Sierra Biopharma is Developing Antigen-Specific Therapy Targeting Autoimmune Diseases

Robert Fairclough and Vu Trinh

Sierra Biopharma, a biotechnology startup founded on intellectual property developed by researchers at the University of California, Davis, is developing a new therapeutic approach to treat autoimmune diseases.

Inventors and co-founders Robert Fairclough and Vu Trinh have set an initial focus on treating myasthenia gravis, a chronic autoimmune disease that affects 1.4 million people globally. Myasthenia gravis causes use-induced muscle fatigue and generalized muscle weakness that can result in life-altering difficulties with seeing, swallowing, talking and walking. The disease stems from a mistake made by the immune system in producing antibodies that bind to neurotransmitter receptors, triggering the immune system to destroy the folded post-synaptic muscle fiber membranes that are vital for repeated muscle contractions.

Sierra Biopharma is taking a new approach to treat the disease with an antigen-specific therapy that attacks the cause of the disease without suppressing the entire immune system. To accomplish this, the company is developing a biologic compound that not only binds to, neutralizes and clears the pathogenic antibodies, but also binds to and eliminates the memory B-cells responsible for producing more of the pathogenic antibodies.

Fairclough and Trinh recently completed the Biotech Innovation Gallery (BIG) Accelerator program led by UC Davis Venture Catalyst. The program provides leaders of UC Davis-associated biotech startups with training on how to develop an effective business model, strategies to protect intellectual property and guidance on how to pitch to potential strategic partners and investors.. The year’s program concluded with a showcase event where 22 startups, including Sierra Biopharma, pitched their value proposition to venture capitalists and biotech companies attending the annual J.P. Morgan Healthcare Conference in San Francisco.

“It was amazing to be surrounded by so many fantastic biotech startups from UC Davis,” said Fairclough, an emeritus associate professor in the UC Davis Department of Neurology. “We were able to pitch our research to so many VCs and companies and they provided us with great insight and guidance in how best to proceed with the company’s development.”

Sierra Biopharma is now scaling up production of the therapeutic biologic and plans to complete the proof of concept and preclinical work in the next six months. The company has accepted an invitation to participate in the 2020 Science2Startup showcase event — a forum for top scientists from around the world to present their ideas and interact with leading investors and executives in the Boston biotechnology hub.

Developing Novel Treatments for Depression and Related Disorders

Developing Novel Treatments for Depression and Related Disorders

Delix Therapeutics, founded by David Olson, an assistant professor in the Department of Chemistry and the Department of Biochemistry and Molecular Medicine, is investigating whether neural plasticity–promoting drugs can lead to new treatments for depression, anxiety and related disorders.

Atrophy of neurons in the prefrontal cortex of the brain is known to play a key role in depression and related diseases. The known antidepressant properties of ketamine, a dissociative anesthetic, may stem from its ability to promote neural plasticity–enabling neurons in the prefrontal cortex to rewire their connections.

In 2018, Olson and his team demonstrated that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA (commonly called Ecstasy), increase the number of neuronal branches, the density of small protrusions on these branches (dendritic spines) and the number of connections between neurons. Rats treated with a single dose of DMT (N,N-Dimethyltryptamine), a psychedelic compound found in Amazonian herbal tea known as ayahuasca, showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. Their work was published in the journal Cell Reports.

While drawbacks of using compounds such as LSD and MDMA as therapeutics include their hallucinogenic and psychostimulant effects, in a significant development Olson and his team discovered how to decouple the beneficial effects of neuroplasticity-promoting compounds from the unwanted hallucinogenic side effects.

This discovery could potentially open doors for the development of novel drugs to treat mood and anxiety disorders. Olson and his team have proposed the term psychoplastogen to describe this new class of “plasticity-promoting” compounds.

The company is investigating several distinct novel chemical scaffolds and molecules capable of promoting plasticity in order to develop safer and more effective alternatives to treat depression and related disorders.

Investigating a Better Therapeutic for Epilepsy

Syncanica Bio, a startup founded by Professor Mark Mascal

Syncanica Bio, a startup founded by Professor Mark Mascal with support from Ph.D. graduate Fei Chang, is investigating a synthetic cannabidiol (CBD) analogue as a novel therapeutic compound for conditions including anxiety, glaucoma and epilepsy.

Products containing CBD derived from cannabis or hemp plants have become popular for their potential health effects in part because CBD is less intoxicating than tetrahydrocannabinol (THC), the major psychoactive component found in marijuana.

Although the U.S. Food and Drug Administration in 2018 approved an oral CBD formulation for the treatment of some seizure conditions, CBD from extracts of cannabis or hemp poses legal problems in some states, as well as under federal law.

Mascal has developed an inexpensive synthetic alternative to CBD known as H2CBD—a molecule with a similar structure but made using commercially available compounds instead of extracts from hemp or cannabis.

