The First CRISPR Treatment: Changing the Fate of Sickle Cell Disease

For decades, sickle cell disease has been treated as a condition to manage rather than one that could be changed at its source, with no known cure on the horizon until recently.

Globally, sickle cell disease affects about 8 million people, and in the United States, about 100,000 people live with the disease. An estimated 90% of those living with sickle cell disease in the US are Black or African American. In fact, the National Heart, Lung, and Blood Institute states that one in every 365 Black babies is sadly born with sickle cell disease, and one in 13 Black individuals carries the sickle cell gene.

Although living with sickle cell disease can look very different from person to person, those living with the disease often experience pain crises. This is when sudden, intense pain is felt in the chest, joints, or bones and can last hours to days, often leading to hospitalizations. According to the Centers for Disease Control and Prevention (CDC), other common symptoms include chronic fatigue and low energy, and the increased risk of stroke, organ damage, and infections.

Until recently, treatment revolved around transfusions, pain control, and preventing organ damage. These interventions could save lives and even extend them, but they did not change the underlying mutation driving the disease. Additionally and unfortunately, despite holding an uneasy place in American medicine, considering the disease is severe enough to warrant repeated hospitalizations and cause early death and strokes, it's often misunderstood. It's also chronically underfunded and politically sidelined compared with other inherited disorders.

For years, there was no widely available treatment that could alter the disease at its source, until a major regulatory decision by the Food and Drug Administration (FDA) regarding Casegvy, the first FDA-approved treatment using genome-editing technology. Specifically, Casegvy utilizes CRISPR or clustered regularly interspaced short palindromic repeats, another FDA first.

Nicole Verdun, M.D., the director of the Office of Therapeutic Products at the FDA, said in the FDA’s press release announcing the decision, “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.”

She further went on to say, “Sickle cell disease is a rare, debilitating, and life-threatening blood disorder with significant unmet need, and we are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease, by approving two cell-based gene therapies today.”

For those living with the disease, the approval of CRISPR therapy carried symbolic value as well as clinical weight because it suggested that the future of gene editing might finally meet the needs of a community that has had to live with delays for generations. Still, getting to that point took years of work. It wouldn’t have been possible without the efforts of hematologist Vijay Sankaran, who began exploring new ways to treat the disease at its bilogical source as a Harvard Medical School MD-PhD student in the mid-2000s.

Vijay Sankaran, now the HMS Jan Ellen Paradise, MD, Professor of Pediatrics at Boston Children’s Hospital, said in a Harvard Medical School article, “The encounter made me wonder, couldn’t we do more for these patients?”

In 2008, Sankaran, Stuart H Orkin, and colleagues found their ‘more.’ They identified a new therapeutic target for sickle cell disease through the development efforts of CRISPR Therapeutics and Vertex Pharmaceuticals. Nearly 15 years later, the FDA’s 2023 approval is a milestone in their research.

David Altshuler, Vertex’s executive vice president and chief scientific officer, said in the same Harvard Medical School article, “It’s an amazing gift to have been able to play a role in such a thing.”

Casgevy is a unique therapy that uses a patient's own blood-forming stem cells that are collected and edited outside the body before being returned after chemotherapy-based conditioning. The edit using CRISPR tools targets a regulatory region tied to BCL11A, which increases fetal hemoglobin. It is fetal hemoglobin that helps prevent red blood cells from adopting the rigid, sickle-shaped form that can block blood vessels and trigger severe pain episodes that define the disease for many patients.

So, Casgevy treatment doesn’t simply mask symptoms but also intervenes at a level much closer to the disease's source. In the FDA review of the therapy, 29 of 31 evaluable patients with sufficient follow-up data were free from severe vaso-occlusive crises for at least 12 consecutive months, suggesting that the therapy can substantially reduce the severe pain episodes that define the disease for many patients.

A 2024 paper in the New England Journal of Medicine reported similar findings. According to the paper, 29 of 30 patients in the primary efficacy group were free from vasco-occlusive crises for at least 12 consecutive months, and all 30 were free from hospitalizations for those crises over the same period.

However, it's prudent to know that even with these outcomes, converting gene therapy into real-world care poses challenges that extend beyond the gene-editing step alone. In fact, some of the most significant constraints currently appear earlier in the treatment process, during the preparation required before cells are collected.

Carly Newton, RN, MBA, who works closely with clinicians and operators involved in sickle cell care and cell and gene therapy preparation at Terumo Blood and Cell Technologies, said via email, “Blood is the critical enabler that unlocks CRISPR and gene therapy for sickle cell disease. The science gets the headlines, but without the transfusion medicine lift behind it, the therapy doesn’t happen.” She added via email, “Clinicians tell us that real-world access to these therapies quietly breaks down at the blood supply, not at the gene-editing step.”

In her experience, before stem cell collection, patients have to undergo weeks of transfusion support to reduce hemoglobin S levels. Hemoglobin S is the abnormal form of hemoglobin that causes red blood cells to sickle. So, lowering those levels can help to stabilize patients before their stem cells are collected for editing. They sometimes need large volumes of closely matched donor blood during this process. With this in mind, this step can become a limiting factor, particularly for patients with complex matching needs.

Newton explained CRISPR in her email, “For heavily alloimmunized patients or those requiring rare phenotype matches, sourcing compatible blood can be the rate-limited step for the entire therapy, not the CRISPR science itself.” So, these constraining realities add an important consideration to the way therapy is understood. This is especially true when one considers how widely it can be delivered to patients in healthcare settings beyond controlled trial environments.

So, although the trial numbers are impressive, the more immediate challenge isn't only how Casgevy is described but how realistically it can reach the people who need it. This is presumably why currently many researchers, developers, and regulators remain cautious because the treatment is potentially curative for many patients, but it's not simple, nor is it universal or particularly easy to deliver. So although science has reached a historic point, the path from approval to everyday access is still incredibly difficult.

At present, aside from the complex blood-supply and transfusion-matching requirements, long-term durability is still being studied, as the treatment isn’t without its risks. It can lead to prolonged low blood counts and other serious complications with the conditioning and transplantation.

Then, there is also the issue of costs and logistics to consider. Casgevy entered the US market with a list price of $2.2 million when the therapy launched and became available to patients 12 and older with recurrent vasco-occlusive crises. Treatment also requires specialized centers, travel, lengthy coordination, and time away from work or school, not to mention the physical and emotional cost of chemotherapy.

Those medical, logistical, and financial barriers have made uptake of the treatment slower than expected. Many living with the disease are hesitant because of the intensity of the process, concerns about fertility, and the understandable desire to see more patient outcomes over time. So, although this is a scientific first, a very real test is underway to determine whether the medicine can deliver a breakthrough for the people who have the most reason to need it. That challenge is also why access has become the next major chapter in this story.

The Centers for Medicare & Medicaid Services (CMS) has developed the Cell and Gene Therapy Access Model to improve Medicaid access to gene therapies for sickle cell disease through outcomes-based agreements with manufacturers. It's also worth noting that fertility preservation support is part of the model. Although many US states are participating in this CMS model, it doesn't erase systemic barriers. It shows that federal policy is adapting to the fact that these therapies are no longer theoretical.

Today, Casgevy is available in the United States and many countries in the Middle East and Europe, but it is not yet approved worldwide. Vertex is actively working to secure approvals in more countries globally, but approval alone will not determine how many patients can actually recieve it. The next several years will show whether health systems can support the demanding clinical process around the therapy, from matched blood supply and transplant capacity to fertility preservation and reimbursement. For many people living with sickle cell disease, that unfinished access question now sits beside the hope created by the science itself.