A microbial engineering platform for sustainable, scalable, and cost-effective production of pharmaceutical grade cannabinoids and related compounds

Abstract Cannabinoids and compounds made from Cannabis have a diverse range of therapeutic potentials, including novel treatments for pain, seizure disorders, neurodegenerative diseases, addiction, and cancer. The Cannabis plant itself produces over 400 unique compounds, 100 of which are bioactive cannabinoids that can activate the endocannabinoid system through activating the G-protein-coupled receptors CB1 and CB2. The interest in developing effective cannabinoid-based pharmaceuticals has only grown in recent years, with four FDA- approved drugs on the market, and 200 trials in progress for a variety of therapeutic applications. Despite their high therapeutic promise, critical issues in cannabinoid production have strained the commercial supply chain. Cannibis plant cultivation uses large amounts of water and energy, and the realities of agricultural production result in variable year-to-year yields and pesticide impurities. Adding to the issue, the purification process of a specific cannabinoid from the many compounds produced by Cannibis plants are extremely labor and manufacturing intensive, leading to prohibitively expensive final products. To overcome these challenges, Cellibre is developing a fermentation-based microbial engineering and biofactory platform to produce high-quality, cost-effective cannabinoids. This method has the potential to reduce the costs of cannabinoid manufacturing by 5-10x and establish Cellibre as cost-effective, environmentally friendly leader in cannabinoid manufacturing. By selecting bacterial and yest strains that naturally produce high concentrations of cannabinoid precursors, then bioengineering them to encourage cannabinoid synthesis, Cellibre has yielded fermentations of THCVA (2.7 g/L), CBGA (3.9 g/L) and other minor cannabinoids (i.e CBCA ~1.5 g/L) of high interest to drug development. To accelerate these breakthroughs from proof of concept to scalable commercial platforms, this Direct to Phase II project has the following two specific aims: 1) De-bottleneck metabolic pathways to achieve >5 g/L of CBGA and THCVA, 2) Establish a process ready for technology transfer with an overall COGS <$500/kg. These aims will result in the development of a pipeline capable of producing therapeutically relevant cannabinoids at commercially viable titers, paving the way for the development and effective production of cannabinoid-based treatments for a wide range of devastating diseases.