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CRISPR Hits Another Snag; But It’s Two Steps Forward, One Step Back

Summary: Market reaction to a report that cells edited with CRISPR technology can activate a cancer-causing gene has been severe for companies developing CRISPR-based therapies. But, the nascent industry has faced and survived such challenges before. Meanwhile, new tools are making gene therapies faster, easier and more accessible than ever, and lowering the industry’s barriers to entry.

Biotech companies developing CRISPR-based therapies received a massive blow this week after new research was published indicating that gene-edited cells could cause cancer.

Gene editing tool CRISPR-Cas9 has been hailed as a breakthrough that could allow scientists to treat and possibly cure genetic diseases, as the technology allows scientists and doctors to modify a living organism’s genome by snipping away genetic diseases. This form of genetic engineering entails inserting, deleting or replacing DNA in the genome using “molecular scissors.”

Standard CRISPR-Cas9 works by cutting both strands of the DNA double helix. That injury causes a cell to activate a biochemical first-aid kit orchestrated by a gene called p53, which either mends the DNA break or makes the cell self-destruct. But, that activation is potentially problematic because p53 can cause cancer. P53 mutations are responsible for nearly half of ovarian cancers; 43% of colorectal cancers; 38% of lung cancers; nearly one-third of pancreatic, stomach, and liver cancers; and one-quarter of breast cancers, among others. In short, the implications seem catastrophic for CRISPR’s future before it has had a chance to take off.

But, this is not the first time CRISPR has faced a major hurdle. Indeed, CRISPR has already dodged two potentially fatal bullets. As covered in our January 18 DIBs titled CRISPR’s Potential as the 21st-Century Cure-All Hits a Major Snag, a report of human immunity to Cas9 sent the stocks plummeting, only for the problem to be later shrugged off as solvable. Then, there was the 2017 claim that CRISPR causes sky-high numbers of off-target effects, which also triggered a sell-off in the stock market. However, following a reassessment, the claim was retracted in March 2018 due to insufficient data to support it. So, while experts are taking the cancer-risk finding seriously, there’s the possibility that a workaround could be found in the future.

Also, it is unclear whether the new findings translate into cells actually used in current clinical studies. In response to this development, Crispr Therapeutics CEO Sam Kulkarni points out that these results are likely to apply to just one type of CRISPR edits (replacing disease-causing DNA with healthy versions) and not the other type (just excising the DNA). And, while Cas9 is the most well-known CRISPR enzyme, there are others — Cpf1, for example — which may not cause the same issues with p53.

In the meantime, efforts to make gene editing easier and faster are bearing fruit, which should lower the barrier of entry for the technology. One of these wins comes from Synthego, a provider of gene editing services for genomics research and experimentation. The company just launched a new suite of products that makes it easier to experiment with programmable biology.

As with many new biological tools, not everyone has the access, time and ability to learn and use CRISPR efficiently to get the results they want. That creates a barrier against experimentation for new applications. Synthego’s service will provide researchers with genetic material that has already been edited using the CRISPR process, that way scientists can test their hypotheses around new treatments for diseases or new expressions of genetic traits faster. Synthego, a VC-backed company, is essentially offering gene editing as a service (GEaaS).

Separately, an international consortium of researchers has found a way to standardize CRISPR technology by simplifying its omplex implementation. The result is a simpler and faster CRISPR that offers a broad platform for off-the shelf genome engineering.

Shares of CRISPR companies plunged following the report about the cancer risk. However, an argument can be made that the downdraft presents an opportunity to buy-the-dip. This setback will likely turn out to be just a bump on the road towards CRISPR transforming medicine. The technology has broad applications, from health to material science to energy to agriculture. The impact on agriculture could be huge, as noted in MRP’s April 15 report – CRISPR Set to Capitalize on Use in Agribusiness.

There’s a long way to go before a viable commercial product comes to market, but patient investors with a strong enough stomach to handle a lot of upside and downside volatility in the stocks may deem the exposure to be worthwhile in these early days.

