Mitochondrial-based Therapies Offer New Ways to Tackle Acute and Chronic Conditions

Photo courtesy of Cohbar

Photo Courtesy of CohBar, Inc. 

CohBar, Inc. is pioneering mitochondrial-based therapies with a candidate in a Phase Ia/Ib clinical trial as a potential treatment for nonalcoholic steatohepatitis (NASH) and obesity, where top-line results are expected later this year. A potential therapy for acute respiratory distress syndrome (ARDS) also is in preclinical development, along with other candidates that have the potential to enter Phase I trials in 2022.

The mitochondria offer a new approach to targeting diseases. The mitochondrial genome is 200,000 times smaller than the nuclear genome and has been largely overlooked by researchers. CohBar discovered that the mitochondrial genome encodes small peptides, some of which affect other systems in the body.

One of its notable programs focuses on COVID-19-triggered ARDS.

“Our novel CB5064 analogs are based on a particular mitochondrial gene sequence that generates a peptide capable of binding to the apelin receptor,” Steven Engle, CEO and director, told BioSpace.

That receptor affects multiple downstream processes implicated in protecting animals in preclinical models from respiratory disease, including potentially the cytokine storm that occurs in severe cases of COVID-19. Apelin is abundant in the lung, as well as in the heart, liver, and kidney. 

In animal models of ARDS, modulating the apelin receptor with CohBar’s novel compounds showed positive results, reducing the levels of fluid accumulation in the lungs, neutrophil infiltration, and cytokine secretion. In January, a few months after those results were announced, CohBar signed a Non-Clinical Evaluation Agreement with the National Institute of Allergy and Infectious Diseases (NIAID) to allow testing of its CB5064 analogs in animal models of COVID-19-associated ARDS.

Other preclinical programs address cancer, including targeting the CXCR4 pathway that is critical to growth and metastasis of many tumors. In animal models, when a standard chemotherapy drug and CohBar’s novel CXCR4 inhibitor (a CB5046 analog) were co-administered, the combination was more effective at reducing melanoma size than chemotherapy alone.

“That particular molecule has a nanomolar binding affinity, so it’s highly potent,” Engle said. “But why would the mitochondria genome encode a peptide with nanomolar binding affinity? We believe the mitochondria are directly regulating an important pathway in cancer. Nobody understood that until now.”

CohBar also is developing CB5138 analogs with potential for treating idiopathic pulmonary fibrosis (IPF), a chronic, progressive, debilitating and usually fatal interstitial lung disease that affects approximately 100,000 people in the U.S., and other fibrotic diseases. Engle said he expects that therapy to enter clinical trials next year. “We still have to run the necessary pre-IND studies.”

Unlike some nuclear DNA-based therapies, CohBar’s mitochondria-based therapies do not edit the mitochondrial genome, he said. Instead, they use the same pathways that mitochondria regulate by adapting mitochondrial peptides, building on millions of years of evolution. The natural peptides are often quite short-lived, with half-lives of a few minutes, but the analogs developed by CohBar have extended half-lives. The natural origin of these analogs also has the potential to result in safer molecules with fewer off-target effects than other approaches.

CohBar’s research, alongside that of a few additional companies, is changing the way scientists think about the mitochondria. “For 60 years people thought the mitochondria were primarily the cell’s powerhouses,” Engle said. Yet research shows they are much more important.

For example, published studies have shown that some of the peptides produced in the mitochondria affect signaling within and between cells, and regulating multiple biological systems, including, possibly, metabolism and the immune system, cell growth, and cell death.

Mitochondrial dysfunction can reduce both production of energy in the form of ATP and the production of mitochondrial peptides, contributing to disease. So far, NASH, obesity, type 2 diabetes, cardiovascular and neurodegenerative diseases, cancer, immune system and inflammatory disorders, fibrotic diseases, and acute respiratory distress syndrome (ARDS) have been linked to mitochondrial disorders.

CohBar’s founders Pinchas Cohen, M.D., dean of the University of Southern California’s Davis School of Gerontology and Nir Barzilai, M.D., director of the Institute for Aging Research at the Albert Einstein College of Medicine of Yeshiva University, created this new field of therapeutics when they discovered a series of peptides encoded within the mitochondria. Some of those peptides affected metabolic regulation and protection, contributing to age-related diseases.

CohBar (a combination of their surnames) was founded in 2009. Since then, researchers at CohBar have discovered more than 100 new peptides encoded in the mitochondrial genome with possible therapeutic potential.

Currently, CohBar is evaluating the library of peptides encoded in the mitochondrial DNA. “We believe that because they are so few that are active, many of them may be important,” Engle said. The team at CohBar has generated more than 1,000 analogs to assess as  possible leads for potential development as druggable compounds.

“We take those mitochondrial-encoded peptides, synthesize them, and test them using in vitro assays to determine their function. Then we create analogs and perform additional tests including efficacy in animal models of disease to hone those functions and develop enhanced molecules,” Engle said.

“We’re not trying to fix the mitochondria,” he stressed. Instead, CohBar is using mitochondria as a source of new medicines, creating compounds that can be injected into the bloodstream to treat acute or chronic diseases.

Why does this mitochondrial dysfunction exist? As Engle elaborated, “In the cellular genome, there is an error correcting system. In the mitochondria, this system is much less robust.”

“The mitochondria generate ATP and, in the process, they also generate reactive oxygen species that can have deleterious effects on the mitochondria genome.” This deterioration can also reduce the production of mitochondrial peptides, potentially contributing to aging and its associated diseases.

Throughout the industry, Engle said, drug development is shifting its focus from organs to cells. As that occurs, researchers are seeing that “the mitochondria affect a large number of systems in multiple ways. Yet, some are still surprised at how one organelle can have so many different effects.”

Increasingly, researchers realize that addressing mitochondrial dysfunction may play an important role in increasing “healthspan” – not extending lifespan, but extending the time during which a person is healthy and can live a productive life.

“Interest in mitochondria focused drug development is rising and moving beyond scientific conferences into the investor conferences”, Engle noted. “It may take center stage as therapeutic solutions are approved in the future.

For now, though, CohBar is focused on the studies needed to advance compounds into the clinic and is anticipating announcing Phase Ib results for CB4211 when they become available. “Next year, we hope to have multiple clinical studies moving along at the same time based on our development activities.”

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