Cannabinoids are a general class of natural compounds that have a wide range of proven therapeutic effects. Studies of cannabinoids led to the discovery of the endocannabinoid system (ECS), regarded as one of the most important modulators of nervous system processes. Cannabinoids have been found to have efficacy in treating pain, neuroinflammation, and bone loss, among many other conditions. Cannabinoids can be found in many plants, the most well-known is Cannabis sativa, but, like many other natural products that have been developed into pharmaceuticals, the production of most of these compounds by the plant are at low levels. The difficulties in sourcing these cannabinoids inhibits research and makes their eventual development and production into pharmaceuticals problematic. To increase the accessibility as well as our basic knowledge of cannabinoids and enable the pursuit of natural cannabinoids as therapeutic agents, Librede has developed a biosynthetic cannabinoid production/drug discovery platform based on genetically engineered yeast with selected portions of Cannabis sativa metabolic pathways. The production of cannabinoids in yeast is an ideal platform because fermentation and genetic engineering are well-established, low cost, and scalable. Since we can choose to engineer yeast strains to produce only a single cannabinoid, the effort and cost of separation/purification are minimized. Furthermore it is a modular platform technology-by adding or removing expression of different enzymes, different cannabinoids can be produced as desired, even cannabinoids produced in low abundance naturally. Using this approach, in preliminary work we have produced Cannabidiolic acid (CBDA) in yeast, the world's first biosynthetically- produced cannabinoids outside of plants. This preliminary work converted hexanoic acid, added to the growth media, to CBDA demonstrating that the production of cannabinoids was possible. In order to increase the yield to provide compounds for early testing and to prepare for large scale production Librede has developed a method to produce cannabinoids from glucose. In the work proposed here, we will add the published glucose?hexanoic acid pathways to our yeast allowing for the production of CBDA from glucose. The platform is modular and can be used to create a wide range of natural cannabinoids. By swapping out the last enzyme in the biosynthetic pathway (e.g change CBDA synthase to CBCA synthase) different cannabinoids can be produced. As a result, we will have a modular, high yield platform for synthesis of specific natural cannabinoids from glucose which is scalable for production of compounds at levels suitable for basic research, clinical trials, and for therapeutic use.

Public Health Relevance

Cannabinoids are natural products with the potential to treat a wide range of diseases, but most are expressed in plants in very low levels, making their production and extraction highly uneconomical. Librede has developed the world's first in vivo biosynthetic platform for cannabinoid production from genetically engineered yeast. We propose to enable practical production with our platform by engineering the yeast to use glucose as a feedstock.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZAT1)
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Pontzer, Carol H
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Librede, Inc.
Sherman Oaks
United States
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