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While much hype has been built around CRISPR-Cas9 and its ability to revolutionize treatment of genetic disorders and disease, the past few weeks have shown that significant barriers to commercialization remain for these therapies. Some major challenges include the potential of off-target effects (both known and yet to be discovered), decelerated clinical trial timelines due to lack of regulatory precedent and heightened oversight, and perhaps most significantly, the fear of the permanence of in vivo human gene modification. Focus thus far has remained on the companies pioneering medicines using the conventional CRISPR-Cas9 duplex; however, recent coverage of impediments to therapeutic application of CRISPR-Cas9 further reinforces the need to track players leveraging CRISPR in novel ways to change the landscape of human health.
Co-founded by a team of Stanford and Berkeley PhDs and leading CRISPR researcher Jennifer Doudna, Mammoth Biosciences emerged from stealth mode earlier this year, announcing $23M in Series A funding this week. The company is developing a rapid, point-of-care (POC) clinical diagnostic using the CRISPR “DETECTR” system developed by Mammoth Diagnostics co-founder Janice Chen and other clinical diagnostics researchers in the Doudna Lab. Instead of using CRISPR’s familiar sidekick, Cas9, DETECTR leverages cousin proteins, Cas12a and Cas13, and associated guide RNAs to locate a target sequence and cleave a fluorescent reporter molecule, triggering a color change that indicates the presence of the target DNA or RNA sequence. The POC diagnostic’s potential lies in its programmability to detect virtually any DNA- or RNA- based disease marker by applying a fluid sample to a credit card-sized strip and instantaneously analyzing results via smart phone imaging. By creating a pregnancy-test-like digital POC diagnostic with applicability to both fast-growing markets (e.g., early cancer detection, liquid biopsy) and legacy diagnostic markets (e.g. infectious diseases), Mammoth is poised to disrupt the diagnostics industry.
Beam Therapeutics, headed by a Broad Institute all-star team including Feng Zheng, David Liu, and Keith Joung, uses a variation of CRISPR-Cas editing called “base editing”. Base editing involves programming a CRISPR enzyme (e.g., Cas9, Cas13b) to be DNA or RNA target-specific and tethering it to an editing enzyme (e.g., a deaminase) that directly converts one base to another (e.g., A-to-G or C-to-T), as opposed to the double-strand break and repair approach that “conventional” CRISPR-Cas9 uses. There are a few advantages to this approach:
(1) By also targeting RNA for editing, base editing paves a pathway for offering transient genomic therapies delivered through re-dosing;
(2) While CRISPR-Cas9 is limited by non-dividing cells’ inability to efficiently repair induced mutations through homology-directed repair (HDR), direct base conversion does not rely on HDR and is thus effective both dividing and non-dividing cells, ameliorating challenges associated with targeting cell types with low division frequency (e.g., hematopoietic stem cells, liver, eye, neurons, muscle); and
(3) The approach uses modified CRISPR enzymes that are deactivated, avoiding creation of a double-strand break in the DNA and allowing precise point mutation repair, reducing the chance of off-target effects.
Beam’s strategy to take on point mutation-based diseases may position them well to compete with the “Big 3” therapeutics companies, as these diseases represent over half of all genetic diseases and are widely perceived as the “low-hanging fruit” in gene editing, due to the relative simplicity of single-base substitution. Despite Beam’s late-start in the race to bring CRISPR into the clinic, the company’s differentiated approach that addresses many of the biggest concerns and shortcomings associated with CRISPR-Cas9 makes Beam a tortoise other gene editing companies should watch closely as clinical trial activity heats up.
While the CRISPR-based human diagnostics and therapeutics space has been quickly carved up by a few leading companies, agricultural and ecological biotech applications of CRISPR remain an open playing field. In October 2017, the Broad Institute, in partnership with DuPont Pioneer, announced open provision of non-exclusive licenses of its foundational IP to interested developers. In March 2018, the USDA released an official statement greenlighting CRISPRed crops as exemptions from genetic modification (GM) regulation. These events mark a significant deviation for the AgTech industry, which has been dominated by large multinational seed producers with the foothold and resources to outcompete emerging players attempting to encroach on their “big-money” genetically modified organisms (i.e., corn, cotton, soy, and wheat).
The relatively democratized field for CRISPRed crop development has given early rise to a number of small companies looking for a seat at the table. Companies like Pairwise Plants, Yield10 Bioscience, and Benson Hill Biosystems have begun developing products ranging from more productive biofuels to big data analytics platforms for identifying new targets for CRISPRed trait development and improved crop performance. Academic institutions like Penn State and Cold Spring Harbor Laboratory have engineered browning-resistant mushrooms and higher-yield, rot-resistant tomatoes. Additionally, a host of DIY “farmhackers” have begun working on proprietary CRISPRed crop variations, hoping to carve out markets for small independent crop development. While early days show promise for a diverse, deregulated, and democratized marketplace for CRISPR agriculture, legacy players like DowDuPont (via subsidiary Corteva Agriscience) and Monsanto (directly and via investments in smaller players like Pairwise) will undoubtedly continue to stake out their claims.
Human therapeutics remains a cornerstone application of the technology that scientists, investors, and the public should keep under close watch; however, one’s understanding of the space must extend beyond this to include novel, alternative approaches and applications subject to different rules, regulations, and fundamental biology that offer equal promise for the future of CRISPR and threaten to disrupt industries beyond therapeutics.
Chris Lew is an Associate at DeciBio interested in innovative genomic and health technologies and their impact on population health. He has experience developing go-to-market strategies, evaluating market and technology opportunities, and supporting commercial due diligence for companies in the NGS, CRISPR, immuno-oncology, and R&D and clinical decision support spaces. Connect with him on LinkedIn.
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