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Gene Therapy for Sickle Cell Disease

Context:

Less than a month after receiving approval from the UK drug regulator for Casgevy, a gene therapy designed to treat individuals aged 12 and above with sickle cell disease and beta thalassemia, the U.S. FDA has now granted approval for two gene therapies—Casgevy and Lyfgenia—to address sickle cell disease in patients over the age of 12.

Relevance:

GS3- Science and Technology

  • Developments and their Applications and Effects in Everyday Life
  • Awareness in the field of Biotechnology

Mains Question:

In the context of recent national and global efforts to treat Sickle Cell Disease, explain the causes and symptoms of the disease. Also, highlight the current developments in its treatment and their efficacy. (15 Marks, 250 Words)

Background: About Sickle Cell Disease:

  • Sickle cell disease (SCD), also known as sickle cell anemia, is a genetic blood disorder that significantly impacts the affected individual’s entire life.
  • It belongs to a group of inherited red blood cell disorders that affect hemoglobin, the protein responsible for carrying oxygen throughout the body.
  • In normal circumstances, red blood cells exhibit a disc-shaped and flexible structure, allowing easy movement through blood vessels. However, in individuals with sickle cell disease, their red blood cells take on a crescent or “sickle”-shaped form.
  • These abnormal cells lack flexibility and can obstruct blood flow, leading to severe complications such as stroke, eye issues, infections, and episodes of intense pain known as pain crises.
  • SCD is an autosomal recessive condition, requiring two copies of the gene for the disease to manifest, while individuals with only one copy have sickle cell trait.
  • Symptoms of sickle cell anemia typically manifest at a young age, with onset occurring around six months, though they may appear as early as four months in babies.
  • The symptoms, which vary in severity across different types of SCD, include fatigue, irritability, fussiness in babies, bedwetting, jaundice (yellowing of the eyes and skin), swelling and pain in hands and feet, frequent infections, and chest, back, arm, or leg pain.
  • Various government initiatives aim to address SCD, including the release of technical operational guidelines in 2016, the establishment of integrated centers for treatment and diagnosis in tribal districts, and the creation of the State Haemoglobinopathy Mission in Madhya Pradesh.
  • The National Health Mission, supported by the Government of India, assists states in preventing and managing sickle cell disease.
  • In the Union Budget 2023-24, the government announced a mission to eliminate Sickle cell Anaemia by 2047.

Working of the Recent Gene Therapies:

  • These significant approvals signal the commencement of gene therapy utilizing the CRISPR-Cas9 tool to address diseases that traditionally could only be cured through bone marrow transplantation.
  • CRISPR is a gene-editing technology that mimics the natural defense mechanism in bacteria. It involves the use of a special protein called Cas9 to cut and replace a specific DNA sequence responsible for the disease. The technology is often likened to “genetic scissors” and offers a programmable and efficient way to address genetic disorders, although the potential for errors exists.
  • While Lyfgenia utilizes a disabled lentivirus as a vector to introduce a new gene for hemoglobin mimicking the healthy version into blood stem cells, Casgevy employs the gene-editing capabilities of CRISPR-Cas9 to disable a specific gene (BCL11A) responsible for inhibiting fetal hemoglobin production in blood stem cells.
  • Approximately 10% of adults naturally continue to produce fetal hemoglobin, while in others, the BCL11A gene hinders fetal hemoglobin production.
  • Disabling the BCL11A gene allows the production of fetal hemoglobin, which lacks the abnormalities of adult hemoglobin, providing effective treatment for patients with sickle cell disease or beta thalassemia.

Analysing the Efficacy of the Therapies:

  • Clinical trials for Casgevy demonstrated that 28 out of 29 sickle cell disease patients receiving the gene therapy experienced relief from the debilitating effects of the disease for one year.
  • In the case of beta thalassemia, 39 out of 42 patients did not require blood transfusions for one year, and in the remaining three, the need for blood transfusion was reduced by over 70%.
  • Clinical trials involving Lyfgenia revealed that 30 out of 32 sickle cell disease patients did not suffer from severe blocked blood flow caused by sickle cells, while 28 out of 32 patients did not experience any blocked blood flow events six to 18 months post-infusion.
  • As both gene therapies involve the use of patients’ own blood cells for gene editing, the potential treatment scope is substantial, eliminating the need for matching bone marrow donors.

Challenges Associated:

  • In practice, these treatments are likely to be prohibitively expensive. Similar to bone marrow transplantation, only specific hospitals will have the capability to extract a patient’s blood stem cells, apply the genetic editing tool to these cells, and subsequently reintroduce them. Consequently, the number of beneficiaries is constrained.
  • Given that clinical trials have assessed the therapies in a relatively small number of patients for a limited duration, the imperative of continuously monitoring their safety and effectiveness through real-world data cannot be overstated.

Conclusion:

The utilization of the CRISPR–Cas9 tool introduces the genuine risk of unintended genetic modifications and the associated side effects. Therefore, careful scrutiny and ongoing assessment are crucial in navigating potential risks and ensuring the therapies’ long-term safety and efficacy.


February 2024
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