THE FUTURE OF EPIGENETIC THERAPIES
There are well over 6,000 known genetic disorders, and new ones are constantly being described in medical literature. Scientists estimate that a majority share involve splicing mutations, either through direct mutation of the splice-site signals or through disruption of other components of the splicing pathway .
We focus on harnessing and utilizing the spliceosome machinery for modulating and correcting ribonucleic acid (RNA) transcript splicing and other post-transcriptional processes. Our platform technology, which is referred to as ASMO - Aptah Spliceosome Modulation Oligonucleotide, provides a unique and powerful therapeutic approach to treating various diseases associated with gene dysregulation.
Compared with the existing splicing-modulating small molecules or oligonucleotides, the ASMO technology goes beyond merely inhibition or suppression of aberrant gene expression and has the potential of restoring and reprograming the dynamic cascade of multiple RNA-protein interactions catalyzed by the spliceosome, including excision of introns and ligation of exons.
For example, the ASMOs may be deployed to specifically bind a pre-mRNA at multiple intron-exon junctions, where each ASMO recruits and stabilizes a spliceosome assembly at a pre-determined splicing site, thereby correcting aberrant splicing of the target pre-mRNA and reducing subsequent expression of proteins prone to misfolding or pathogenic aggregation. Neither RNAi- nor ASO-mediated knockdowns are capable of more generally addressing gene expression issues stemmed from aberrant transcript splicing or other post-transcriptional events.
Wang & Cooper 2007
The molecules can be designed to address different genetic disorders.
The same molecule specifically bind a pre-mRNA at multiple intron-exon junctions, with no off targets.
Control of Gene Expression
The molecules can be adjusted to precisely control the gene expression.
Our first target is the MAPT gene, which produces 6 isoforms of TAU, a protein that plays a fundamental role in maintaining brain cells healthy. Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain, derived from RNA mis-splicing, resulting in transcriptome perturbations that are implicated in Tau-mediated neurodegenerative mechanisms.
Tauopathies encompass more than 20 clinicopathological entities, including Alzheimer's disease, the most common tauopathy, progressive supranuclear palsy, Pick's disease, corticobasal degeneration and post-encephalitic parkinsonism , affecting millions of people worldwide. To date, there are no approved and established pharmacologic treatment options for tauopathies.
Aptah has developed a novel molecule that is able to ensure the correct binding of the pre-transcriptional proteins (U1 Complex) at multiple intron-exon junctions of the pre-mRNA, thus avoiding abnormal forms (instability and unbalance) of TAU and its neurofibrillary tangles (aggregation), a common cause to all Tauopathies.