By Jonathan Algoo and Richard Murphey
In this post, we provide a list of biotech startups funded in October 2020 and dig into the tech of two of these companies: Scribe Therapeutics and Be Biopharma.
If you are interested in other biotech startups that raised in October 2020, below is a spreadsheet with details on many of the companies that raised money, including their pipeline (targets, stage and indications), team, patents and publications.
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Scribe Therapeutics, founded by Nobel laureate Jennifer Doudna along with collaborators at UC Berkeley, raised $20M in its series A round led by Andreessen Horowitz. Scribe is building a platform of technologies designed to make in-vivo gene editing more readily usable, and the company has ambitious goals of using its platform to treat a wide variety of conditions. Scribe’s first announced program, a collaboration with Biogen to develop a CRISPR-based therapy for ALS, netted the company $15M initially with the potential of receiving more than $400M if research and development goals are met.1
Scribe’s major differentiator is their tech: they are using novel CRISPR-Cas technologies and exploring various delivery methods to enable in-vivo editing. They have used molecular engineering to augment an enzyme called Cas-X in order to make it more amenable for use in human therapeutic applications. Cas-X is part of the Cas family of proteins, which are bacterial defense mechanisms that locate and destroy viral DNA, but can be programmed to cut locations within the human genome. The most famous of these proteins, Cas-9, is being used by a number of different companies, such as CRISPR Therapeutics and Intellia Therapeutics, predominantly for ex-vivo gene editing therapeutics, which requires cells to be extracted, edited, and then re-administered. Scribe is focused on in-vivo editing, where gene editing works within body itself.
One difference between Cas-X and Cas-9 is its size: it is about 40% smaller than Cas-9.2 This allows it to be more readily incorporated into adeno-associated virus (AAV) vectors, which Scribe is using as a delivery modality for in vivo gene editing of target cells. AAV is a commonly used and effective vector for delivering gene therapies, but AAV has limited carrying capacity. Cas-9 and guide RNA strands packaged together can take up 4.2 kb, which is a significant part of the around 5 kb AAV capacity.3,4 The additional room left over by using an alternative such as Cas-X or another smaller Cas variant can be used to deliver other genomic tools.
Cas-X offers other benefits besides a smaller size. These include a better immunogenicity profile - unlike Cas-9, Cas-X is not found in bacterial cells within the body, so there is less likely to be pre-existing immunity to Cas-X.2 Scribe also claims its engineered Cas-X has a high editing efficiency rate, although it hasn’t released any specific data on this metric, and also claims to have high specificity.
Broadly, Scribe is one of many companies and research groups aiming to discover and develop new gene editing systems for use in both in vivo and in vitro gene editing applications. One example is Metagenomi, who recently raised a $65M Series A led by Leaps by Bayer and Humboldt Fund. Metagenomi is using artificial intelligence to mine environmental DNA samples for new gene-editing systems and developing them for use in gene editing.5 Smaller Cas-9 orthologs have been discovered as well, such as a 2.95kb-sized Cas-9 discovered in a bacteria called Campylobacter jejuni.6 All of these editing systems are quite early in development with limited published data on their efficiency, specificity, immunogenicity, and other important factors.
Be Biopharma aims to program B cells to secrete therapeutic proteins. The company, which raised $52M in a Series A round led by RA Capital and Atlas Venture, builds on research by David Rawlings and Richard James of the Seattle Children’s Research Institute that was spun out and seeded by Longwood Fund. The company hasn’t released any information about its pipeline, but noted that its cell therapies could be used for a variety of conditions ranging from cancer to infectious disease.7 These therapies capitalize on the intrinsic properties of B cells, which are a part of the humoral immune system and are responsible for producing antibodies to counteract foreign pathogens. These properties include the ability to produce a therapeutically significant amount of protein and a potentially decades-long cell survival time.8
Rawlings and James published a paper in 2017 describing a method of engineering B cells to produce and secrete proteins. In it, the researchers used CRISPR/Cas-9 to create a double-stranded break in the DNA of primary B cells. Concurrently, they provided a nucleotide template containing the gene that encoded for the protein they wanted expressed. They supplied this template using an adeno-associated virus (AAV). Through homology-directed repair, a natural mechanism the cell uses to avoid DNA damage by repairing double stranded breaks, the protein-encoding gene was integrated into the break. As a proof of concept for the therapeutic potential of the method, they knocked-in to the B-cells a gene coding for the FIX protein, a protein that causes hemophilia B when deficient. After the primary B cells differentiated into plasma B cells, they were able to verify the production of the FIX protein.9
The company does not disclose specific target indications, but hemophilia seems like a good example of a disease for which Be’s approach may be well-suited: diseases treatable by injection of a missing protein, but where protein replacement therapy has significant limitations.
Hemophilia is caused by loss of function mutations in genes coding for proteins that help blood clot. Patients experience spontaneous bleeding which can result in severe complications. Treatment includes replacement of the missing protein via injection into a patients’ vein so the blood can clot properly. Patients are treated episodically (during a bleeding episode) and prophylactically (to prevent future bleeding episodes).10
However, protein replacement therapy in hemophilia has limitations. It is estimated that only 20% of patients worldwide have regular access to protein replacement due to economic reasons, and 40% of adults do not routinely have access to prophylactic therapy.11,12 Thus gene therapy, which would reduce or eliminate the need for frequent injections, is attractive.
Many gene therapies are being developed with promising initial results, but there are some concerns about durability of protein expression. These concerns resulted in FDA’s refusal to approve Biomarin’s hemophilia gene therapy this August.13 While other gene therapies may prove effective and durable for hemophilia, the potential durability advantage of Be’s B cell therapies, combined with ability to re-dose (gene therapies typically cannot be redosed as the body develops an immune response to the viral vector), make their approach an interesting alternative therapeutic modality for hemophilia.
2 https://innovativegenomics.org/news/the-little-enzyme-that-can-meet-the-gene-editor-casx/
3 https://blog.addgene.org/a-match-made-in-heaven-crispr/cas9-and-aav
4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927556/
6 https://www.nature.com/articles/ncomms14500
9 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835153/
10 https://www.cdc.gov/ncbddd/hemophilia/facts.html
11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349562/
12 https://www.ajmc.com/view/ace0024_mar15_hemophilia_bauer
13 https://www.biospace.com/article/fda-rejects-biomarin-s-hemophilia-a-gene-therapy/