An Epic in miniature: CRISPR pioneer's startup reels in $55M to use tiny Cas for epigenetic engineering

CRISPR co-inventor Stanley Qi, Ph.D., is out with a new biotech that wants to make a big splash by going small. The startup, Epic Bio, corralled a investor syndicate willing to bet $55 million on its vision to use the smallest known Cas protein in epigenetic engineering. 

Epic Bio is the result of research to address one of the limitations of existing CRISPR-Cas systems. Many Cas fusion proteins exceed the maximum payload of adeno-associated virus (AAV) vectors, closing off a potential way to get them into cells. The discovery of Cas12f, which has around half as many amino acids as Cas9 and Cas12a, provided a starting point for the development of a more compact payload. 

Seeking to build on the discovery, Qi, the Stanford University scientist who founded Epic Bio, worked with his colleagues to apply RNA and protein engineering to the nuclease. The goal was to create a compact, efficient and specific system for mammalian genome engineering. 

Having published the results of his work last year, Qi has now taken the wrapping off Epic Bio. The West Coast biotech held its coming out party on Tuesday, putting out news of a $55 million series A round that positions it to explore the therapeutic potential of the protein, dubbed CasMINI.   

“Our vision at Epic Bio is nothing short of transformative: To create a new class of genetic medicines that can treat diseases for which there’s no effective treatment today,” Epic Bio CEO Amber Salzman, Ph.D., said in a statement. “We have a unique platform that enables in vivo delivery of our compact gene modulation components using AAV vectors that have already been de-risked in the clinic.” Salzman previously led biotechs including Ohana Biosciences and Adverum Biotechnologies.

Epic Bio’s initial hit list for CasMINI features five indications: Facioscapulohumeral muscular dystrophy (FSHD)​, heterozygous familial hypercholesterolemia, alpha-1 antitrypsin deficiency​, retinitis pigmentosa 4 and retinitis pigmentosa 11. 

FSHD, Epic Bio’s lead indication, is one of the more common forms of muscular dystrophy but is yet to be treated. The genetic disorder causes weakness of muscles in the face, shoulder blades and upper arms. The symptoms, which typically start before the age of 20, are thought to be linked to a mutation that affects the expression of the gene DUX4. Salzman sees FSHD as a good fit for Epic Bio’s GEMS platform.

“We wanted to address a great medical need where the biology was well understood, the cells needing correction were accessible with an AAV vector and our platform could address the root cause of the disease. It is well understood that FSHD is due to the D4Z4 region being hypomethylated leading to the toxic expression of DUX4. Our GEMS platform can target this specific site and re-methylate it to suppress DUX4 expression and therefore correct the cause of the disease. There is robust clinical data on the use of AAV to target myocytes,” the CEO said.

Multiple research groups have gone after DUX4, with Fulcrum Therapeutics running a phase 3 trial of an oral small molecule designed to reduce expression of the gene and Arrowhead presenting preclinical data on its RNAi candidate. However, Epic Bio sees a chance to improve on what has gone before in FSHD and has “a clear line of sight to clinical entry next year.” 

Epic Bio is moving into the clinic on the strength of studies including in vitro tests that have shown methylation of D4Z4 normalizes apoptosis. Seeing that as the “truest measure of disease correction in an in vitro assay,” Salzman has high hopes for the molecule. 

“Our treatment has the potential to achieve long-term re-methylation of D4Z4 in one single treatment and to stop stochastic expression of DUX4, which is crucial to restore normal tissue homeostasis. Since we are correcting the cause of the disease in a very targeted way, we will not be dependent upon downstream effects and reduce the risk of off-target toxicity,” the CEO said.