U.S. FDA Approves Pair of Gene Therapies for Sickle Cell Disease

Relevance: GS3 Science & Technology, Biotechnology, Sickle cell disease, Gene therapy, CRISPR Technology, Developments in Biotechnology & their Applications & Effects in Everyday Life

Primary Source: The Hindu

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Why in the news?

• The U.S. Food and Drug Administration (FDA) has approved two gene therapies for sickle cell disease.
• The therapies include Lyfgenia by bluebird bio and Casgevy by Vertex Pharmaceuticals and CRISPR Therapeutics.
• These treatments are notable for being the first to use CRISPR gene editing technology in sickle cell disease treatment.

What is Sickle Cell Disease?

• Sickle Cell Disease (SCD) is a group of inherited red blood cell disorders. It's characterized by an abnormality in the oxygen-carrying protein hemoglobin found in red blood cells.
• Genetic Cause: SCD is caused by a mutation in the gene that tells the body to make hemoglobin, the protein in red blood cells that carries oxygen throughout the body. People with SCD inherit two abnormal hemoglobin genes, one from each parent.
• Sickle-Shaped Red Blood Cells: In SCD, the abnormal hemoglobin causes red blood cells to become rigid and shaped like crescent moons or sickles, instead of the normal, round shape.
• These sickle cells can get stuck in small blood vessels, which can slow or block blood flow and oxygen to parts of the body.
• Symptoms:
  • Painful Episodes: Known as sickle cell crises, these are caused by the obstruction of blood flow due to the sickle-shaped cells.
  • Anemia: Due to the shorter lifespan of sickle cells (10-20 days compared to the normal 120 days), patients often suffer from anemia.
  • Infections: People with SCD are more prone to infections, especially in childhood, due to the spleen damage caused by sickle cells.
  • Delayed Growth: Children with SCD may experience slower growth and reach puberty at a later age.
  • Vision Problems: Blockage of blood vessels in the eyes can lead to vision problems.
  • Complications: SCD can lead to chronic pain, acute chest syndrome (a lung-related complication), stroke, organ damage, and increased risk for severe bacterial infections.
  • Treatment: Treatment includes pain management, blood transfusions, and other interventions to relieve symptoms and prevent complications. Bone marrow or stem cell transplants may offer a cure for a small number of patients.

What is CRISPR Technology?

• Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a form of gene editing technology that mimics the defense strategies bacteria use against viruses, utilizing a special protein known as Cas9.
• This process, a type of genetic engineering, typically involves either introducing a new gene or inhibiting an existing one. However, CRISPR itself does not require adding any external genes.
• Often described as 'Genetic Scissors,' CRISPR-Cas9's functioning is comparable to the 'cut-copy-paste' or 'find-replace' features found in standard computer programs.
• In this process, a problematic segment of DNA, responsible for a disease or disorder, is identified, excised, and then substituted with a 'correct' sequence.
• The tools for this procedure are biochemical, consisting of specific proteins and RNA molecules.
• This technology mirrors a natural defense mechanism used by certain bacteria, which employs a similar approach to fend off viral attacks.
• The advent of CRISPR-Cas9 technology promised a transformative impact on healthcare, particularly in treating conditions like sickle cell anemia, and in the field of agriculture.
• This tool has significantly enhanced the resilience of crops by tweaking their genetic makeup to increase resistance to drought and pests.
• Additionally, the technology has been instrumental in developing novel cancer therapies, and many specialists anticipate its potential role in eradicating hereditary diseases.

Gene Therapies for Sickle Cell Disease

The U.S. Food and Drug Administration (FDA) has recently approved two groundbreaking gene therapies for the treatment of sickle cell disease (SCD) in patients aged 12 years and older. These therapies, named Casgevy and Lyfgenia, are the first cell-based gene therapies for SCD, marking a significant advancement in the field.

1. Casgevy

• Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, is notable for being the first FDA-approved therapy that utilizes CRISPR/Cas9, a novel genome editing technology.
• This therapy works by editing the DNA in a patient's hematopoietic (blood) stem cells using CRISPR/Cas9.
• The modified stem cells, which are transplanted back into the patient, produce increased levels of fetal hemoglobin, preventing the sickling of red blood cells.
• Clinical trials have shown promising results, with a significant percentage of patients achieving freedom from severe vaso-occlusive crisis episodes for at least 12 consecutive months during the 24-month follow-up period.

2. Lyfgenia

• Lyfgenia, developed by Bluebird Bio Inc., uses a different approach.
• It employs a lentiviral vector for gene delivery to modify the patient's blood stem cells to produce a gene-therapy derived hemoglobin that functions similarly to normal adult hemoglobin.
• This modification reduces the risk of sickling and obstruction of blood flow in red blood cells.
• Clinical trials for Lyfgenia also reported favorable outcomes, with a majority of patients treated showing complete resolution of vaso-occlusive events within a specified period following infusion.

