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A Crippling And Painful Disease
Sickle Cell Disease (SCD) is a blood disease caused by a genetic mutation. This mutation creates 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.
This also causes red cells to die off in just 10 to 20 days instead of the normal 120 days, causing anemia in the patients.
This is a disease affecting more than 20 million people worldwide, of which 100,000 are in the USA.
It also disproportionately affects people of African ancestry, with 1 in 13 Black or African American babies being born with sickle cell trait and 1 in every 365 Black or African American babies being born with sickle cell disease.
Because the disease affects each individual blood cell produced by the body, efficient treatments have long been impossible to develop, with most healthcare limited to reducing the severity or consequences of the symptoms.
Red cells are also constantly produced and recycled in the body, so ideally, a cure would repair the body's capacity to create functional/normal red cells.
The Gene Therapy Miracle
What made SCD so difficult to cure, its genetic origin, is also what makes it uniquely fit for the novel tools of gene therapy, especially gene editing. The mutation affects only one gene and, in most cases, only a single nucleotide (one letter of the genetic code).
This means that if we could modify that one letter in the patient's DNA, we could cure the disease entirely for life.
Previous generations of gene therapies struggled to be precise enough to provide a cure for SCD. But this might soon become possible with the emergence of CRISPR technology, which is able to target and edit genes one nucleotide at a time precisely.
Many companies are working on this technology, with SCD the prime focus of many of them.
Gene Editing Companies Working On An SCD Cure
CRISPR Therapeutics was founded by CRISPR Cas9 co-discoverer and 2020's Nobel Prize winner Emmanuel Charpentier. The company focuses on applying to human medicine the CRISPR Cas9 system.
CRISPR Therapeutics is working in close collaboration with larger biotech Vertex to develop therapies for blood diseases (Beta-thalassemia and SCD), as well as a potential cure for Type-1 diabetes.
For curing both Beta-thalassemia & SCD, CRISPR Therapeutics is looking to 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 cure could work for both because SCD patients have the wrong type of hemoglobin, while beta-thalassemia do not have enough hemoglobin. Adding enough HbF would solve the problem for both.
The stem cells producing the blood cells are genetically modified ex-vivo (out of the body, in a lab), and then re-injected in the patient’s body under a process branded as “Exa-cel”.
In the Exa-cel clinical trial, 42 out of 44 beta-thalassemia patients have stopped blood transfusion, with the other 2 having reduced transfusion volume by 75% and 89%. All 31 SCD disease patients were free of the painful vaso-occlusive crisis (VOC), one of the most indicative and debilitating symptoms of SCD. You can read more about the clinical trial and its results in the dedicated presentation by CRISPR Therapeutics.
The Marketing Authorization Application (MAA), which is the demand for authorization to commercialize a new therapy, has already been submitted for Exa-cel, making CRISPR Therapeutics the most advanced gene therapy for Beta-thalassemia & SCD.
Editas was founded by the other CRISPR-Cas9 discoverer, Jennifer Doudna. You can also read an overview of all of Jennifer Doudna's companies in the corresponding article “Top Jennifer Doudna Companies to Watch.”
Editas started working with Cas9 but is now focused on a proprietary version of Cas12 that they engineered: AsCas12a.
You can read more about Cas12a's unique properties in our dedicated article “What Is CRISPR-Cas12a2? & Why Does It Matter?”.
To resume it shortly, Cas12as's uniqueness is because:
- Hard-to-solve problems with Cas9 could be workable with Cas12a
- It results in higher chances of gene editing happening than with Cas9.
- More than one gene can be modified at once with CAs12a
In addition, this gives Editas an exclusive license for AsCas12a, and the company does not require any commercial license for CRISPR Cas9 to commercialize its SCD therapy.
Editas is strongly focused on Sickle Cell Disease (SCD) and beta-thalassemia, with 40 patients in a clinical trial at phase 1/2, with the first results expected by the end of 2023. You can read more about the clinical trial design and early results in the dedicated presentation.
In October 2023, Editas was granted by the FDA the Regenerative Medicine Advanced Therapy (RMAT) designation for EDIT-301 for treating severe SCD. This overall should speed up the clinical trial process, which is the goal of RMAT, including through priority review of the biologics license application (BLA).
The company has also planned to reduce spending, allowing for “a decreased cash burn, extending operational runway into 2025.
The company was founded in 2017, focusing on developing the technology of “base editing.” This promises more precise gene editing than traditional CRISPR-Cas9 technology. It could also edit multiple spots in a gene or multiple genes at once.
“Many existing gene editing approaches are like ‘scissors’ that cut the genome. Base editors are like ‘pencils’ that enable erasing and rewriting one letter of the genome at a time.”
GIUSEPPE CIARAMELLA, President and Chief Scientific Officer.
Beam Therapeutics is at an earlier stage than other CRISPR companies, with its manufacturing facilities expected to start only in late 2023. Most of its pipeline is still at the research stage of entering phase 1/2 of clinical trials.
It has pretty much the same focuses as CRISPR therapeutics: hematology (sickle cell disease), oncology, and rarer genetic diseases (impaired glycogen metabolism and Alpha-1 Anti-trypsin Deficiency – AATD).
In October 2023, BEAM Therapeutics announced its intention to prioritize BEAM-101 and ESCAPE for sickle cell disease and BEAM-302 for alpha-1 antitrypsin deficiency.
The news came with the pausing of its Hepatitis-B program and a reduction of headcount by 20%, or around 100 employees. Together with a cost reduction program, this should provide the company with enough funding to operate until 2026 with its current cash balance.
Considering rising interest rates and the difficulty of raising more money in the current environment, this sounds like a cautious but wise strategy for a pre-revenue company with a promising product that should be done with clinical trials by 2026.
Most CRISPR therapies for SCD (and other diseases) also target an “ex-vivo ” approach, where cells are extracted from the body, modified in labs, and re-injected in the patient. This makes gene editing a lot easier and safer, but it also comes with a whole different set of problems in getting the re-injected cells to perform normally and cure the patients.
In theory, in-vivo therapies could be easier to handle and have fewer side effects. In practice, it can be difficult to have the gene therapy precisely editing the right cells and no others, as well as precise and predictable gene editing, or affecting a large enough percentage of the body's cells in order to be effective.
This is, nevertheless, the approach favored by Precision BioSciences, which granted it a partnership for curing SCD in vivo with Novartis in 2022. It relies not on CRISPR but on ARCUS, a system using an editing enzyme, I-CreI, found in algae.
The company is still at a very early stage for its potential SCD treatment, with its most advanced program, a potential therapy for ornithine transcarbamylase deficiency, in partnership with Ecure.
Precision Biosciences is not solely focused on SCD but might be the long-term future of gene therapies unless CRISPR therapies prove to be fully sufficient in curing most SCD cases before the ARCUS system can be validated through clinical trials.
Abandoned Or Delayed Gene Therapies
Biotech development is a difficult task, and some programs that looked promising in treating SCD have been abandoned recently.
Notably, Intellia Therapeutics, Inc. (NTLA) saw its partner Novartis (NVS) pulling the plug on a CRISPR therapy in the work in 2014. At the time, Intellia mentioned its interest in pursuing an in-vivo method but has communicated little about SCD since.
Source: IntelliaSangamo Therapeutics (SGMO) and Graphite Bio (GRPH) have also stopped their SCD gene therapy programs. Sangamo therapy relied on zinc-fingers gene editing, and Graphite Bio had poor results in preliminary clinical trials.