CRISPR has been used in research for a long time, but we’re now starting to see companies utilise this technology to create novel therapeutics. It is undeniable that CRISPR will change the world, and is going to cause a seismic shift in how we treat our patients. So the companies that can successfully take this technology to the market will undoubtedly be a giant of the industry for a long time to come.
But a lot of investors don’t understand what CRISPR is and its potential applications and you should never invest in something that you don’t understand. So in this article, we’re going to discuss what CRISPR is, who the main companies are in this space, and who I think is best positioned to succeed.
Now at this point, it’s important to point out I am not a financial advisor; you should always do your own research when thinking about investing in anything. I’m simply here to give you my thoughts on the technology as a doctor and medical technologist and it’s up to you to make your own decision on if you agree with me.
So before we can understand CRISPR, we first need to understand a bit about DNA, or deoxynucleic acid. DNA has a double-helix structure and is made up of four different nitrogen-based molecules: adenine (A), thymine (T), guanine (G) and cytosine(C). These are collectively known as bases.
These bases pair up with one another to form the double helix, but only with their complementary base. So Adenine always pairs with Thymine while Guanine always pairs with Cytosine.
The order these bases appear in your genetic code determines everything about us, genetically-speaking. Eye colour, how tall we’re likely to be, whether we’re susceptible to certain diseases, it’s all written out in base pairs in our genetic code.
How this works is based on the essential dogma of DNA, and that is that DNA makes RNA makes protein. But what does this mean?
So DNA is stored in the nucleus of our cells, but the information stored in our DNA can’t be used directly to make the proteins that make up your individual characteristics. In order for that process to happen, DNA must first be converted into something called RNA, or ribonucleic acid. RNA is almost identical to DNA, but there is one important difference. Instead of the base thymine, RNA uses a similar base called Uracil. The same pairing rules apply, but instead of thymine binding to cytosine, uracil binds instead.
In order to make RNA, the DNA unzips its double helix and exposes its bases. RNA bases can then bind to the exposed bases and makes their own RNA strands which are a complementary sequence to the DNA.
RNA then travels to specialised proteins in the cell called ribosomes. The ribosomes then use the genetic code in the RNA to produce proteins by assembling amino acids, which are the building blocks of proteins. The order of amino acids depends on the order of your genetic code.
Don’t worry about the details too much but having this basic understanding will help us in understanding CRISPR.
What is CRISPR?
CRISPR is actually a natural process which evolved as a way for some species of bacteria to defend themselves against viral invaders. Each time they faced a new virus, bacteria would capture snippets of DNA from that virus’ genome and create a copy to store in its own DNA.
These snippets of viral DNA act as like a memory bank of the individual virus’ the bacterium had encountered — each one containing the data that allows the bacterium to recognise and quickly kill off a virus next time it invades.
In-between these chunks of useful DNA there are slightly less useful chunks of repetitive DNA keeping them separate — like a divider between each viral segment. These repeating segments of DNA are what gives CRISPR its name. CRISPR stands for “clustered regularly interspaced short palindromic repeats”. CRISPRs are a specialized region of DNA with two distinct characteristics: the presence of nucleotide repeats, so short sections of repeated bases, which are adjacent to sections referred to as spacers. The spacers are somewhat confusingly named as it’s these regions that actually contain the reference to the viral DNA, and the nucleotide repeats that partition the different spacers.
Once a spacer is incorporated and the virus attacks again, a portion of the CRISPR is transcribed and processed into CRISPR RNA, or “crRNA.” So the nucleotide sequence of the CRISPR acts as a template to produce a complementary sequence of single-stranded RNA. Each crRNA, therefore, consists of a nucleotide repeat and a spacer portion.
This is where something called the cas9 protein comes in. The Cas9 protein is an enzyme that cuts up DNA. An enzyme is just a protein that acts as a catalyst to speed up a particular biochemical reaction.
The cas9 protein binds to the crRNA as well as another section of RNA that’s encoded in the bacterial hosts DNA, called tracrRNA (or “trans-activating crRNA”). The two then guide Cas-9 to the target site on the viral DNA. If the crRNA is complementary to a section on the viral DNA, then this activates the Cas-9 enzyme. The enzyme then cuts the viral DNA which deactivates the virus.
Pretty clever really!
But how does this allow us to edit genes?