Notable stocks in the space include CRISPR Therapeutics (CRSP), Editas Medicine (EDIT), Intellia Therapeutics (NTLA), and Sangamo Therapeutics (SGMO).

We’ve also summarized the following articles related to this topic…

 

CRISPR: Gene editing just got easier

An international team of researchers has made CRISPR technology more accessible and standardized by simplifying its complex implementation. The simpler, faster CRISPR, which is presented in the journal Nature Communications, offers a broad platform for off-the shelf genome engineering that may lower the barrier of entry for this powerful technology.

The ‘traditional’ CRISPR approach presents some challenges, such as constraints on the sequences that can be targeted, the possibility of off-target effects and the requirement of a unique guide RNA for each target gene.

The new approach removes the need to design and clone a guide RNA and simplifies the strategy for constructing a rescue template. Also, the Keio collection can be found in laboratories across the globe and individual clones are available for a nominal fee from centralized genetic stock centers. The developed platform based on CRISPR technology will be valuable to many researchers in microbiology allowing them to perform rapid single nucleotide editing of their genes of interest or to generate chromosomal mutant collections, one of the first steps in understanding gene function. BCM.edu

 

CRISPR: Synthego’s pre-edited genetic material makes CRISPR research faster and easier

Synthego, a provider of gene editing services for genomics research and experimentation, has launched a new suite of products that give researchers access to edited genetic material to make experimenting with programmable biology easier. The company’s new service will provide researchers with genetic material that has already been edited using the CRISPR process so that scientists can test their hypotheses around new treatments for diseases or new expressions of genetic traits faster.

What Synthego is offering is basically gene editing as a service, according to the company’s chief executive Paul Dabrowski. Synthego’s first set of products were designed to simplify the process for identifying and designing genetic material for experimentation. This next set of tools are supposed to help scientists by providing them with the material they want to observe or experiment with. The new tools are significant because they’re among the first in the industry to guarantee the efficacy of genetically modified material.

Ultimately, the goal is to bring down the cost of targeted gene therapies and make them accessible for everyone. GLP

 

CRISPR: A serious new hurdle for CRISPR: Edited cells might cause cancer, two studies find

Editing cells’ genomes with CRISPR-Cas9 might increase the risk that the altered cells, intended to treat disease, will trigger cancer, two studies published on Monday warn — a potential game-changer for the companies developing CRISPR-based therapies.

Standard CRISPR-Cas9 works by cutting both strands of the DNA double helix. That injury causes a cell to activate a biochemical first-aid kit orchestrated by a gene called p53, which either mends the DNA break or makes the cell self-destruct. Whichever action p53 takes, the consequence is the same: CRISPR doesn’t work, either because the genome edit is stitched up or the cell is dead. That might explain something found over and over: CRISPR is woefully inefficient, with only a small minority of cells into which CRISPR is introduced, usually by a virus, actually having their genomes edited as intended.

The flip side of p53 repairing CRISPR edits, or killing cells that accept the edits, is that cells that survive with the edits do so precisely because they have a dysfunctional p53 and therefore lack this fix-it-or-kill-it mechanism. The reason why that could be a problem is that p53 dysfunction can cause cancer. And not just occasionally. P53 mutations are responsible for nearly half of ovarian cancers; 43 percent of colorectal cancers; 38 percent of lung cancers; nearly one-third of pancreatic, stomach, and liver cancers; and one-quarter of breast cancers, among others.

But don’t worry, the CRISPR revolution is far from over. First: these are very early-stage studies presenting “preliminary results” – it is unclear if the findings translate into cells actually used in current clinical studies.

Second, the studies focus on just one type of CRISPR edit: replacing disease-causing DNA with healthy DNA (“gene correction”) using CRISPR-Cas9. While Cas9 is the most well-known CRISPR enzyme, there are others — Cpf1, for example — and we don’t yet know if they’d cause the same issues with p53. We can also use CRISPR to simply knock out disease-causing DNA without replacing it (“gene modification”). This type of edit can stick even when p53 is functional.

