Anti-sense oligonucleotide platform for rare genetic diseases of the nervous system

Project SummaryAntisense oligonucleotide platform for rare genetic diseases of the nervous system Rare diseases affect nearly one in ten people in the United StatesApproximately two million of those individuals suffer from rare diseases of the nervous system such as ALSFragile X SyndromeRett Syndromeand severe epileptic encephalopathiesOrphan disease variants are often not of interest to large pharmaceutical companiesAs a resulthundreds of thousands of patients are left not knowing the causepotential treatmentsor prognosis for their disease creating a large unmet medical need globallyAntisense oligonucleotides or ASOs have several characteristics that make them amenable to a precision medicine approach for treating underlying genetic defectsThe FDA has recently approved multiple ASO products for the treatment of rare genetic disease in severe cases unresponsive to traditional drug therapiesThese include nusinersen for the treatment of spinal muscular atrophyeteplirsen for the treatment of Duchene muscular dystrophy and mipomersen for the treatment of homozygous familial hypercholesterolemiaTherapeutic ASOs are generallynucleotides in length and complementary to mRNA or pre spliced mRNA to either inhibit translation through RNAseH mediated mRNA decay or induce exon skipping or inclusion during mRNA splicingThe type of disease causing variantwhether recessivedominant gain offunction or dominant loss offunctionhaploinsufficiencyand intended mode of action of the ASO dictate the design requirement for ASO treatmentDespite the recent clinical successesASO design is not rational and requires hundreds of ASO candidates to be synthesized and then evaluated in cell based assays to identify top ASO candidatesMany of these ASOs often contain undesirable characteristics reducing the probability of positive outcomes in in vivo models and in safety evaluationIn Phasewe propose to construct a variant classification algorithm to determine which variants may be amenable to ASO treatment and construct an algorithm to design an appropriate ASO therapy for the associated rare disease variantWe will use ASOs designed through these algorithms to test their efficacies in patient derived iPS cell derived neurons with causative variants for early infantile epileptic encephalopathya devastating neurological disease associated with rare variants in KCNQand KCNToften resulting in significant intellectual development impairment and mortality in childhoodWe will expand our ASO platform to new genetic diseases and ASO methodologies in Phasewith the goal of developing treatments for patients with rare neurological disorders Project NarrativeAntisense oligonucleotide platform for rare genetic diseases of the nervous system Although the FDA has recently approved multiple antisense oligonucleotidesASOsfor the treatment of rare genetic diseasesthere remain several shortcomings in the existing tools used to design and validate ASOWe propose to construct a variant classification algorithm to determine which variants may be amenable to ASO treatment and construct an algorithm to design an appropriate ASO therapy for the associated rare disease variantWe will use ASOs designed through these algorithms to test their efficacies in patient derived neurons with causative variants for early infantile epileptic encephalopathya rare devastating neurological disease associated with variants in in the genes KCNQand KCNToften resulting in significant intellectual development impairment and mortality in childhood