Application
Point mutations in the genes HNRNPH2 and PCDH19 each cause a rare childhood neurodevelopmental disease. These diseases are characterized by developmental and intellectual retardation, muscle hypotonia, autism spectrum disorders, and severe epileptic seizures. Both genes are located on the X chromosome, and the disease is manifested in a heterozygous setting (in females) or mosaic expression (in males). The arbitrary process of X inactivation in females, likewise the mosaic expression of the mutation in males, creates a mixture of cells; some with intact protein and others with mutated protein, a situation which is believed to be the driver of the neurological phenotype. Furthermore, genetic testing of patient families suggests that these genes are dispensable.
Our Strategy
Our strategy is to silence HNRNPH2 orPCDH19, each in their respective disease, using antisense oligonucleotides.
We use GAPmers, which are short oligonucleotides composed of both DNA and modified RNA bases that are directed against the transcript of the target gene and have shown improved delivery in vivo over other oligonucleotide-based methods. HNRNPH2-or PCDH19-targeted GAPmers are expected to cause mRNA degradation of the respective transcript, thereby reducing the expression of the mutant protein. We predict that these GAPmers will be effective therapeutic agents to reverse the neurological phenotypes seen in affected children.
