Isabel Aznarez, Co-Founder and Senior Vice President of Discovery Research at Stoke Therapeutics explored how her Stoke Therapeutics’ TANGO (Targeted Augmentation of Nuclear Gene Output) technology can upregulate gene expression in the context of severe genetic diseases.
The technology targets pre-mRNA and is inherently cell type and tissue-specific. Aznarez added: “We don't need to worry about off-target expression or ectopic expression because we can only selectively boost the expression of the target gene where that target gene is expressed. By leveraging the wild type copy of a normal copy of the target gene, we are able to develop one drug one treatment for an entire patient population.” The main advantage of this approach is that it is mutation-independent, and the technology is not limited by the type or size of the gene.
TANGO was applied in the context of haploinsufficiency diseases. Haploinsufficiency diseases are caused by mutations in one allele while the other allele is normal meaning that one of the alleles cannot produce any functional proteins. The TANGO antisense oligonucleotide is used to target a non-productive inducing exon and then exclusively generate productive mRNA from both alleles. Aznarez noted that although the productive mRNA from the mutant allele would not lead to any functional protein, the increased levels of productive mRNA from the wild type allele will generate increased levels of protein to counter the loss of the mutant allele.
Aznarez outlined the technology’s potential in treating Dravet Syndrome, a severe form of epilepsy caused by mutations in the SCN1A gene leading to a 50% reduction in Nav 1.1 protein. A single dose of STK-001 restored NAV1.1 protein to near-normal levels in mice, improved survival rates, and reduced seizure frequency in mouse models. Regarding clinical data, Aznarez stated: “The single and multiple doses of STK-001 up to 45 milligrams have been very well tolerated in patients. Three doses of STK-001 of 45 milligrams is leading to a reduction of 55% median in convulsive seizures.”
Stoke Therapeutics has 4 targets in its pipeline for CNS diseases but has recently extended into ophthalmology, specifically autosomal dominant optic atrophy (ADOA). ADOA is caused by mutations in the OPA1 gene resulting in mitochondrial dysfunction and a 50% reduction in the OPA1 protein. The preclinical results for their drug candidate, STK-002, showed that cells treated with the TANGO ASO showed increased OPA1 protein levels and enhanced mitochondrial respiration.
In summary, the preclinical findings and early clinical data for STK-001 (Dravet Syndrome) and STK-002 (ADOA) show promising therapeutic potential to address the root causes of severe genetic diseases. Further research and collaborations in this area could change the treatment paradigm around haploinsufficient diseases.