Gene Therapy and Precision Medicine

Gene Therapy & Precision Med - Future Forward

• Gene Therapy: Introducing, removing, or altering genetic material to treat/cure diseases.
  • Somatic: Non-heritable changes in patient's cells (e.g., Zolgensma for SMA).
  • Germline: Heritable changes in sperm/eggs/embryos; significant ethical concerns.
  • Delivery: Viral vectors (AAV, lentivirus), non-viral methods.
• Precision Medicine: Tailoring medical decisions and treatments to individual patient characteristics.
  • Focus: Genomics, proteomics, metabolomics, lifestyle factors.
  • Pharmacogenomics: Optimizing drug therapy based on genetic makeup.
• Horizon: CRISPR-Cas9, RNA therapies, CAR T-cells, AI in diagnostics.
  • Considerations: Ethical, Legal, Social Implications (ELSI), cost, accessibility.

⭐ Precision medicine utilizes biomarkers like EGFR mutations in lung cancer to guide targeted therapy with TKIs (e.g., Osimertinib).

Gene Therapy - Fixing Faulty Genes

• Goal: Introduce genetic material to treat disease by correcting faulty genes.
• Types:
  • Somatic: Targets body cells (non-heritable). E.g., for SCID, hemophilia.
  • Germline: Targets reproductive cells (heritable). Ethically restricted.
• Vectors (Delivery):
  • Viral (common):
    • Retroviruses/Lentiviruses: Integrate into DNA; long-term. Risk: insertional mutagenesis.
    • Adenoviruses: Episomal; transient. Risk: immune response.
    • AAVs (Adeno-associated viruses): Low immunogenicity; broad tropism; mostly non-integrating.
  • Non-viral: Liposomes, nanoparticles. Safer, lower efficiency.
• Delivery Methods:

![In Vivo Gene Therapy Diagram](https://ylbwdadhbcjolwylidja.supabase.co/storage/v1/object/public/notes/L1/Internal_Medicine_Genetics_and_Disease_Gene_Therapy_and_Precision_Medicine/821b07fb-78ea-418a-b9e9-951462b1071d.png)
> ⭐ AAV vectors are widely used in gene therapy (e.g., Luxturna for Leber congenital amaurosis) due to their safety and efficacy in targeting various tissues, including non-dividing cells like neurons and photoreceptors. 

Precision Medicine - Tailored Treatments

Tailors treatments to individual patient characteristics, often genetic.

• Pharmacogenomics: How genes affect drug response.
  • Key for optimizing drug choice & dose.
  • CYP2D6 variants: codeine, tamoxifen metabolism.
  • CYP2C19 variants: clopidogrel efficacy.
  • Warfarin dosing guided by CYP2C9 & VKORC1 variants.
• Targeted Therapies: Drugs for specific molecules in disease.
  • Monoclonal Antibodies: Trastuzumab for HER2+ breast cancer.
  • TKIs: Imatinib for CML (BCR-ABL).
• Companion Diagnostics: Tests selecting patients for targeted therapies (e.g., HER2 test for Trastuzumab, EGFR for gefitinib).
• Biomarkers: Indicators (genetic, molecular) for diagnosis, prognosis, treatment response.

⭐ Trastuzumab (Herceptin) targets the HER2 protein, overexpressed in some breast cancers, revolutionizing treatment for HER2+ patients.

Applications & Ethics - Healing Hopes & Hurdles

• Key Applications (Gene Therapy):
  • SCID (e.g., ADA-SCID): Restores immunity.
  • Hemophilia A/B: AAV-mediated factor replacement.
  • Cystic Fibrosis (CFTR): Ongoing research.
  • Cancers: CAR T-cells (CD19+ leukemias/lymphomas), oncolytic viruses.
  • Spinal Muscular Atrophy (SMA): Zolgensma (SMN1 gene).
  • Inherited Retinopathies: Luxturna (RPE65 mutations).
• Precision Medicine: Tailoring treatment based on genetic/molecular profiles (e.g., cancer pharmacogenomics).
• Hurdles:
  • Off-target effects, immunogenicity.
  • Vector delivery & efficiency.
  • Durability of therapeutic effect.
  • High cost & accessibility issues.
• Ethical, Legal, Social Implications (ELSI):
  • Somatic vs. Germline editing (heritable changes raise concerns).
  • Equity: Access, affordability (critical in India).
  • Informed consent, genetic privacy.

  ⭐ Luxturna (voretigene neparvovec) is the first FDA-approved gene therapy for an inherited disease (RPE65-mediated retinal dystrophy).

High‑Yield Points - ⚡ Biggest Takeaways

• Gene therapy aims to correct genetic defects by introducing therapeutic DNA, often via viral vectors like AAV.
• Distinguish somatic cell gene therapy (non-heritable, common) from germline gene therapy (heritable, ethical concerns).
• Precision medicine customizes healthcare using an individual's genetic makeup, lifestyle, and environmental factors.
• Pharmacogenomics, a core of precision medicine, predicts drug efficacy and toxicity (e.g., Warfarin dosing, Trastuzumab for HER2+ cancer).
• CRISPR-Cas9 is a powerful gene editing tool with significant therapeutic potential.
• Key applications include treating monogenic disorders (e.g., SCID, DMD) and advancing cancer immunotherapy (e.g., CAR T-cells).