H2CBD is non-intoxicating and easier to purify than the plant extract. It also eliminates the need to use agricultural land and irrigation for hemp or cannabis cultivation, avoids possible pesticide contamination and could circumvent the legal complications involved with cannabis-related extracts. Most importantly, unlike CBD, H2CBD cannot be converted to THC, eliminating the potential for abuse.

H2CBD was compared against herbal CBD in rats with induced seizures. H2CBD and CBD were found to be equally effective for the reduction of both the frequency and severity of the seizures. The work was published May 23, 2019, in the journal Scientific Reports.

Mascal is currently working with colleagues at the UC Davis School of Medicine to carry out additional studies in animals with the goal of moving into human clinical trials. UC Davis has applied for a provisional patent on anti-seizure use of H2CBD and its analogues.

UC Davis licenses novel compound that helps stem cells regenerate bone to treat bone diseases

Hybrid molecule LLP2A-Alendronate could have implications for osteonecrosis, fractures, osteoporosis and inflammatory arthritis.

From Left: Fred Tileston (RABOME, Inc.), Ruiwu Liu, Nancy Lane, Christy Pifer, Wei Yao, Kit Lam and Jiwei Chen (RABOME, Inc.)

From Left: Fred Tileston (RABOME, Inc.), Ruiwu Liu, Nancy Lane, Christy Pifer, Wei Yao, Kit Lam and Jiwei Chen (RABOME, Inc.)

The University of California, Davis, is pleased to announce a licensing agreement with Regenerative Arthritis and Bone Medicine, Inc. (RABOME) for a class of drugs developed at UC Davis that hold potential for treating diseases associated with bone loss and inflammatory arthritis.

The license, negotiated by the InnovationAccess team within the UC Davis Office of Research, provides the university affiliated startup with rights to four families of patents and patent applications related to the novel composition of a hybrid molecule, LLP2A-Alendronate, which has been found to effectively direct mesenchymal stem cells (MSCs) to induce bone regeneration in animal models. The compound works by guiding transplanted and endogenous MSCs to the surface of the bone where they differentiate into bone-forming cells, thereby increasing bone mass and strength. These cells are also immune-modulating which help to reduce inflammation at the target sites.

Distal femur from mouse showing more bone marrow (pink) and bone marrow filled with red sinusoids, a sign of higher vascularity, when treated with LLP2A-ALE for 90 days.

Distal femur from mouse showing more bone marrow (pink) and bone marrow filled with red sinusoids, a sign of higher vascularity, when treated with LLP2A-ALE for 90 days.

The use of stem cells as therapeutic agents is a growing field, but directing stem cells to travel and adhere to the surface of bone for bone formation has been an elusive goal in regenerative medicine.

“There are many stem cells, even in elderly people, but they do not readily migrate to bone,” said Wei Yao, co-inventor and associate professor at UC Davis. “Finding a molecule that attaches to stem cells and guides them to the targets we need provides a real breakthrough.”

Translating discovery into societal and commercial impact

Late last year, RABOME received approval from the Food and Drug Administration to begin Phase I clinical trials to evaluate the safety of the drug in humans. The study sites are currently screening patients for enrollment.

“We are pursuing several indications for use, but our initial focus is in developing a treatment for osteonecrosis, a disease caused by reduced blood flow to bones,” said Fred Tileston, president and chief executive officer of RABOME. As many as 20,000 people per year in the United States develop osteonecrosis.

RABOME also plans to pursue other indications for use including fracture healing, osteoporosis and inflammatory arthritis.

“We are pleased that this very promising technology is being shepherded by Mr. Tileston, who is an experienced business leader and entrepreneur,” said Dushyant Pathak, associate vice chancellor for Technology Management & Corporate Relations at UC Davis. “It is exciting to see the team’s progress in translating the discovery into commercial and societal impact.”

Breaking barriers through cross-discipline collaboration

The development of the novel therapy is the result of a successful research collaboration between two teams at UC Davis: a group of experts on bone health, led by Nancy Lane and Wei Yao from the Center for Musculoskeletal Health, and a group of medicinal chemists led by Kit Lam and Ruiwu Liu from the Department of Biochemistry and Molecular Medicine.

“This research was a collaboration of stem cell biologists, biochemists, translational scientists, a bone biologist and clinicians,” said Lane. “It was a truly fruitful team effort with remarkable results.”

Lane and Yao received a Disease Team Therapy Development research grant in 2013 from the California Institute for Regenerative Medicine (CIRM), which along with federal grants from the NIH, supported the preclinical research. CIRM was established in 2004 via California Proposition 71 to fund stem cell research in attempt to accelerate and improve treatments for patients where current needs are unmet.

About RABOME, Inc.

RABOME, Inc., was launched in 2013 to commercialize a class of drugs based on targeting mesenchymal stem cells to various sites of clinical relevance. The company is located in Hillsborough, California.

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