But of course, this is only useful if you’re a bacterium, which the majority of you reading, probably aren’t. So how did we take a bacterial antiviral system and make it into a gene-editing system?
So effectively the bacterial mechanism gave us the blueprints of how a system like this could work. But scientists have now taken this one step further and manufactured their own CRISPR regions in the lab. If you think about it, all you need to do is find a region in your target DNA that you want to edit, and then create a strand of DNA complementary to that region.
So if we had a DNA strand like this, and we wanted to target this section of the DNA, we’d just need a complementary RNA strand like this:
Once you know what section of DNA you want to target, CRISPR-Cas9 complex can get to work. The Cas9 enzyme starts by unzipping bits of the DNA double helix while the RNA molecule works its way along the exposed base pairs looking for a perfect match. Once the perfect match is found, Cas9 cuts out the gene at this location.
At this point, the cells natural DNA repair mechanism kicks in. The DNA can be repaired in two ways, the first is by simply reconnecting the two strand ends, but this process of repair is very error-prone so usually results in an inactive gene, so if your intent is to disable the function of a particular gene, then this can be a very effective method.
However, genes can also be repaired by injecting another strand of DNA at the section where the split in the DNA was made, therefore editing the function of the gene. This is true genetic engineering and is far more complicated to do than simply knocking out the function of a gene.
Should you invest in CRISPR?
So now we understand a basic overview of CRISPR and how it works, let’s go through the main players in this space before taking a deep dive into the company I’m particularly interested in.
Crispr Therapeutics - When talking about big players in CRISPR, CRISPR therapeutics has to be on the list. The company was founded by Emmanuelle Charpentier, one of the co-discoverers of CRISPR technology and co-recipient of the 2020 Nobel Prize in Chemistry. CRISPR Therapeutics has a slew of therapies in the works. The company’s main focus at the moment is CTX001, which treats patients with sickle cell disease and transfusion-dependent beta-thalassemia. Another candidate in its pipeline is CTX110, a treatment for patients with relapsed or refractory non-Hodgkin lymphoma, which just enjoyed positive early results in its Phase 1 trial in late October. These are just two candidates among many that Crispr is working on, and any one of them could be incredibly profitable for the biotech company — and its shareholders.
Editas Medicine - Next on the list is Editas Medicine. Gene editing can take two forms. The first is in vivo, in which genes are edited while still inside of a patient’s body. The second is ex vivo, in which genes are edited and then implanted within a patient’s body. Editas Medicine does both, giving the company a wide range of treatments in its pipeline that are focused on three areas: blood diseases, cancers and ocular diseases. In addition, one treatment — EDIT-101 — has entered its Phase 1/2 trial for the treatment of Leber congenital amaurosis 10 (LCA10). This is the first time an in vivo CRISPR treatment has entered a clinical trial, and positive results could instantly make Editas a leader in this new field, most CRISPR companies are focussing on ex vivo treatments, so treating cells outside of the body and then injecting them into people. Editas completed its equity offering in the second quarter of 2020 and strengthened its cash position, providing the company with enough funding for operations through 2023. So it’s in a good position.
Intellia Therapeutics - Intellia Therapeutics is another big name in the CRISPR space. CRISPR is such new technology that there are still very few experts in the field — but Intellia Therapeutics co-founder Jennifer Doudna is one of them. Along with Emmanuelle Charpentier, the founder of CRISPR Therapeutics, Doudna received the 2020 Nobel Prize in Chemistry for the discovery of CRISPR technology back in 2012 — today, Intellia is utilizing that same technology to create therapies for a number of genetic diseases. At the top of the company’s pipeline is NTLA-2001, an in vivo treatment for the genetic disease transthyretin amyloidosis, or ATTR, which began its Phase 1 clinical study in early November. Intellia has two other strong candidates, NTLA-2002 (for the treatment of hereditary angioedema) and NTLA-5001 (for acute myeloid leukaemia), on deck for regulatory submission in 2021. Another company with a great pedigree and a broad range of potential therapies make Intellia a strong option in this space.
Beam Therapeutics Inc - Now the final company I am going to include on this list is Beam Therapeutics. The company made its public debut in February, and shares quickly sank along with the rest of the market in the following month. But that was no reflection on the quality of the company, just an unfortunate circumstance of the wider market. The stock has quickly bounced back, as the team at Beam has some very good ideas for how to utilize CRISPR technology. The company focuses on base editing, a technique in which it changes individual bases in the DNA. According to the company, “If existing gene-editing approaches are ‘scissors’ for the genome, our base editors are ‘pencils,’ erasing and rewriting one letter in the gene.” Investors have good reason to be excited about this technology, and Beam has a whopping 12 programs in various preclinical stages that have a lot of potential.
