# APOE-targeted therapy for precision medicine in late onset Alzheimer's disease: A novel epigenome editing approach for downregulation of APOEe4 expression

> **NIH NIH R41** · CLAIRIGENE, LLC · 2022 · $492,903

## Abstract

ABSTRACT
Alzheimer'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 Alzheimer'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
NIA'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 ani...

## Key facts

- **NIH application ID:** 10481174
- **Project number:** 1R41AG077992-01
- **Recipient organization:** CLAIRIGENE, LLC
- **Principal Investigator:** Elaine Hamm
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $492,903
- **Award type:** 1
- **Project period:** 2022-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10481174

## Citation

> US National Institutes of Health, RePORTER application 10481174, APOE-targeted therapy for precision medicine in late onset Alzheimer's disease: A novel epigenome editing approach for downregulation of APOEe4 expression (1R41AG077992-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10481174. Licensed CC0.

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