing the OPA1 protein deficiency, the primary cause of ADOA. With ADOA affecting approximately 1 in 30,000 people, the findings suggest a path toward disease-modifying treatment. Key results include a 35% to 47% increase in OPA1 protein isoform expression and improved mitochondrial bioenergetics.

Positive

• Demonstrated in-vitro improvement in mitochondrial function in OPA1-deficient fibroblasts.
• Increased OPA1 protein isoform expression by 35% to 47%.
• Potential for TANGO approach to provide a disease-modifying treatment for ADOA.

Negative

• None.

Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company dedicated to addressing the underlying cause of severe diseases by up-regulating protein expression with RNA-based medicines, today announced new preclinical data demonstrating in-vitro protein upregulation and improved mitochondrial function in OPA1 protein-deficient fibroblasts derived from patients with ADOA. OPA1 protein deficiency is the primary cause of ADOA and reduced OPA1 levels are associated with impaired mitochondrial function. The data will be presented today at The Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting and at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting on Tuesday, May 11, 2021 from 8:00 AM – 10:00 AM Eastern.

“These findings are important because they offer the first evidence from patient cells that our TANGO approach can address the underlying cause of ADOA by upregulating OPA1 protein production and increasing mitochondrial function,” said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. “ADOA represents a strong fit for Stoke’s science and our strategy: targeting severe genetic diseases that are caused by protein deficiencies and that have limited, if any treatment options. A disease-modifying approach would represent a significant advancement in the treatment of this disease.”

ADOA affects approximately one in 30,000 people globally with a higher incidence in Denmark of one in 10,000 due to a founder effect. An estimated 65% to 90% of cases are caused by mutations in the OPA1 gene, most of which lead to a haploinsufficiency resulting in 50% OPA1 protein expression and disease manifestation.

“By demonstrating an improvement in the mitochondrial function of patient cells across different OPA1 mutations, the data suggest that ASO mediated increase in OPA1 could be sufficient to slow or reduce disease progression in a mutation-independent manner,” said Gene Liau, Ph.D., Chief Scientific Officer of Stoke Therapeutics.

The data presented today provide in-vitro proof-of-concept for TANGO ASOs in ADOA patient fibroblasts. Highlights from today’s presentation include new data that demonstrate ADOA patient fibroblast cell lines treated with TANGO ASOs exhibit:

• Reduced non-productive exon inclusion and increased total OPA1 mRNA expression in three patient fibroblast cell lines with different mutations;
• Increased expression of multiple OPA1 protein isoforms by ~35% to 47%; and
• A dose-dependent improvement in mitochondrial bioenergetics.

Details of today’s presentation are as follows:

Presentation Title: Antisense oligonucleotide mediated increase in OPA1 improves mitochondrial function in fibroblasts derived from patients with autosomal dominant optic atrophy (ADOA)

Session Date & Time: Tuesday, May 4, 2021; 2:15 p.m. – 3:45 p.m. E.T.

Session Title: Gene therapy in ocular diseases

Presenter: Aditya Venkatesh, Ph.D., Senior Scientist, Stoke Therapeutics

The presentation at ARVO is now available online on the Events and Presentations section of Stoke’s website at https://investor.stoketherapeutics.com/.

About Autosomal Dominant Optic Atrophy (ADOA)

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic nerve disorder. It is a rare disease that causes progressive and irreversible vision loss in both eyes starting in the first decade of life. Symptoms typically begin between the ages of 4 and 6 years old, affecting males and females equally. The severity of the condition by adolescence reflects the overall level of visual function to be expected throughout most of the individual’s adult life. Roughly half of people with ADOA fail driving standards and up to 46% are registered as legally blind. ADOA is considered a haploinsufficiency disease, as most people living with ADOA have genetic mutations in the OPA1 gene that result in only half the necessary OPA1 protein being produced. More than 400 OPA1 mutations have been reported in people diagnosed with ADOA. Currently there is no approved treatment for people living with ADOA. ADOA affects approximately one in 30,000 people globally with a higher incidence in Denmark of one in 10,000 due to a founder effect. An estimated 65% to 90% of cases are caused by mutations in the OPA1 gene, most of which lead to a haploinsufficiency resulting in 50% OPA1 protein expression and disease manifestation.

About TANGO

TANGO (Targeted Augmentation of Nuclear Gene Output) is Stoke’s proprietary research platform. Stoke’s initial application for this technology are diseases in which one copy of a gene functions normally and the other is mutated, also called haploinsufficiencies. In these cases, the mutated gene does not produce its share of protein, so the body does not function normally. Using the TANGO approach

FAQ

What new data did Stoke Therapeutics present regarding ADOA?

Stoke Therapeutics presented new preclinical data demonstrating significant in-vitro protein upregulation and improved mitochondrial function in fibroblasts from ADOA patients.

How does the TANGO approach work for treating ADOA?

The TANGO approach targets the underlying cause of ADOA by increasing OPA1 protein production, thereby enhancing mitochondrial function.

What is ADOA and its prevalence?

Autosomal Dominant Optic Atrophy (ADOA) is a rare inherited optic nerve disorder affecting about 1 in 30,000 people globally, with a higher incidence in Denmark.

When and where will the data on ADOA be presented?

The data will be presented at the ARVO 2021 Annual Meeting on May 4, 2021, and at the ASGCT Annual Meeting on May 11, 2021.

What are the implications of Stoke's preclinical data for ADOA treatment?

The findings suggest that the TANGO-mediated increase in OPA1 could potentially slow or reduce disease progression in ADOA.