Both Casgevy and Lyfgenia require the extraction of the patient's blood stem cells, which are then modified and re-infused back as a one-time treatment. This process is accompanied by myeloablative conditioning (high-dose chemotherapy) to prepare the body for the modified cells.

Significance of the Gene Therapies

• Innovative Use of Gene-Editing Technology: Casgevy, is the first FDA-approved therapy utilizing CRISPR/Cas9 gene-editing technology for SCD. CRISPR/Cas9 is a groundbreaking technology that allows for precise modifications to DNA.
• Targeting the Underlying Cause of SCD: Both therapies are designed to address the root cause of sickle cell disease. By modifying the patient's own stem cells, these treatments aim to produce healthier red blood cells that are less likely to sickle, which is a major problem in SCD.
• Potential for Long-Term Benefits: These therapies are considered a one-time treatment, potentially offering long-term relief from the symptoms and complications of SCD. This is a significant shift from the current standard treatments that primarily manage symptoms.
• Improvement in Quality of Life: Clinical trials have shown that these therapies can significantly reduce or eliminate painful vaso-occlusive crises, which are common in SCD and can lead to hospitalizations.
• Broader Implications for Genetic Diseases: The approval of these therapies is a milestone in the field of gene therapy and may pave the way for similar treatments for other genetic disorders.

Concerns regarding the Gene Therapies

• Accessibility and Cost: One of the primary concerns is the accessibility and cost of these treatments. Both therapies are expected to be quite expensive which poses a significant barrier to many patients.
• Eligibility and Availability: Not everyone with sickle cell disease may be eligible for these therapies. There are also concerns about the limited number of healthcare providers initially offering these treatments, which may restrict access for many patients.
• Potential Adverse Effects and Long-Term Outcomes: Both therapies involve complex processes, including chemotherapy, which can have its own side effects like infertility or secondary cancer.
• Equity Issues: There is recognition that while these treatments could be transformative, they might not be equally accessible to all, especially considering the majority of sickle cell patients are from marginalized communities.
• Scientific Differences Between the Therapies: Casgevy uses CRISPR-based gene editing, a novel approach in treating sickle cell disease, while Lyfgenia uses gene addition via a lentiviral vector. Each has its unique scientific methodology and potential issues.
• Scepticism: Experts express caution, preferring to call these therapies transformative rather than cures, as patients will still have sickle cell disease post-treatment.

Conclusion

The FDA's approval marks a significant advancement in treating sickle cell disease using gene editing technology. Despite the promising nature of these therapies, experts advise caution in viewing them as outright cures due to the chronic nature of sickle cell disease and limited data on long-term effects.

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1. The Serum Institute of India produced COVID-19 vaccine named Covishield using mRNA platform.
2. Sputnik V vaccine is manufactured using a vector based platform.
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1. These vaccines are effective against pneumonia as well as meningitis and sepsis.
2. Dependence on antibiotics that are not effective against drug-resistant bacteria can be reduced.
3. These vaccines have no side effects and cause no allergic reactions.

Select the correct answer using the code given below:

(a) 1 only

(b) 1 and 2 only

(c) 3 only

(d) 1, 2 and 3

Question: RNA interference (RNAi)’ technology has gained popularity in the last few years. Why? (UPSC 2019)

1. It is used in developing gene silencing therapies.
2. It can be used in developing therapies for the treatment of cancer.
3. It can be used to develop hormone replacement therapies.
4. It can be used to produce crop plants that are resistant to viral pathogens.

Select the correct answer using the code given below:

(a) 1, 2 and 4

(b) 2 and 3

(c) 1 and 3

(d) 1 and 4 only

Question: What is the Cas9 protein that is often mentioned in the news? (UPSC 2019)

(a) A molecular scissors used in targeted gene editing

(b) A biosensor used in the accurate detection of pathogens in patients

(c) A gene that makes plants pest-resistant

(d) A herbicidal substance synthesised in genetically modified crops

Question: Recombinant DNA technology (Genetic Engineering) allows genes to be transferred: (UPSC 2013)

1. Across different species of plants
2. From animals to plants
3. From microorganisms to higher organisms

Select the correct answer using the codes given below:

(a) 1 only

(b) 2 and 3 only

(c) 1 and 3 only

(d) 1, 2 and 3

Question: Which gene editing technology, recently used in a therapy for sickle cell disease, won the Nobel Prize in 2020?

(a) TALEN

(b) Zinc Finger Nuclease

(c) CRISPR

(d) RNAi

Question: What is the primary pathological feature of sickle cell disease?

(a) Overproduction of white blood cells

(b) Production of sickle-shaped hemoglobin

(c) Lack of insulin production

(d) Excessive clotting factors