Cannabinoids are a class of natural products shown to treat a wide range of diseases, including epilepsy, one of the most common neurological disorders. Epilepsy affects people of all ages, with over 50 million epileptics worldwide and over 150,000 new cases of epilepsy each year in the United States alone. Even with numerous anti-epileptic drugs (AED) available, 1/3 of patients have uncontrollable seizures that do not respond to treatment. Without proper seizure control the effects of epilepsy are more pronounced, and in children lack of seizure control not only interrupts early stage brain development but can also lead to social isolation. Recently, the endocannabinoid system (ECS) has been shown to play a powerful role in a number of neurological diseases, including epilepsy, creating a new therapeutic approach to control seizures where other AEDs have failed. One of the most effective and promising ECS-targeting therapeutics for seizure control is cannabidiol (CBD), a non- psychotropic naturally occurring cannabinoid. CBD is available over the counter in the United States and pharmaceuticals containing CBD are approved for use in many countries (currently in Phase III clinical trials in the United States). CBD is especially attractive since it has been shown to control seizures in patients with pharmaco-resistant seizures, especially children, with no significant side effects. Although CBD is effective with few side effects, pharmaceutical CBD has limited availability and high cost, primarily as a result of production shortcomings. The only source of pharmaceutical or consumer CBD is through agricultural production, purified from the cannabis or hemp plant. Further, pharmaceutical CBD is slated to cost $80-$160/day once approved in the United States. These high costs create a treatment gap between poor and wealthy patients and preclude access for the overwhelming majority of epileptics. To address this issue, Librede has developed a scalable yeast-based cannabinoid production technology capable of producing CBD in bulk for <10% of the cost of current production methods, allowing a broader population access to life-changing medicine. In Phase I work, we successfully engineered yeast to produce CBD using a low cost glucose feedstock. In the Phase II work proposed here, we will optimize CBD production through genetic, metabolic, and fermentation engineering to yields > 100 mg per liter of culture. Librede will combine targeted genetic optimization with a screened library approach to efficiently select yeast strains having improved CBD yield. Librede will also optimize growth and extraction conditions using commercial bioreactors (up to 300 L) to improve yield and develop methods compatible with high volume commercial production. At the conclusion of this work Librede will have a fully developed process for producing and purifying CBD at large scale and low cost. Widely available low cost CBD has the potential to make a significant difference in the lives of millions of epileptic sufferers worldwide.

Public Health Relevance

Cannabidiol (CBD) is a naturally occurring cannabinoid shown to be highly effective in treating pharmaco- resistant epilepsy with no side effects, particularly significant for children. Current plant-based production of CBD leads to high therapeutic costs and low availability, precluding access to treatment by the majority of the population. To address this problem, Librede has developed a yeast-based biosynthetic CBD production platform capable of large scale, low cost production. In this work we will optimize and scale CBD production yields.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Hopp, Craig
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Librede, Inc.
Sherman Oaks
United States
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