Gene therapy: a promising solution for sickle cell disease

Image/Elena Resko
Gene therapy for sickle cell disease

Sickle cell disease is debilitating, and many people who suffer with it find that their lives are defined by pain. This means a curative treatment would be completely life–altering, and, as we observe World Sickle Cell Day on June 19, we explore how gene therapy could be the most promising solution for curing sickle cell disease. 

A disease of the red blood cells – which are vitally important and carry oxygen from the lungs to the rest of the body – sickle cell disease is characterized by an abnormality in the protein hemoglobin, causing the red blood cells to become hard, sticky, and C-shaped, like a ‘sickle’ (a farm tool) instead of smooth and round like they should be.

This then blocks the blood flow, triggering episodes known as ‘pain crises’ or, as they’re formally called, vaso-occlusive crises. These episodes are excruciatingly painful, and can last for hours or even weeks, with people often needing to visit the emergency department because of them. 

The lack of blood flow can also result in organ damage over time, and can cause strokes, kidney failure, acute chest syndrome (a severe lung-related complication), and death of bones. 

Issues with current treatments

For such a severe disease, the treatment options at the moment are very much lacking and do very little to relieve symptoms. 

According to Preeti Attri, healthcare research and data analyst in Clarivate’s infectious, niche, and rare diseases team, hydroxyurea – an antimetabolite that helps prevent the formation of sickle-shaped red blood cells – is the mainstay first-line treatment, in combination with prophylactic penicillin, analgesics, and blood transfusions. 

The U.S. Food and Drug Administration’s (FDA) approval of Emmaus Life Sciences’ Endari (L-glutamine), Global Blood Therapeutics’ Oxbryta (voxelotor), and Novartis’ Adakveo (crizanlizumab) also provides patients with newer treatment options.

In terms of a curative treatment, there is the option of allogenic hematopoietic stem cell (HSCT) transplantation but, as Attri pointed out, it is generally reserved for patients with severe disease, and not all patients with severe disease are even eligible for the procedure. 

“Despite the launch of newer therapies, most patients continue to experience clinical symptoms, progressive organ damage, and other substantial morbidities, which contribute to decreased quality of life, sociopsychological challenges, and early mortality,” said Attri.

However, the lack of an accessible cure for people with severe sickle cell disease could change in the very near future, all thanks to gene therapy.

Vertex Pharmaceuticals and CRISPR Therapeutics’ gene therapy for sickle cell disease edging closer to approval

Vertex Pharmaceuticals and CRISPR Therapeutics are currently involved in a collaboration to develop a gene therapy for both sickle cell disease and beta thalassemia.

The gene therapy, called exa-cel, works by turning on a protein called fetal-globin, which people have as a fetus, as well as when they are born. However, this protein usually turns itself off after the first year of life. 

“It’s known that fetal-globin can essentially make it so that you have no symptoms if you have sickle cell disease or beta thalassemia, because babies who are born with sickle cell disease and beta thalassemia have no symptoms until after the fetal-globin turns off,” said David Altshuler, chief scientific officer (CSO) of Vertex Pharmaceuticals.

“And there’s a small number of people with a very rare genetic mutation called hereditary inherited persistence of fetal-globin; it never turns off. And, if it never turns off, people with sickle cell disease and beta thalassemia will never get sick.”

Exa-cel essentially involves taking cells out of a patient’s body, genetically modifying them to turn on fetal-globin again, and then putting them back in the body through a bone marrow transplant.

Altshuler called the results from pivotal trials of exa-cel ‘quite remarkable’, with 16 out of 17 patients treated with exa-cel meeting the primary endpoint of going one year without having a vaso-occlusive crisis. 

Additionally, just this month, the FDA accepted the Biologics License Applications (BLA) for exa-cel and granted priority review for sickle cell disease.

Bluebird bio submits lovo-cel application to the FDA

Bluebird bio is also developing a gene therapy for sickle cell disease, called lovo-cel, which is meant for patients aged 12 and over who have a history of vaso-occlusive events. 

Lovo-cel is designed to add functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic (blood) stem cells, which will allow their red blood cells to produce anti-sickling hemoglobin that decreases the proportion of abnormal hemoglobin, reducing sickle red blood cells, hemolysis, and other complications.

It was announced in April that bluebird submitted its BLA to the FDA, seeking a priority review for lovo-cel. 

The submission is supported by efficacy results from 36 patients with 32 months of follow up data, as well as two patients with 18 months follow up.

Can gene therapy for sickle cell disease decrease healthcare costs?

Because gene therapy works as a curative treatment, and it is a one-time procedure for each sickle cell disease patient, it can also potentially have a positive impact in decreasing the overall healthcare costs that go towards hospital admissions and treating patients with the disease.

“If we look at recently approved gene therapy (Bluebird Bio’s Zynteglo) in a sister indication (beta thalassemia), it is priced at $2.8 million based on its clinical value to beta thalassemia patients, and Bluebird Bio developed an access strategy where it will reimburse up to 80% of the cost of the therapy to commercial and government payers if the drug is not able to achieve and maintain transfusion independence up to two years after infusion in a patient,” commented Attri. 

“Although we do not have many details on potential value-based pricing of emerging gene therapies in sickle cell disease yet, similar rebate agreements for sickle cell disease gene therapies can be anticipated.”

As an example of how much sickle cell disease hospitalizations cost, a 2021 report stated that statistics from 2004 showed that more than 80,000 hospitalizations were incurred by adult patients with sickle cell disease in the U.S., costing nearly $500 million. And, this comes despite only around 100,000 Americans being affected by the disease. 

Therefore, as Altshuler pointed out regarding the potential cost of exa-cel, it may be resource-intensive and still fairly expensive, but it won’t be anywhere near as expensive as actually having the disease. 

With the multiple benefits that a gene therapy for sickle cell disease could offer patients in terms of complete symptom relief and taking away healthcare costs, it seems the approval of the first gene therapy for the disease couldn’t come soon enough.

“For those with sickle cell disease, managing the next vaso-occlusive crisis or pain crisis event can be daunting. Gene therapy could potentially provide sickle cell disease patients with a sense of normalcy by providing a curative treatment option, especially for severe sickle cell disease patients who are not eligible for HSCT,” said Attri.

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