Stoke Therapeutics Presents New In-Vivo Data Demonstrating Dose-Related Target Engagement and OPA1 Protein Upregulation in Retinal Tissue Following Administration of STK-002

Stoke Therapeutics announced new preclinical data that demonstrated dose-related target engagement and increases in OPA1 protein levels in retinal tissue of non-human primates (NHPs) following intravitreal (IVT) administration of STK-002. Target engagement and OPA1 protein increases were sustained for at least 8 weeks post-injection. A dose-related increase in OPA1 protein was also detected in retinal ganglion cells (RGCs) of NHPs treated with STK-002. STK-002 is a proprietary antisense oligonucleotide (ASO) in preclinical development for the treatment of Autosomal Dominant Optic Atrophy (ADOA), the most common inherited optic nerve disorder. The data were presented at the Association for Research in Vision and Ophthalmology (ARVO) 2022 Annual Meeting. 

ADOA affects approximately one in 30,000 people globally with a higher incidence (one in 10,000) in Denmark 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.

“The progressive vision loss experienced by people living with ADOA is typically the result of a mutation in their OPA1 gene, which leads to insufficient protein production and a loss of retinal ganglion cells,” Edward M. Kaye, MD, Chief Executive Officer of Stoke Therapeutics, said in a company news release. “Stoke’s approach is to selectively boost protein production from the healthy copy of the OPA1 gene to prevent damage to the RGCs and, ultimately, slow or even stop vision loss. These data are encouraging because they show, for the first time, that we can increase protein levels in retinal tissue and in the retinal ganglion cells, giving us additional confidence that STK-002 could address the underlying cause of ADOA.”

In this study, NHPs were given bilateral IVT injections of either placebo or STK-002 at low, mid or high doses. Assessments were made at 4 weeks for all dose groups and at 8 weeks for the mid- and high-dose groups.

Highlights from the presentation include:

• IVT administration of STK-002 was well-tolerated in NHPs;
• Target engagement was demonstrated by the dose-related reductions in nonsense-mediated decay (NMD) transcripts in retinal tissue observed at 4 weeks and 8 weeks;
• Significant increases in OPA1 protein in retinal tissue at four weeks that persisted at 8 weeks in the mid- and high-dose groups;
• Dose-related increase in OPA1 protein in RGCs treated with STK-002 was detected using immunofluorescence;
• Concentrations of STK-002 in retinal tissue persisted at substantial levels at 4 weeks and at 8 weeks in the mid- and high-dose groups; and
• Dose-related increases in STK-002 in RGCs were observed.

Details of Stoke’s presentations at the ARVO Annual Meeting:

Presentation Title: STK-002, an Antisense Oligonucleotide (ASO) for the Treatment of Autosomal Dominant Optic Atrophy (ADOA), is Taken Up by Retinal Ganglion Cells (RGC) and Upregulates OPA-1 Protein Expression After Intravitreal Administration to Non-human Primates (NHP)

Presenter: Karen Anderson, D.V.M., PhD, Ophthalmology Program Lead, Stoke Therapeutics

Session: Gene therapy and other novel therapeutics in ophthalmic diseases 1

Date: May 2, 2022

Presentation Number: 1111

In addition, a presentation of data from an in vitro ADOA model of OPA1 haploinsufficient RGCs was presented in a poster session today. In this study, haploinsufficient induced pluripotent stem cells (iPSCs) carrying OPA1 mutations were treated with STK-002 and showed a dose-responsive reduction of non-productive OPA1 mRNA and an increase in total OPA1 mRNA in total neurospheres. The results support the hypothesis that TANGO ASOs can potentially be used to treat ADOA caused by OPA1 haploinsufficiency and provide a useful in vitro model to evaluate TANGO ASOs.

Poster Title: Models of Autosomal Dominant Optic Atrophy (ADOA) using iPSCs and response to Targeted Augmentation of Nuclear Gene Output (TANGO) Antisense Oligonucleotides (ASOs) Treatment

Presenter: Raymond Oh, Ph.D., Associate Principal Scientist, Stoke Therapeutics

Session: Animal models of human ocular disease

Date: May 2, 2022

Poster Number: 1895 – A0041

The presentations at ARVO are now available online on the Investors & News section of Stoke’s website at https://investor.stoketherapeutics.com/events-and-presentations.