New Medicines, Markets, and Manufacture: CRISPR for Sickle Cell Disease and β-thalassemia

Published on: 
BP Elements, BioPharm International's BP Elements, December 2023, Volume 2, Issue 12

Exagamglogene autotemcel seen as synechdoche.

In sickle cell anemia mishappen and sticky hemoglobin cells cannot carry oxygen properly and frequently clump, clogging blood vessels and sometimes causing searing pain termed a vaso-occlusive crisis. It is debilitating. β-thalassemia isn’t etiologically closely related, however, similar to sickle cell disease (SCD), genetic defects are passed on from both parents, which leads to low hemoglobin production. This creates fatigue, jaundice, shortness of breath and irregular heartbeats. A fresh (Nobel prize winning) tool to redress both mutational situations was recently given Medicines and Healthcare products Regulatory Agency (MHRA) approval, in a world-first approval for complicated next-generation therapeutics (1). Clustered regularly interspaced short palindromic repeats (CRISPR) was successfully applied to both disease states, in a therapeutic called Casgevy (exagamglogene autotemcel, or exa-cel).

CRISPR is so new that this MHRA approval caused quite a stir in both the medical and pharmaceutical worlds. Even at the end of November 2023 the American society of Hematology didn’t appear to convey much about this news, nor the attendant questions and issues that must still be addressed. These include potential immunogenicity because of biology outside of the CRISPR itself, and also access alongside cost and reimbursement.

Casgevy galvanizesproduction of a form of hemoglobin normally made only in developing fetuses. “Production of this fetal hemoglobin is typically shut off soon after birth by a gene called BCL11A. [Casgevy] disables BCL11A, allowing fetal-hemoglobin production to resume. This provides some hemoglobin that is not misshapen and dampens the effects of the abnormal form. Vertex and CRISPR Therapeutics reported that, at nine months after treatment, 31 of 32 participants in their clinical trial had not had a single vaso occlusive crisis. Before treatment, they’d had an average of about four each year” (2).

CRISPR remains somewhat controversial for potential off-target effects. On top of this, after it makes its cut in the DNA of the BCL11A gene, CRISPR relies on the cell’s natural DNA repair machinery to stitch the strands back together. The step can introduce new errors. All of this is well known and becoming better understood; however, in its advisory committee briefing, Vertex stated: “There is no known or hypothesized mechanism whereby a DNA edit would revert to reduce the reactivation offetal hemoglobin (HbF) after exa-cel treatment. The long-term engraftment of edited cells also demonstrates the successful editing of long-term hematopoietic stem cell (HSCs) that are known to persist for a person’s lifetime” (3).

What is potentially equally worrisome for Casgevy are new findings from Wellcome Sanger Institute, University of York, and Boston Children’s Hospitalscientists outlining an observation that “cell competition” following gene therapy, may increase leukemia incidence. “The cause is likely not the gene therapy treatment itself, say researchers, but the therapy process, which involves gene editing outside the body and re-transplantation of stem cells back into the patient.” The authors go on to say “Instead, the process of genetically modifying these stem cells outside the body and re-transplanting them back into the patient makes blood stem cells that already have these mutations more prominent, thereby increasing their influence on the blood and immune systems.” The authors hypothesize younger patients might be an easier cohort to manage these therapies through, as their stem cells inherent have fewer mutations to “select” as triggering undesirable outcomes, and that “Continuously tracking these mutations and gaining a deeper understanding of these processes will profoundly impact the future well-being of sickle cell patients around the world.” (4)

While they are approximately 100,000 SCD patients in the United States, the disease seems related to malaria, and hence the vast majority of sufferers live in resource-poor nations. Vertex Pharmaceuticals said it had not yet established a price for the treatment in Britain and was working with health authorities “to secure reimbursement and access for eligible patients as quickly as possible. In the US, Vertex has not released a potential price for the therapy, but a report by the nonprofit Institute for Clinical and Economic Review said prices up to around $2 million would be cost-effective. By comparison, research earlier this year, showed medical expenses for current sickle cell treatments, from birth to age 65, add up to about $1.6 million for women and $1.7 million for men.” (5)


Not only cost but access to the “manufacture” of this treatment is also a barrier to widespread implementation. “In the US, there are approximately 200 specialized centers for bone marrow transplants. There are only three such centers for all of sub-Saharan Africa—in Nigeria, Tanzania, and South Africa. Making these types of CRISPR-based therapies available throughout the continent will require massive investment in clinical infrastructure. The road from now, having gene editing that is possible and implemented where most people live, it’s not that close,” said Ambroise Wonkam, a geneticist at Johns Hopkins School of Medicine and the University of Cape Town who also serves as president of the African Society of Human Genetics. “We have to put that into perspective” (6).

Casgevy was used here as synecdochic for the surging tidal wave of new modalities. The choice might well have fallen to ARCT-154, a self-amplifying messenger RNA (sa-mRNA) COVID-19 vaccine for initial vaccination and booster for adults 18 years and older, which was even more recently given approval by Japan's Ministry of Health, Labor and Welfare (MHLW). While ARCT-154 was tested on 16,000 patients compared to Casgevy in 40 patients only, and. while the cost and access is no barrier compared with Casgevy, both therapeutics herald new ways of thinking, new types of testing and validation, and new types of manufacture and end-point monitoring. Following on from the revolutionary COVID-19 vaccines, what comes next is more complicated, more difficult to price for reimbursement, and more effective in terms of cure rates. The toothpaste is out of the tube, and the industry must learn to adapt to take best advantage of what is becoming available, no matter how messy the process.


1. MHRA. MHRA Authorizes World-First Gene Therapy that Aims to Cure Sickle-Cell Disease and Transfusion-Dependent β-thalassemia. Press Release, Nov. 16, 2023
2. Ledford, H. Is CRISPR Safe? Genome Editing Gets Its First FDA Scrutiny. Nature 2023, 623 (7986), 234–235. DOI: 10.1038/d41586-023-03317-7
3. FDA. Cellular, Tissue, and Gene Therapies Advisory Committee October 31, 2023 Meeting Announcement., Oct. 31, 2023.
4. Wellcome Sanger Institute. New Research Sheds Light on Cancer Risk in Gene Therapies., Nov. 16, 2023.
5. Cheng, M. The World’s First Gene Therapy for Sickle Cell Disease Has Been Approved in Britain., Nov. 16, 2023.
6. Molteni, M. With CRISPR Cures on Horizon, Sickle Cell Patients Ask Hard Questions about Who Can Access Them., March 7, 2023.

About the author

Chris Spivey is the editorial director for BioPharm International.