Innovative Epigenome Editing Adds to Precision Medicine Approach for Alzheimer Disease


Boris Kantor, PhD, associate research professor of neurobiology, and Ornit Chiba-Falek, PhD, professor in neurology, both faculty at Duke University, discussed research on an innovative epigenome therapy targeting the APOE gene, a significant genetic risk factor for Alzheimer disease.

Boris Kantor, PhD, associate research professor of neurobiology, Duke University

Boris Kantor, PhD

Genetic predisposition significantly influences the onset of Alzheimer disease (AD) and the e4 allele of apolipoprotein (APOE) is the most prominent genetic risk factor for the disease. Patients with the APOE e4 heterozygous allele experience a 3-fold increased risk of developing AD, while those with the APOE e4 homozygous have a 15-fold higher risk. Recent advances in large-scale genome-wide association studies have revealed numerous genetic loci that contribute to the risk of AD, although their individual effects are considerably smaller compared with the impact of APOE e4.1

In a recent study, a epigenome therapy strategy demonstrated efficacy in editing the epigenome landscape of APOE region in human induced pluripotent stem cells (hiPSC) -derived neurons and the human isogenic APOE e4 organoids, ultimately reducing the levels of APOE-mRNA and the protein in both models.2 Presented at the 2023 Alzheimer’s Association International Conference, July 16-20, in Amsterdam, the Netherlands, the epigenome therapy platform was designed to reduce APOE and APOE e4 alleles specifically by targeting modification of the epigenome landscape in APOE locus, based on the CRISPR/dCas9-editing strategy.

Recently, lead author Boris Kantor, PhD, associate research professor of neurobiology, and senior author Ornit Chiba-Falek, PhD, professor in neurology, both faculty at Duke University, sat down with for an interview NeurologyLive® to discuss the research further. They talked about how the epigenome therapy targets the APOE gene and reduces its expression. Also, they shared some critical points on the focus of this intervention before moving to clinical trials, especially in terms of safety and dose escalation studies. Additionally, Kantor and Chiba-Falek explained how the innovative epigenome editing approach differs from other gene editing methods and the advantages it offers for treatment in AD.

Ornit Chiba-Falek, PhD, professor in neurology, both faculty at Duke University

Ornit Chiba-Falek, PhD

NeurologyLive: Could you just give a brief overview of your presentation of your research?

Ornit Chiba-Falek, PhD: We presented a poster that described in vivo and in vitro proof of concept of our APOE targeted epigenome therapy for AD. We used an all-in-one viral vector comprises of a CRISPR-repressor caste system and targeted to the APOE region, which is the strongest and the most reproducible genetic risk factor for AD. Once the system is ‘navigated’ and ‘finds’ the genomic region of APOE, it's closing the chromatin around the APOE region and leading to reduction in the risk APOE allele expression. In the presentation, we described the development of the system, and showed in vitro and in vivo proof of concept for target engagement of the system to reduce APOE levels in both hiPSC-derived cerebral organoids and the hippocampus of mice models, and the efficacy to rescue pathological features of AD.

What are your thoughts on the findings from your research?

Ornit Chiba-Falek, PhD: The findings are very promising and pivotal for moving forward to IND-enabling studies towards obtaining approval for clinical trials with this intervention.

Boris Kantor, PhD: We have a long way to go with models we utilize in our small animal models all the way to patient. It’s a long way with a lot of challenges. The approach is completely novel. We have very solid data demonstrating efficacy in targeted engagement, and partially a safety profile of this quite unique innovative system. It's what people call a “New generation” approach. We don't have an answer whether it will be translatable all the way. All we can say at this point is that we have solid data to support the development target engagement and efficacy of the system in small animal models.

The next step would be for us gather safety information utilizing these animal models in AD as well as non-animal models such as iPCs, organoids,etc. Once again, to gain as much information as possible on the safety profile, any possibilities for off target effects, and sustainability of the effect. This will support moving the system to the next step which will be larger animal models, such as nonhuman primates. Then, hopefully they're optimistic [enough] about this technology and its development to move into to human patients.

What else do you think would be the next steps of investigating this research?

Ornit Chiba-Falek, PhD: The next steps are proceeding to the IND enablement studies so we can move forward with clinical trial. These will focus on comprehensive safety studies, assessments of other route of administration, and the durability of the effect.

Boris Kantor, PhD: Some critical points are safety. We will conduct dose-escalating studies with different concentrations to make sure we’re hit the correct dose because after injection you cannot go back to change the dosage. These dose-escalating studies will help select the appropriate dose for next step in nonhuman primates. The second point is the rules of injection. So far, we have proof that our system is very efficient in indirect injection into the brain, otherwise called stereotactic injection. We would love to develop something we’ll have to test and apply it in less radical, medical injections, such as injections deep into the brain to potentially moderate any side effects.

The third important point is durability in vivo with this so far. In this poster, we have data from six weeks and it's very encouraging. We see a vast and persistent effect that is down on the regulation of APOE expression. We see a very good response and outcome in these six weeks and the question is whether the effect will persist further. The idea behind gene therapy application is to utilize one time injection and correct the phenotype that is associated with Alzheimer disease. Again, it’s a long road, but at least it's very encouraging and satisfying to see the efficiency of the system so far. These are the few points that will be crucial in order for the FDA to move this technology to a clinical trial.

What are the advantages of using this type of innovative approach for treatment in AD?

Boris Kantor, PhD: Epigenome editing approach is innovative based on technology that introduces no changes to DNA compared with the classic way of gene editing, which is active enzyme Cas9. We use a deactivated, or dead, version of cas9, which cannot cut DNA, so there is no damage to DNA. Damage to DNA has been shown off-target, as I mentioned before, as active cas9 can induce apoptosis. It can impair signaling by activating this PG pathway and causing apoptosis. So, no DNA damage, at least, based on our preliminary results and less off-target effects. And this technology operates very early on, on the transcription level. Other technologies, antibodies developed to target amyloid plaques, operate downstream, offering a disadvantage when the disease is already established and the damage is done. You can improve symptoms and help these patients,but in many cases, these treatments are conducted in the final stages of progression when the harm is done. Our technology may be used in a much earlier development progression of the disease.

It even can be aimed in prophylactic work for prevention of AD, which is a long way away. But with all these biomarkers in genetic testing for APOE, it's very easy. It only needs a DNA sample, and it can tell you whether you are homozygous or heterozygous to APOE. Genetic testing and biomarkers are extensively promising. You can utilize these systems and these assessments to target the patient population and then apply this technology, which again targets very upstream, and that's a huge advantage.

Ornit Chiba-Falek, PhD: This is precision medicine. We are taking it forward and looking specifically for patients living with AD because of the pathogenic form of APOEe4. By this, we are advancing the field towards precision medicine in AD.

Transcript edited for clarity. Click here for more coverage of AAIC 2023.

1. Stocker H, Trares K, Beyer L, et al. Alzheimer's polygenic risk scores, APOE, Alzheimer's disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years. Alzheimers Res Ther. 2023;15(1):129. Published 2023 Jul 29. doi:10.1186/s13195-023-01277-8
2. Kantor B, Rittiner J, Odonovan B, Chiba-Falek O. APOE-targeted epigenome therapy for late onset Alzheimer’s disease. Presented at: 2022 Alzheimer’s Association International Conference; July 16 to July 20; Amsterdam, the Netherlands. Abstract 80698.
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