Joseph R. Anticaglia, MD
Medical Advisory Board
Britain’s medicines regulators in November 2023 approved the gene editing technology, CRISPR-Cas9, for the treatment of genetic diseases, such as sickle cell disease and thalassemia. This is the first licensed treatment aimed at curing the above two diseases. Much credit belongs to 2020 Nobel Prize laureates Jennifer Doudna. and Emmanuelle Charpentier for their innovating, landmark gene editing work.
Sickle cell disease (SCD), also called “sickle cell anemia,” is an inherited, lifelong blood disease that’s passed down from parents to child. This genetic disorder causes the body to make abnormal red blood cells (RBC’s). Hemoglobin, Hgb, is the protein in the RBC’s that delivers oxygen to all parts of the body and sends carbon dioxide to the lungs to be exhaled from the body. When the structure of Hgb is altered, symptoms follow. Sickle cell patients are prone to experience fatigue, headache, severe infections, anemia, aching bones, pain crises, and organ dysfunction.
Gayle, a 15 y/o Africa American female was diagnosed with sickle cell disease (SCD) when she was an infant. She has been haunted and stressed every step of her life since that time. She had a flareup of her symptoms on the day she was admitted to the medical wing of the hospital for treatment.
In this admission she was in between pain crises. She was extremely tired, anxious, jaundiced and her hands were swollen. She had been experiencing lightening jabs of excruciating pain in her arms, legs and abdomen, as well as chest discomfort. When these cruel spirits of nature attacked her limbs, her screams became louder, more piercing, and the pain was unbearable. She was in agony; the nurses felt miserable, some moved to tears.
Laboratory blood work reported she was anemic with crescent (sickled) shaped hemoglobin (hemoglobin S). Hgb S red blood cells are fragile, crescent shaped that rupture easily (hemolysis) leading to anemia. They have a short life span surviving just 10 to 20 days, compared to 120 days of normal red blood cells. The misshaped hemoglobin S can block the flow of blood in the body depriving it of oxygen, leading to episodes of pain crises and complications such as stroke.
When Gayle’s mother asked the doctor about curing this disease for her daughter, Gayle and her mother all too often have heard their doctor say,
“I’m very sorry, we don’t have a cure for this disease at this time, but doctors and scientists are working hard to cure this this disease.” The treatment available at that time included pain medications, intravenous fluids and blood transfusions.
Gayle’s story happened years ago, but similar pain crisis stories are unfortunately still told today. However, modern SCD research has progressed from the laboratory bench to clinical trials to successful outcomes. An inflection point has been reached in the war against SCD, in large part, because of two, female pioneering scientists.
Jennifer Doudna and Emmanuelle Charpentier ignited a scientific revolution in 2020 for their Nobel Prize, pioneering work in gene editing (also called genetic engineering or genome editing). This landmark technology, CRISPR-Cas9, allows scientists to repair genetic flaws in a person’s DNA.
CRISPR Is the technology for editing DNA. The CRISPR method of gene editing is not new. What’s new is how researchers adapted the CRISPR-Cas9 system. There are two main components of the CRISPR-Cas9 system:
1 — gRNA — guide ribonucleic acid identifies and matches a target gene.
2 — Cas9 — is the cutting protein. It cuts the double stranded DNA allowing modification of a person’s genetic information (modifies a person’s DNA’s instruction manual).
Guide RNA recognizes and pinpoints the unwanted sections or sequences of DNA. The cutting Cas9 protein is guided to the specific site gRNA, and cuts the unwanted sections of DNA. The unwanted sequences would be removed, the cut ends joined together, or replaced with new genetic material.
in an effort to get a better picture of CRISPRCas9, Dr. Jennifer Doudna put it this way, Look at CRISPR-Cas9 as being analogous to word processing and the text of the document as being a DNA instructional manual.