The authors of the two new studies admit their research doesn’t mean CRISPR-Cas9 is “bad or dangerous,” we just need to proceed with caution. STAT Futurism

 

CRISPR: Crispr goes global: A snapshot of rules, policies, and attitudes

The gene editing technology Crispr has sparked great excitement, and provoked many concerns, regarding the economic, social, biosafety, bioethical, and biosecurity implications of Crispr-related work. And despite the scientific and policy interest in Crispr within the United States, no published studies have described how gene editing technologies are developing within and across specific country contexts.

To counter this, a study of gene editing developments from 2012 to 2018 in the following countries was conducted: Australia, Canada, China, France, Germany, Iran, Israel, Jordan, Kuwait, Malaysia, Qatar, Saudi Arabia, Singapore, South Korea, the United Kingdom, and the United States.

What the findings underscore is that the policy landscape for gene editing is highly contingent—and that a variety of enabling and constraining social factors will, in unpredictable and nontrivial ways, influence the development of gene editing within and across countries. Scientists and policy makers worldwide, as they formulate domestic and international policies on gene editing, will need to give appropriate weight to societal interests and concerns.

Transnational flow. An analysis of scientific developments in gene editing in each of the countries studied reveals a striking amount of transnational collaboration—in some cases, of an unexpected nature. Within and across these countries, universities, multinational corporations, and start-up companies are conducting gene editing research.

Regulatory issues. Within and across the countries studied, one sees that a varied and contingent regulatory landscape surrounds gene editing. To date, no internationally agreed-upon regulatory framework for gene editing exists, so each country is in the process of evaluating whether, and to what extent, current regulations are adequate for research conducted with, and applications and products related to, gene editing.

Varied stakeholders. The policy debate surrounding gene editing features diverse (and at times surprising) stakeholders who either favor or oppose use of the technology. In Australia, the National Association for Sustainable Agriculture Australia, a group that represents organic farmers, has come out strongly against efforts to relax regulations on gene editing. In contrast, environmental and conservation groups such as the nongovernmental organization Island Conservation—as well as government entities including the Institute for Marine Science—are pushing for deregulation of gene editing so that Crispr research might help protect Australia’s dying coral reefs.

Excitement and concern. Particularly outside Western countries, public opinion data regarding gene editing is often lacking. Across countries, more detailed research studies are needed to better understand public opinion about various facets of gene editing research and applications.

Open process. A consistent theme that emerged across various countries was the need for multi-stakeholder conversations about gene editing and an open, transparent process for discussing concerns and regulatory changes. Bulletin

 

CRISPR: CRISPR growing in cancer care, but will insurance companies pick up the cost?

Modern-day gene therapies often carry a $1 million price tag. However, treatments using CRISPR don’t yet have an estimated cost. But because the impact will be so dramatic, hopefully, the number of treatments should be low so in the long term the costs of treatment will be substantially reduced.

Christiana Care is developing CRISPR to lessen the burden of chemotherapy on patients with lung cancer. Since lung cancer is Delaware’s number 1 cancer killer, the hope is insurance companies will help cover CRISPR’s costs. Edmund Pezalla, the founder and CEO of Enlightenment Bioconsultant, says insurance companies tend to cover therapies that benefit the highest number of people. That means insurance companies likely won’t pay for treatments using CRISPR until there’s enough data available that demonstrates its effectiveness.

Generally though, they will pay for therapies approved by the FDA. And how much and what kind of CRISPR therapies are going to be FDA-approved versus there are going to be procedures done at various medical centers will change how it’s covered. Medical professionals looking to get a new treatment approved have to demonstrate outcomes and safety. The bar will be high before insurance companies will be willing to agree CRISPR demonstrates both.

Christiana Care and the Delaware Biotechnology Association held their first ever CRISPR Gene Editing 360 symposium on Friday, hoping to start conversations about the ethics of gene editing, rights to the technology and insurance coverage. DPM

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