Why in the news?

  • Scientists recently tested a gene-editing method called adenine base editing to fix two severe mutations that cause -thalassemia, a genetic blood disease.

Adenine Base Editing

  • What is it?
    • Adenine base editing (ABE) is a CRISPR-based genome editing technology that enables precise conversion of adenine (A) to guanine (G) in DNA, resulting in A- T to G- C base pair changes without inducing double-strand breaks. 
    • Developed through directed evolution of TadA deaminase fused to a catalytically impaired Cas9 (dCas9 or nCas9), it offers higher precision than traditional CRISPR-Cas9 for point mutations.
  • Mechanism
    • ABE operates via three key components: a deactivated Cas protein for targeting, a guide RNA (gRNA) for locus specificity, and an adenine deaminase for base modification.
    • Cas9 (nickase or dead) binds DNA via gRNA, forming an R-loop that exposes the single-stranded non-target strand (NTS).
    • TadA deaminase converts A to inosine (I) on NTS; inosine pairs with cytosine during repair.
    • Nick on target strand (TS) directs repair, incorporating G- C pair post-replication.
  • Features
    • Editing window typically spans positions 3-12 relative to PAM (e.g., NGG), with variants like ABE8e/9e optimizing efficiency and reducing bystanders.
    • Low indel rates (<1%) compared to DSB-based editing; evolved versions (ABE7.10 to ABE8s) boost activity 1.5-3x at key sites.
    • Applicable in human cells, plants (e.g., rice), and for research/therapeutics
  • Applications
    • Human Health
      • Correcting monogenic disorders caused by A→G mutations: Sickle Cell Disease,β-thalassemia, Familial hypercholesterolemia, Duchenne muscular dystrophy, etc.
      • Potential for in vivo gene therapy using viral vectors (e.g., AAV).
    • Agriculture
      • Creating high-yield, stress-tolerant, or disease-resistant crops without inserting foreign genes.
      • Useful for precision breeding and non-transgenic crop improvement.
    • Biotechnology & Research
      • Functional genomics, studying protein function, metabolic pathway alterations.
  • Benefits
    • High precision editing at single-base level.
    • No double-strand breaks → safer than CRISPR-Cas9.
    • Extremely low off-target activity.
    • More efficient and predictable than earlier gene-editing tools.
  • Limitation
    • Works mainly for A→G conversions (other base edits need separate editors).
    • Targeting restrictions due to PAM dependency of CRISPR.
    • Delivery challenges for in vivo therapeutic use.
    • Ethical & regulatory concerns similar to CRISPR.

Thalassaemia

  • What is it?: It is the name for a group of inherited conditions that affect a substance in the blood called haemoglobin.
  • Cause: Caused by mutations in HBA1/HBA2 (alpha genes) and HBB (beta gene).
  • Symptoms
    • Chronic anemia
    • Fatigue, weakness
    • Pale skin (pallor)
    • Slow growth in children
    • Enlarged spleen (splenomegaly)
    • Bone deformities (especially facial bones)
    • Jaundice (due to hemolysis)
  • Diagnosis
    • CBC: Low hemoglobin, microcytic hypochromic anemia.
    • Peripheral smear: Target cells, anisopoikilocytosis.
    • Hemoglobin electrophoresis / HPLC: ↑ HbA₂, ↑ HbF in β-thalassaemia.
    • Genetic testing for mutation confirmation.
    • Prenatal diagnosis: Chorionic villus sampling / amniocentesis.
  • Treatement
    • Blood transfusions– regular blood transfusions treat and prevent anaemia; in severe cases these are needed around once a month.
    • Chelation therapy – treatment with medicine to remove the excess iron from the body that builds up as a result of having regular blood transfusions
    • The only possible cure for thalassaemia is a stem cell or bone marrow transplant

Source: The  Hindu