So which company do I like?
So which company do I like most. Well it’s important to note, they’re all really good companies. But for me, the best in class at present is CRISPR therapeutics. Let me explain why.
Firstly, the company has a very impressive pipeline. The company have established a portfolio of programs by selecting disease targets based on a number of criteria, including unmet medical need, technical feasibility, advantages of CRISPR/Cas9 relative to other approaches, as well as taking into account the time required to advance the product candidate into and through clinical trials.
Taking their leading program, CTX001, as an example. The inherited hemoglobinopathies β-thalassemia and sickle cell disease (SCD) result from mutations in a gene that encodes a key component of haemoglobin, the oxygen-carrying molecule in the blood. These are great therapeutic candidates for CRISPR because they are due to a defect in one gene.
Both diseases currently require lifetime treatment that can result in the need for regular transfusions, and cause painful symptoms and chronic hospitalizations. And sadly, both of these diseases result in reduced life expectancy. So for a cure for these diseases has been sought for a long time.
Both diseases become apparent in the first few months after birth, and this is due to how different forms of haemoglobin are expressed. In the fetus, the predominant form of haemoglobin is fetal haemoglobin, which is a form of haemoglobin that has a particularly high affinity for oxygen.
After birth, the relative amount of fetal haemoglobin decreases and is replaced by adult haemoglobin, until at approximately month 3 adult haemoglobin is the vast majority of haemoglobin. It is at this point that the symptoms of sickle cell disease and beta-thalassaemia become apparent. This is because fetal haemoglobin is not affected by the mutations in beta-thalassaemia and SCD, but adult haemoglobin is.
However, a small subset of people continues to express fetal haemoglobin into adulthood and suffer from many reduced symptoms as a result. As a therapy, CTX001 exploits this phenomenon by artificially increasing the expression of fetal haemoglobin. The treatment involves isolating a patient’s own blood stem cells, editing them with CRISPR/Cas9 to increase HbF expression, and then returning the edited cells to the patient. The theory is that over time these edited blood stem cells will generate red blood cells that have increased levels of HbF, which may reduce or eliminate patients’ symptoms.
CRISPR Therapeutics also has potential cancer therapies utilising CRISPR technology. Over the past several decades, scientists have sought to engineer immune cells to seek and destroy cancer cells. These efforts came to fruition when the FDA approved two chimeric antigen receptor (CAR) T cell therapies in 2017. A therapy that effectively retrains an individual’s immune system to attack and destroy their cancer.
At CRISPR Therapeutics they are developing there own portfolio of CAR-T cell product candidates based on their gene-editing technology. Using the precision of CRISPR-Cas9 the company believes they can overcome some of the challenges faced by current CAR-T therapies. For one, with CRISPR/Cas9, allogeneic CAR-T cells can be produced, meaning cells that are not derived from the patients own tissue. These have distinct advantages over the autologous (patient-derived) products currently on the market. CRISPR/Cas9 can also be used to eliminate or insert genes to create new classes of CAR-T products, the main intention of which is improving applicability to solid tumours.
Let me explain what I mean by this.
Current CAR-T cell therapies provide excellent treatment results for some patients but take several weeks to manufacture, due to the fact that they are derived from the patients own cells, which is what autologous means, during which time many patients experience disease progression. The manufacturing process may also fail, and even if successful, the CAR-T cells that result may have low potency due to the variability in the patients own cells.
The way to fix this problem is by creating CAR-T products that don’t need to be derived from a patient’s own cells, referred to as allogeneic products. And because this process is controlled, not relying on the individual patient’s tissues, it can be more easily perfected and theoretically produce CAR-T cells with higher efficacy. CRISPR Therapeutics believes their CAR-T candidates will be superior to current offerings due to several factors, including:
- Immediate availability: administered off-the-shelf
- Increased potency: due to the starting material derived from healthy donors
- Greater consistency: meaning that ****each batch yields many doses
- Flexible dosing: ability to titrate dosing or re-dose
But how does the company hope to achieve these results? The CAR-T cells made by CRISPR therapeutics differ from current CAR-T cells in 3 key ways.
