Finally, Useful Gene Editing
Every organism’s life is controlled by its genetic code, which contains the “manual” for building the proteins performing all biological functions. As a result, any genetic anomaly can be deadly or cause crippling diseases.
This is why doctors and scientists have been looking at how to edit genes since they were discovered.
The issue that blocked most progress is that our genetic material is very complex, and locked away inside the cells’ nucleus. And that most of the affected tissues would need to be modified genetically for symptoms to disappear.
So until recently, any genetic modification had to be done in a relatively crude way, with little control over where the newly inserted gene would go, creating many side effects. This would also not be enough when a treatment would require the repair of a defective gene.
This has all changed with the discovery of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in 2012, a mechanism by which some bacteria can perform precise and controlled gene editing.
This discovery would quickly revolutionize the entirety of biotechnology, and received the Nobel Prize of Chemistry in 2020, a remarkably short time after its discovery compared to the average of most Nobel awards.
Source: Nobel Prize
One of the 2 women awarded this Nobel Prize, Emmanuelle Charpentier, would go on and found the company leading the charge to commercialize this technology, becoming the first ever company to get a CRISPR gene editing therapy approved by the FDA: CRISPR Therapeutics.
CRISPR Therapeutics AG (CRSP -0.3%)
What Is CRISPR?
CRISPR-Cas9, the CRISPR system that was awarded the Nobel Prize, allows us to “edit” genes in a targeted fashion, pinpointing a specific spot of the genome to be replaced by the genetic sequence of interest.
CRISPR can be used in multiple ways to interrupt a gene already present, delete a specific sequence, or edit/insert the right genetic sequence.
Source: CRISPR Therapeutics
In each case, gene editing will only be done in one specific section of the whole genome in an entirely predictable fashion. This is important as undirected gene insertion has been linked to major problems, notably cancer risks, making their therapeutical use difficult and controversial.
In addition, the CRISPR-based gene modification process is mostly harmless for the targeted cells, reducing the treatment’s toxicity by an order of magnitude compared to previously used methods.
Future of CRISPR
CRISPR is now investigated for many applications, of which the most advanced and important are likely to treat incurable genetic diseases, as well as cancers. This is important, as rare diseases, which have genetic causes for 72% of them, have been some of the hardest-to-cure diseases.
CRISPR could also be used to create new methods to deal with plastic pollution, create organic fertilizer solutions, meat substitutes, safer GMOS, etc.
In the long term, CRISPR technology is likely to be greatly aided by progress in AI.
For example, we saw in 2024 the release of “OpenCRISPR-1“, an open-source tool to design better CRISPR systems or CREME (Cis-Regulatory Element Model Explanations), a neural network to predict in-silico the potential of CRISPR genetic modification.
CRISPR Therapeutics History
Correctly identifying CRISPR’s potential to be first used in treating genetic disease, CRISPR Therapeutics has been from its inception in 2013 focused on this topic.
The company decided to exclusively use CRISPR-Cas9, contrary to some of its competitors, notably Jennifer Doudna’s companies (the co-discoverer of CRISPR), who also pursued slightly different systems like CRISPR-Cas12a. Ultimately, this would prove to be the correct strategy, with CRISPR Therapeutics proving to be the quickest in obtaining FDA approval for its first therapy in 2023.
Only 10 years between the company’s founding and first approval is rather quick in biotechnology and record-breaking for such a novel type of technology.
A key factor has been the partnership with the more established biotech company Vertex Pharmaceuticals (VRTX +0.15%), itself a specialist in rare diseases with an initial focus on cystic fibrosis and now diversifying.
CRISPR Therapeutics Blood Diseases Therapy
The original target of CRISPR Therapeutics was to cure the blood disease Sickle Cell Disease (SCD). It is caused by a genetic mutation that forms abnormal hemoglobin, the oxygen protein in the blood’s red cells.
As a result, red cells are shaped like sickles and tend to get stuck in blood vessels, causing reduced blood flow and obstruction. Such obstruction can cause extreme pain, swelling, vision problems, and infection sensitivity.
Source: Wikipedia
CRISPR’s solution to SCD is to change the genetic code of the stem cells producing the patient’s blood cells. In this “ex-vivo” approach, the stem cells modified in a lab are then re-injected into the patient, instead of being modified directly.
They use CRISPR gene editing to modify some of these stem cells and replace the deficient hemoglobin with fetal hemoglobin (HbF), which is naturally present in all people before birth and with a higher affinity for oxygen than adult hemoglobin.
The same method can be used to cure another blood disease, beta-thalassemia. This disease is caused by the patient not having enough hemoglobin. Adding enough HbF can solve this problem as well.
Source: Healthline
FDA Approval And Commercialization
The therapy for SCD was approved in 2023, and commercialized under the brand name CASGEVY and the technical name exa-cel.
It covers an addressable market of 60,000 patients in the areas where it is approved (including the US and the EU), making it the first credible chance of eradicating these two diseases.
Further approvals are expected in Middle Eastern markets (another 23,000 potential patients in just Bahrain and Saudi Arabia), and more sales from non-US markets. To support it, the company has been organizing the expansion of its manufacturing capacity, with an agreement with drug producer Lonza.
Source: CRISPR Therapeutics
Exa-cel / CASGEVY treatment resulted in 94.2% of beta-thalassemia patients reaching independence from transfusion, and 97.4% of sickle cell disease patients, a number made even more impressive as this is the first ever treatment to reliably cure it instead of just dealing with the symptoms.
