Generation of potent, safe and deliverable human Tau targeting siRNA for treatment of Tauopathies

Project SummaryOverall goalThis phaseSBIR application requests support to perform a large scale screen for highly active siRNA s targeting all hTau isoformsas well asRTau specific candidates as a first step in developing novel therapeutics for TauopathiesAn essential part of the proposed drug discovery and lead characterization work is the use of DTx Pharma s novel lipid conjugation technology to enable safe and effective delivery of bioactive siRNA into neuronal cells in vivoInitial animal work is focused on in vivo deliverytarget engagement in hTau transgenic mTauKO animalsand early safety assessments to select candidate siRNAs to advance into disease model proof of concept experiments and IND enabling work in a subsequent phaseapplicationThe timeline for these experiments ismonthsCompany Thesis and BackgroundDTx Pharma is a San Diego based startup developing a new technology for efficient delivery of nucleic acid medicines direct conjugation of novel lipid structuresproprietaryto siRNA or antisenseThe expertise of the founding team includes oligo therapeuticsIonisRegulusArcturuslarge pharmaPfizerJandamp JAstra Zenecaand neurodegenerative diseaseCurePSPTau ConsortiumDTx has identified novel lipid motifs that solve the fundamental problem of cellular uptake for siRNA creating molecules that are essentiallyself transfectingThe lead lipid motif works with any siRNA tested and appears to be a universal delivery reagent allowing efficient uptake into a wide array of cultured mammalian cell typesIn vivo the most extensive data comes from ocular administration where prolongedsafe and durable knockdown of several targets has been demonstrated in the retinaInitial experiments using intraventricular injection for CNS application have also been encouragingdemonstrating significant knockdown in multiple anatomic regionsHereDTx requests support to continue to develop this novel siRNA delivery technology as a new modality to tackle neurodegenerative diseases characterized by protein accumulation with hTau mRNA protein being the first targetSuccessful deployment of DTx delivery technology to achieve gene knockdown in the CNS would have a significant impact on the direction of the companyand if successfulwould open an avenue for the broader pharma community to use siRNA s safely and effectively against validated CNS targets where there is enormous unmet medical needHypothesis to be testedThe underlying hypothesis is that reducing Tau protein levels in neurons of patients with PSPCBDAD and other Tauopathies will slow or prevent disease progressionThis proposal covers initial steps and tests feasibility of developing a new modality to achieve therapeutic reduction of Tau expressionIn this phaseapplicationspecific lipid structures designed at DTx Pharmawill be directly conjugated to thepassengerstrand of siRNA sto improve cellular uptake and in vivo PK PD properties such that siRNA mediated therapeutic gene knockdown becomes feasible in the CNSin this applicationby targeting expression of TauProject NarrativeGeneticspathology and protein biochemistry all identify abnormalities in the Tau gene protein as being a cause of brain degeneration in rare diseases such as Progressive Supranuclear PalsyPSPCorticobasal DegenerationCBDChronic Traumatic EncephalopathyCTEand in the much more common Alzheimer s DiseaseADThese observations have suggested to many scientists and clinicians that reducing Tau protein in brain might slow or prevent neurodegenerationThis proposed study will generate and test DTx Pharma s proprietary lipid modified siRNAs targeting human Tau mRNAthereby reducing production of Tau proteinwith the goal of identifying and advancing a new drug candidate suitable for development as a treatment for the Taumediated disorders listed above