On December 8th, 2023, the U.S. Food and Drug Administration approved two gene therapy treatments for Sickle cell disease (SCD).1 This is the first time gene therapies have been approved as a potential treatment, marking a breakthrough in medical advancements. This also marks huge strides in the treatment of SCD. Previously, symptoms could be treated, but the only cure available for SCD was a bone marrow transplant: a major procedure that requires finding a matching donor and carries a risk of rejection from the person’s immune system.2 Gene therapy is promising not only in treating SCD, but other genetic diseases as well.
SCD impacts the red blood cells in the body.3 These red blood cells contain hemoglobin, a protein that binds to oxygen in the lungs and releases it in the tissues. Red blood cells are round and flexible, which allows them to travel through narrow capillaries. In SCD, there is a mutation in the hemoglobin protein that causes it to malform. This malformation makes the red blood cells become hard and sticky and form a sickle shape, reducing proper function and causing early death of the cells. This is detrimental to the transportation of oxygen throughout the body. Furthermore, people with SCD can have a vaso-occlusive crisis (VOC), where the sickle-shaped blood cells attach to a vessel and block blood flow to tissues.4 VOCs are recurrent and unpredictable, posing a serious health issue. Not only can it lead to tissue death, but it can also trigger a large inflammatory response from the body resulting in substantial pain.5 VOCs are a major risk for people with SCD and can lead to life-threatening disabilities and/or death.1 SCD disproportionately affects people of African, Middle Eastern, and Indian descent, impacting millions of people around the world.6 With limited treatment options, gene editing may be able to help.
CRISPR-Cas9 is a new gene editing technology that is making breakthroughs in biomedicine. It is cheaper, faster, and easier to use than other gene editing tools.7 Development of this technology led to Emmanuelle Charpentier and Jennifer Doudna winning the 2020 Nobel Prize in Chemistry. The CRISPR-Cas9 system was adapted from a natural genome editing system in bacteria.8 Like humans, bacteria can be infected by viruses called bacteriophages. When bacteriophages inject their DNA into a bacterium, the bacterium captures small pieces of the bacteriophage DNA and inserts it into its own genome. These pieces of DNA are known as clustered regularly interspaced palindromic repeat (CRISPR) array that provides a memory of the infection. If the bacteriophage infects the bacterium again, the bacterium can produce RNA segments from the CRISPR arrays that will recognize and bind to the complementary regions on the bacteriophage DNA. Then, the bacterium uses the enzyme Cas9 to cut the DNA apart, preventing further infection. This system was adapted for gene editing by introducing a guide RNA that binds to a specific DNA target. The DNA target is then cut by Cas9, or another enzyme, this cut then allows researchers to replace the targeted DNA sequence with a DNA sequence of choice. The body then repairs the DNA damage, incorporating this new DNA sequence into the genome.
Two genome editing treatments for SCD were approved by the FDA for people aged 12 and older: Casgevy and Lyfgenia.1 Casgevy, developed from Vertex Pharmaceuticals and CRISPR Therapeutics, uses CRISPR to edit the patients DNA in their stem cells.2 Lyfgenia, developed by bluebird bio, delivers a functional version of hemoglobin-producing gene to cells using a lentivirus, which is a virus that is engineered to deliver genetic information of interest into cells.9 Both treatments start with a series of blood transfusions over 3-4 months.2 The patient’s stem cells are then extracted from their bone marrow and edited in a lab, either via CRISPR or a lentivirus. The patient then undergoes chemotherapy to destroy their bone marrow and any remaining stem cells. Then, the edited stem cells are reinfused into the patient, post reinfusion patients then have 1-2 months of in-hospital recovery, giving the new stem cells time to differentiate and multiply. From a total of 44 patients who were treated with Casgevy, 31 patients had sufficient time for a follow-up, and 29 of those patients were cured.1 Some of the common side effects for Casgevy during the treatment were mouth sores, nausea, abdominal pain, fever, and headache. For Lyfgenia, 28 out of 32 patients had complete resolution of VOCs. The most common side effects for Lyfgenia included fever and mouth sores. During the clinical trial, however, there were two cases of blood cancer in patients treated with Lyfgenia.2 The FDA has therefore issued a black box warning, the highest warning, for Lyfgenia. While the success rates of both therapies are promising, the long-term effects are currently unknown. These companies plan on having follow-ups with patients who have been treated for 15 years.6
Although the new therapies are an exciting development, there is a major barrier in accessibility. The therapies are expensive, with Casgevy having a wholesale price at $2.2 million and Lyfgenia having a wholesale price at $3.1 million.6 These companies will sell their drugs at this price to a wholesaler or direct purchaser, who will then sell them to a pharmacy.10 It has not yet been determined if or how insurance companies will cover the treatments, and what the out of pocket cost may be for the patients.9 Additionally, treatment with either is technically complex and includes multiple trips to the hospital, a bone marrow transplant, and a lengthy hospital stay.6 Due to the complexities, the treatments might only be available at large medical centers and in more affluent countries.