CAR stands for chimeric antigen receptor (CAR). It’s this region that allows CAR-T cells to target and kill cancer cells. A CAR has two key domains: one that binds to the surface of cancer cells and another that activates the T cell. The current generation of CAR-T products use randomly-integrating viruses to deliver the CAR construct to the DNA of T cells. In contrast, CRISPR therapeutics use the CRISPR/Cas9 system to insert the CAR construct precisely into the TCR alpha constant (TRAC) locus, which the company expects will result in a safer, more consistent product.
The second difference is in the T-cell receptor. T cells are parts of the immune system and help fight infections. T cells use the T cell receptor (TCR) to recognize and kill cells presenting foreign antigens, this is one way the immune system fights infections. Donor T cells could also recognize a patient’s cells as foreign through this receptor, leading to an unwanted side effect known as graft versus host disease (GvHD). This isn’t an issue when you use the patients own cells as in current offerings, but because CRISPR want to use allogeneic donor cells, they need to deactivate the TCR region on the cells. As you’ve probably guessed, they use CRISPR/Cas9 to eliminate the TCR with high efficiency, which reduces the risk of GvHD occurring during off-the-shelf use.
And finally, they also eliminate the class I major histocompatibility complex (MHC I) expressed on the surface of our CAR-T product candidates. If present, MHC I could lead to rejection of the CAR-T product by the patient’s own T cells. So the opposite of graft versus host disease. Eliminating this molecule should mitigate that effect.
There are 3 CAR-T projects that CRISPR therapeutics are currently working on. CTX110, CTX120, and CTX130.
CTX 110 targets CD19, an antigen expressed in various B-cell malignancies, such as B-cell lymphoma, while CTX120 targets BCMA, an antigen expressed in multiple myeloma.
CTX130 is particularly exciting, targeting CD70, an antigen expressed on both hematologic cancers, including certain lymphomas, and some solid tumours, including renal cell carcinoma. Currently, CAR-T has not been proved as an effective treatment for solid tumours so if this were to be successful in clinical trials that would be a big step forward in cancer treatment.
Does it work?
So all of this is good in theory right? But if it doesn’t work, then it has no value. So where are these projects in development?
So all of the projects mentioned have now started phase 1 and 2 clinical trials and we have yet to get formal results from these trials.
But we do have some early data from the phase 1 trial of the CTX110 candidate in the treatment of B-cell malignancies.
From this early data, CTX110 has shown dose-dependent efficacy and response rates that are comparable to the early autologous CAR-T trials. CTX110 also showed ab acceptable safety profile, which could make CAR-Ts more widely accessible. So while longer follow-up is required, these early data support the potential for CTX110 to become an effective off-the-shelf CAR-T therapy for patients with relapsed or refractory B-cell malignancies.
These early results are exciting and a big win for the company, but we’ll have to wait for the full results of the trials, which are likely to be published later this year or early 2022.
Why CRISPR Therapeutics in particular?
So why is CRISPR therapeutics my choice?
Now at this point, I think it’s worth reiterating I am not a financial advisor I’m just telling using my industry-specific knowledge which is the one I’m most interested in.
So when working out the possible profitability of a therapy, it’s dependent on a few important factors.
- The number of people with that condition
- The length of treatment required
- Possible competition that could take some of your market share and compete for you on pricing.
I think an important differentiator in the companies I’ve mentioned is the incidence of the conditions they’re targeting.
Let’s just take the primary project from each company for comparison, for this analysis we’re going to assume that all of these companies are successful in clinical trials and produce an effective therapy with the main projects in their pipeline, for this, I am only including those projects that have made it to at least phase 1 clinical trials.
Here is a list of each companies CRISPR therapies that have currently made it to clinical trials and the number of people diagnosed each year with the condition each therapy is targeting.
It’s worth noting Beam Therapeutics is also targeting sickle cell anaemia and beta thalassaemia. But importantly, non of there therapeutic targets have entered phase I / II clinical trials.
So looking at these figures, if CRISPR therapeutics is successful in its clinical trials, and that is, of course, a big if, then the potential market for their therapeutics is massive, much larger than some of its immediate competitors.
Although Beam Therapeutics didn’t meet my criteria for this analysis. I’ll be following them very closely, although none of their projects is currently in clinical trials, their precise method of editing DNA holds a lot of potential.