CRISPR-Cas9 allows you to cut out unwanted sections, (genetic flaws of DNA) “just as you would cut out the text or change it when writing a document in word. Think of it as cut and paste” with genetic scissors
Casgevy and the British Connection
In a landmark decision, and the world’s first-of-its-kind treatment, Britain’s regulators have authorized the use of CRISPRCas9 technology for the treatment of sickle cell anemia and beta thalassemia.
Casgevy is the brand name for CRISPR-based technology. This gene editing tool utilizes guide RNA and Cas9 protein to target specific locations of genetic code (instructions) and to edit the DNA at those precise locations. It’s the one-time gene therapy treatment developed by Vertex Pharmaceuticals of Boston and CRISPR Therapeutics of Switzerland.
On June 9, 2023, Vertex Pharmaceuticals announced positive results from pivotal trials of CRISPRCas9 gene edited therapy (exa-cel) for severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). In company trials, 28 out of 29 sickle cell patients were free of severe pain and 39 of 42 beta thalassemia patients no longer needed blood transfusions for at least a year
- Casgevy is a one- time-gene-editing therapy treatment.
- Blood producing stem cells from the bone marrow of patients are extracted.
- The extracted stem cells undergo gene editing.
- CRISPRCas9 technology edits the extracted stem cells (cut and paste) targeting the BCL11A gene; the gene that silences fetal hemoglobin production.
- Myeloablation — the process that destroys bone marrow cells (see below)
- After the bone marrow cells are destroyed, the edited, modified stem cells are intravenously returned, transplanted back into the patient’s body where they give rise to red blood cells containing fetal hemoglobin
- Successful outcomes for SCD and TDT patients.
- Cost is a deterrent to gene-editing therapy
Myeloablation destroys bone marrow cells using chemotherapy or radiation therapy. This is done to make space for the new cells to grow and to prevent the immune system from rejecting them. The myeloablation process can take several weeks, and patients are usually hospitalized during this time.
Accolades to the two women who shared the Nobe Prize, for giving 100,000 Americans, mainly African Americans, and others around the world who are afflicted with sickle cells disease, hope to be cured of this dreadful disease and the outlook of a pain-free, normal life span.
Casgevy is a milestone in the treatment of SCD and B-thalassemia. However, the availability of this gene editing treatment is likely to be limited due to the complexity of CRISPR-based technology and the high cost of therapy which is estimated to be in the millions.
Also, the long term efficacy of treatment needs to be evaluated, the complications documented, and gene editing treatment made accessible to more people with SCD and TDT.
- Joseph R. Anticaglia, MD; A 21st Century Scientific Revolution? CRISPR-Case 9; Doctor’s Column HC Smart, April 5, 2021
- Joseph R. Anticaglia, MD; Sickle Cell Disease and CRISPR-CAS-9; Doctor’s Column HC Smart, April 15, 2021
- Vertex; Positive results from pivotal trials of exa-cel for transfusion dependent beta thalassemia and severe sickle cell disease; June 9, 2023
- BCL11A; BCL transcription factor A (human); Gene, November 23, 2023
- Ryan O’Hare; UK approves world-first gene-editing treatment for blood disorders; Imperial College London, November 16, 2023
Victoria Gray is the first sickle cell anemia patient to recover with CRISPR gene editing therapy
CRISPR — clustered regularly interspaced short palindromic repeat
MHRA — United Kingdom’s Medicines and Healthcare Products Regulatory Agency
Casgevy is the gene editing brand name made by Vertex Pharmaceuticals in Boston and London, and CRISPR Therapeutics in Zug, Switzerland.
exa-cel — (exagamglogene autotemcel) is an ex vivo CRISPRCas9 gene edited therapy for sickle cell disease and thalassemia, which are edited to produce high levels of hemoglobin in red blood cells.
Thalassemia is a genetic blood disease causing severe anemia and fatigue requiring frequent transfusions…
SCD — Sickle cell disease
TDT — Transfusion dependent thalassemia
This article is intended solely as a learning experience. Please consult your physician for diagnostic and treatment options.