CLAIRIgene — Department of Health and Human Services STTR Phase I: NIA

Description

ABSTRACT Alzheimerandapos;s disease (AD) is the most common cause of dementia in aging. With a rapidly growing aging population, the number of AD cases is growing fast and projected to rise drastically over the next three decades. Therefore, AD poses a huge economic burden on society, placing overwhelming strain on the healthcare system. These trends will worsen because there are no therapies to halt or prevent AD, projected to cost more than $1.1 trillion annually by 2050. Despite all the research effort, money, and commitment, there is no cure for AD, nor any disease-modifying therapies (DMT) to slow down or even delay the progression of the disease. Moreover, numerous clinical trials to identify disease-modifying therapies (DMT) for AD have failed. Thus, AD remains a critical unmet medical need, and there is an urgent need to refocus on other targets and shifting the paradigm of AD drug development towards precision medicine. Apolipoprotein E (APOE) is the strongest and most reproducible genetic risk factor for late-onset Alzheimerandapos;s disease (LOAD). Recent studies in cellular and mouse models demonstrated that 50% reduction in APOE levels has beneficial effects. Collectively these observations lend support to the development of APOE as a new emerging therapeutic target for LOAD. CLAIRIgene, and partners at Duke University in this STTR Phase 1 propose to develop epigenome editing tools to downregulate APOE expression precisely and in e4 allele-specific manner. The technology prototype is based on CRISPR/deactivated(d)Cas technologies fused with epigenome modifiers that repress gene expression and delivered by lentiviral (LV) vehicle. We will develop this technology prototype by accomplishing two specific aims. Aim 1 will develop the system to precisely reduce APOE e4-allele expression and evaluate the efficacy and specificity of the technology using isogenic hiPSC lines carrying the e4/4, e3/4 and e3/3 genotypes. We expect specific reduction in APOE e4-mRNA and protein levels amounted to ≥50%. Aim 2 will validate the beneficial impact of the system using hiPSC derived from a patient homozygote for the APOE e4 allele that will be differentiated into neurons, astrocytes and microglia-like cellular models. We expect that these experiments will provide proof-of-concept for the feasibility of the system to effectively rescue pathological phenotypes characteristic of LOAD. The expected outcomes are relevant to the NIAandapos;s mission of the development of innovative products that may advance progress in preventing and treating AD and related dementias (ADRD). Upon completion of Phase 1, CLAIRIgene will have proven the feasibility of targeted epigenome editing to reduce APOE e4 levels specifically and efficiently and provide an in vitro proof- of-concept that this strategy has beneficial effects in reversing molecular and cellular pathological phenotypes related to LOAD. This will provide the foundation for Phase II which will focus on in vivo validation in AD animal models, and ultimately to advance this APOE-targeted epigenome therapy towards clinical studies for precision medicine in LOAD.PROJECT NARRATIVE Late onset Alzheimerandapos;s disease (LOAD) is a critical unmet medical need, and the disease process starts decades before plaques or tangle neuropathologies are detectable; thus, early identification of individuals at- risk and administering interventions in the preclinical stage will be beneficial. The APOE gene has shown the strongest genetic association with LOAD and the APOE e4 allele is the major risk factor in the development of LOAD, nonetheless, APOE as a therapeutics target has been understudied. CLAIRIgene seeks to develop viral-delivered epigenome therapy to downregulate precisely the expression of APOEe4 allele based on CRISPR/deactivated(d)Cas technology fused with gene expression repressors. The development of our innovative product will advance the discovery of preventive therapies and/or delay onset treatments targeting molecular events caused by the APOEe4 allele pathogenesis, that occur early, years before the manifestation of neuropathological changes and clinical symptoms.