Multi-dose pre-clinical studies in rat for E1-targeting antisense oligonucleotides

Abstract The objective of this project is to develop a multi dose safety profile for a novel drug candidate to treat a devastating neurodegenerative disease called Spinal Muscular AtrophySMASMA is an autosomal recessive disorder that is the leading genetic cause of infantile deathoccurring inlive birthsThe gene responsible for SMA is called survival motor neuronSMNSMNis nearly identical to SMNhowevermutations in SMNhave no clinical consequence if SMNis retainedThe reason SMNcannot prevent disease development in the absence of SMNis that most SMNderived transcripts are alternatively splicedresulting in a truncated and unstable proteinThe presence of SMNoffers exciting therapeutic strategies including modulating the pathogenic alternative splicing of SMNexonIn this projectwe will build upon the findings in the Lorson lab at the University of Missouri that identifiedElementEas a potent repressor of SMNexoninclusionThey discovered a single Phosphorodiamidate Morpholino OligomerPMOan antisense oligoASOtargeting Elementsignificantly extended survival in two important SMA animal modelsRigorous analysis of Elementsequence led to the design of several additional PMOssome of which simultaneously targeted both ends of thenucleotide EA panel screen of these ASOs identified a lead candidate exhibiting greater efficacy across a range of doses examined in cellular and SMA animal modelsThis compounda singlebase PMO called E vis the focus of this Phase I proposalThe Lorson lab has collected data from single dosedose range studies with E vin SMA mice showing single doses that extend survival of SMA mice more thandaysHoweverrepeat dosing is necessary for treatment in humansThusShift proposes a pilot safety study modeled from both FDA guidelines and pre clinical studies for Spinrazafirst FDA approved SMA drugto prepare for Investigational New DrugINDenabling studiesAs part of the investigational drug processFDA requires safety data from two modes of deliveryand adult and juvenile animals for drugs to treat pediatric patientsIn Aimwe will collect toxicology data in a multi dose study of intrathecal injections of E vPMO in adult Sprague Dawley ratsAimwill collect toxicology data in a multi dose study of subcutaneous injections of E vPMO in juvenile SpragueDawley ratsThis project brings the exceptional properties of PMOsefficacysolubilitytolerabilityto an entirely unique genetic target within SMNthe Erepressor regionSMA is a complex genetic disorder with a broad clinical spectrumWith the recent FDA approval of Spinrazait is important to continue to develop additional unique SMA therapeuticsWe believe an E vPMO will be a powerful and valuable addition to the SMA drug portfolio Project narrative Spinal Muscular AtrophySMAis a devastating neurodegenerative disease that is the leading genetic cause of infantile death worldwideIn this proposala novel drug will be critically assessed and moved closer to the clinic for treatment of SMA