Selonterra Publishes Novel Proprietary Mechanism for APOE4 in Alzheimer’s Disease

Selonterra LLC, a biotechnology company discovering therapies for Alzheimer’s disease and Parkinson’s disease announced the publication of the article "Identification of a Nuclear Respiratory Factor 1 Recognition Motif in the Apolipoprotein E Variant APOE4 linked to Alzheimer’s Disease" in Scientific Reports, a peer-reviewed journal of the Nature Publishing Group.

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects tens of millions of people worldwide. The most important genetic factor associated with late onset AD is APOE4, a DNA variant of the apolipoprotein E gene. Selonterra discovered that APOE4 is part of a short sequence repeat typically observed in DNA regulatory regions (transcriptional enhancers). The single nucleotide change in the APOE4 DNA generates a de novo binding motif for the transcription factor NRF1, a protein known to regulate key metabolic and mitochondrial genes. This mechanism allows for the integration of environmental factors known to influence AD, offers a new path towards understanding the tissue-specific progression of AD neurodegeneration and presents opportunities to discover novel AD therapies.

"The importance of APOE4 for AD has been recognized for decades but this has not translated to approved therapies" said Anne Urfer-Buchwalder, PhD, Co-Founder and CSO of Selonterra LLC. "In contrast to an involvement of the APOE4 protein in AD, our discovery suggests that it is the DNA sequence of the APOE4 variant itself that controls the expression of genes located in close vicinity to the APOE gene. The APOE4 / NRF1 -mediated expression of these genes may lead to the known hallmarks of AD."

"AD is one of the defining health challenges of our time" said Roman Urfer, PhD, Co-Founder and CEO of Selonterra LLC. "Therapies targeted at this novel mechanism have the potential for disease-modification because they will address the genetic root cause of AD. We hope that our discovery will serve as a stimulus for further research towards an effective treatment of this disease."

Selonterra intends to expand on these findings with an aggressive research and development effort to identify lead compounds acting on unexploited targets linked to this novel APOE4 mechanism.

About Alzheimer’s disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no reliable and effective methods for diagnosis, treatment or prevention. AD is caused by a combination of environmental, lifestyle, medical history and genetic factors. AD often goes unrecognized in its early stages where some treatments might be most effective. Current approved Alzheimer’s drugs offer symptomatic therapy but do not slow down the disease process or treat the underlying neuronal dysfunction.

About APOE4
APOE4 is a variant of the apolipoprotein E gene and arises from a single nucleotide transition. Many individual studies demonstrated a strong genetic link of APOE4 to AD and this variant accounts for the vast majority of the genetic contribution to AD. The APOE4 variant displays a life-time risk to develop AD (penetrance) of >65% in homozygotes, similar to well accepted disease causing genes such as BRCA for breast cancer. The APOE4 variant is present in over 50% of AD patients.

About Selonterra LLC
Selonterra LLC pursues transformative approaches to the development of therapies of Alzheimer's disease and Parkinson's disease. We harness human genetics, molecular pathway analysis and gene regulatory networks to identify proprietary disease-causing mechanisms and molecular targets, and exploit these to discover effective therapeutics. Selonterra’s founders and advisors are scientists and executives with decades of biotech and pharma experience. Our focus and passion has been the pursuit of therapies for neurodegenerative disorders.