Along with the high cost of treatment, there are additional concerns with gene editing. The CRISPR-Cas9 technology has been shown to have off-target effects.11 The Cas9 enzyme can make random cuts in other areas of the genome, leading to downstream disrupted functions in the body. For instance, a cut gene may not produce a functional protein, which is required for an important cellular process. With that protein now gone, the cellular process would falter and lead to malfunction in the body. There are tools available to predict or find off-target effects, such as software and genome sequencing technologies. More research is currently being done to improve the specificity of Cas9.
While there are more gene editing treatments in the works, there is some difficulty in what exactly can be targeted. Gene editing is straightforward in situations where a single mutation in a gene causes a condition, like SCD. However, there are many diseases and conditions where the genetic link is not clear. Some conditions have genes associated with them, such as the APOE4 allele, which can double or triple your risk of getting Alzheimer’s Disease (AD).12 While editing the APOE4 allele to resemble the protective APOE2 may reduce your risk of getting AD, it won’t prevent it entirely. It is also not clear if it would cure someone who already has AD. Therefore, gene editing may not be the be-all, end-all cure for every medical condition.
Casgevy and Lyfgenia were the first gene editing treatments approved by the FDA for use in targeting Sickle Cell Disease. Gene editing is a long and complicated process, but Casgevy and Lyfgenia have high success rates, making them promising treatment/ cure options. However, there are some concerns about severe, but rare side effects with Lyfgenia, as well as the cost and availability of both treatment options. As promising as gene editing based treatments are, there are still issues with off-target effects, and treatments may not work for every condition or disease. As their applications are expanded and refined, gene editing treatments seem to be the new frontier in medicine. The possibility of curing serious genetic diseases is promising. It will be interesting to see how this new medical field progresses and how scientists will face current and future concerns.
References
- U.S Food & Drug Administration. (2023, December 8). FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease.
- Lovelace, B & Kopf, M. (2023, December 8). FDA approves cure for sickle cell disease, the first treatment to use gene-editing tool CRISPR. NBC News. https://www.nbcnews.com/health/health-news/fda-approves-cure-sickle-cell-disease-first-treatment-use-gene-editing-rcna127979.
- Centers for Disease Control and Prevention. (2023). Sickle Cell Disease (SCD). https://www.cdc.gov/ncbddd/sicklecell/index.html.
- Manwani, D & Frenette, PS. (2013, December 5). Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood, 122(24): 3892-8. doi: 10.1182/blood-2013-05-498311.
- Wexler, M. (2022, January 4). Vaso-Occlusive Crisis. Sickle Cell Disease News. https://sicklecellanemianews.com/vaso-occlusive-crisis/#:~:text=What%20is%20a%20vaso%2Docclusive,tries%20to%20rectify%20the%20problem.
- Stein, R. (2023, December 8). FDA approves first gene-editing treatment for human illness. NPR. https://www.npr.org/sections/health-shots/2023/12/08/1217123089/fda-approves-first-gene-editing-treatments-for-human-illness.
- Cross, R. (2020, October 9). CRISPR genome editing gets 2020 Nobel Prize in Chemistry: Emmanuelle Charpienter and Jennifer A. Doudna share award. C&EN news. https://cen.acs.org/biological-chemistry/gene-editing/CRISPR-genome-editing-2020-Nobel/98/i39.
- Medline Plus: Trusted Health Information for You. (2022). What are genome editing and CRISPR-Cas9? https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/.
- Macmillan, C. (2023, December 19). Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease. Yale Medicine. https://www.yalemedicine.org/news/gene-therapies-sickle-cell-disease.
- Mattingly, Joey. (2012, June 20). Understanding Drug Pricing. US Pharmacist: The Pharmacist’s Resource for Clinical Excellence. https://www.uspharmacist.com/article/understanding-drug-pricing.
- Guo, C., Ma, X., Gao, F., & Guo Y. (2023, March 9). Off-target effects in CRISPR/Cas9 gene editing. Front Bioeng Biotechnol, 11:1143157. doi: 10.3389/fbioe.2023.1143157.
- Mayo clinic. (2023, April 29). Alzheimer’s genes: Are you at risk? https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-genes/art-20046552#:~:text=Having%20at%20least%20one%20APOE,%2C%20about%20eight%2D%20to%20twelvefold.