CRISPR Therapeutics Pipeline
Besides ex-vivo blood disease therapy, CRISPR Therapeutics has been working on more applications of CRISPR technology. In the long run, this should make the company an expert in the technology with diversified markets.
Source: CRISPR Therapeutics
In-Vivo Gene Editing
One important step will be to test for in-vivo gene editing for blood disease, which should make the treatment much less expensive, more tolerable for the patients, and overall more efficient by directly modifying the stem cells in the bone marrow. It would also remove the need for extensive manufacturing facilities cultivating in lab the modified cells, as the gene modification would occur directly in the body.
Source: Research Gate
CRISPR Therapeutics’ favored approach for this in-vivo strategy is to use Lipid NanoParticles (LNP) similar to those used for mRNA vaccines. The studies on primate animal models is ongoing, and this method could ultimately reach 400,000+ patients worldwide, as it could address other blood disorders.
Once mastered for the blood disease therapies, progress in in-vivo gene editing could be deployed to other types of treatment.
In particular, cardiovascular diseases and other rare diseases are the focus of the company, with a total of 6 different molecules/therapies at various stages of development in the R&D pipeline.
Source: CRISPR Therapeutics
Among the diseases potentially addressed by these experimental therapies are atherosclerotic cardiovascular diseases (ASCVD), with up to 4 million people in the US and Europe with genetic dyslipidemias and 14 million high-risk patients in total.
In this case, the concept would be to edit the genes of liver cells so they can reduce cholesterol and triglyceride levels, the root cause of ASCVD.
Source: CRISPR Therapeutics
Rare Diseases
CRISPR Therapeutics is looking to expand to other major rare diseases, like muscular dystrophies (Duchenne’s muscular dystrophy – DMD & Myotonic dystrophy type I – DM1) and cystic fibrosis.
These diseases are good targets for the company, as they are both incurable so far, and caused by a single gene dysfunction. They also affect in total many people, even if they are still “rare diseases:
- 20,000 children are born with DMD per year.
- 25 children per 10,000 for DM1.
- 40,000 children and adults living with cystic fibrosis just in the United States.
These programs are, however, relatively in the early stage and will likely impact investors in the company only many years down the road.
Cancer Therapies
To fight cancer, a method called CAR-T can be employed. It consists of genetically modifying lymphocytes (white cells part of the immune system) so they detect and destroy the cancer cells. It is part of the larger “precision therapy” field, predicted to be a $4T opportunity.
Source: Leukemia and Lymphoma Society
This method implies complex gene editing, with the lymphocyte cells often having to be edited with 4-5 different additional genes for one therapy.
CRISPR Therapeutics is pursuing 3 different CAR-T programs. The targeted cancer types are very diverse, from blood cancer to cancers of the kidney, liver, etc.
Source: CRISPR Therapeutics
Cancer therapies are a very competitive market, but the expertise of CRISPR in gene editing could give it an edge in improving standard CAR-T therapies, especially for cancers that are resistant to current treatments.
Diabetes Therapy
This is by far the largest market considered by CRISPR Therapeutics, and also potentially the most lucrative.
The idea would be to modify pancreatic cells so they are able to produce insulin without being destroyed by the immune system (the root cause of type 1 diabetes).
CRISPR is looking to achieve this first by putting the modified cells in a medical device that would be implanted in the patient, creating an artificial pancreas from the patient’s own cells. This procedure is now in phase 1 of clinical trials.
Source: CRISPR Therapeutics
Another strategy for a device-less cure would use a different type of genetic engineering, to completely avoid the immune system.
This protocol was initially developed jointly by Vertex Pharmaceuticals, but since then, Vertex has decided to let CRISPR handle this project alone. So currently, the company has 2 fully owned diabetes potential therapies and one legacy collaboration with Vertex.
Source: CRISPR Therapeutics
Nevertheless, this collaboration delivered $130M in upfront and milestone payments in 2023, with $160M still in potential revenues for additional research and development milestones. Later on, if the therapy is approved, CRISPR would also collect royalties on the future product.
A reason for Vertex backing out of the deal in January 2024 might be that it prefers to favor its own fully owned VX-264 program, which uses a protective device that would eliminate the need for immunosuppressive therapy by gene editing or other means.
Gene Editing Technology
Besides the development of therapies, CRISPR Therapeutics is also working on new intellectual properties in the gene editing space. This includes the lipid nanoparticles (LNP) for delivery of gene edition to liver cells and other organs for in-vivo therapies previously mentioned.
This also covers CRISPR-X, an improved CIRSPR-Cas9 system focused on editing genes (more than replacing them), including for non-viral DNA delivery and all-RNA systems.
Conclusion
CRISPR Therapeutics has quickly (by the biotech industry standards), gone from an ambitious startup with an interesting technology, founded & led by a Nobel Prize-winning scientist, and grown into a proven developer of innovative therapy for previously deadly and incurable diseases.
In that context, the approval of CASGEVY for blood disease is likely to be a first step, before more success with other genetic diseases, which would bring the company profits despite its massive R&D budget.
Investors are, however, likely to greatly benefit only if the company can make a serious breakthrough in some other markets like, for example, diabetes, cancer treatment, or cardiovascular diseases root causes.
In all its future programs, the speed at which CRISPR Therapeutics can bring its new treatment to the market will be a determining factor. Especially as other companies are also pursuing similar goals; notably Jennifer Doudna’s Editas Medicine (EDIT -1.2%) that had to make a pivot to in-vivo editing following CRISPR Therapeutics “winning the race” to approval for ex-vivo SCD and beta-thalassemia therapy.