Human Gene Therapy 2

  • Overview of Gene Therapy

    • Gene therapy focuses on treating human genetic conditions through strategies to avoid and cure diseases.
    • Genetic diseases (e.g., cystic fibrosis, Huntington's disease) often arise from the loss of gene function.
    • The introduction of a functional 'wild-type' copy of such genes holds therapeutic potential.

  • Case Study: Cystic Fibrosis

    • Caused by mutations in the cystic fibrosis transmembrane regulator gene, leading to protein non-functionality.
    • Early targets for gene therapy, with efforts dating back to the 1990s.

  • Challenges in Gene Therapy

    • Getting DNA into the patient’s cells in vivo poses a significant challenge due to hydrophilic nature of DNA and cell membrane's hydrophobic structure.
    • Viral Vectors used include:
    • Adenoviruses:
      • DNA viruses that do not integrate into the host genome; provide short-term therapy.
      • Can elicit an immune response and can be pathogenic.
    • Adeno-associated viruses (AAV):
      • Require co-infection for replication, non-pathogenic, can infect non-dividing cells, and can integrate into the host genome at specific sites (e.g., chromosome 19).
    • Retroviruses:
      • Derived from HIV, modified to be safe, integrate therapeutic genes into the host genome for long-term expression.

  • Chemical and Physical Methods for DNA Delivery

    • Use of reagents such as liposomes that have both hydrophobic and hydrophilic properties to facilitate DNA transport across the membrane.
    • Other methods include:
    • Adhering DNA to ceramic particles for cellular uptake.
    • Gene guns that physically inject DNA into cells.
    • Direct injection of DNA, with some reported success despite inefficiency.

  • Gene Integration vs. Non-Integration

    • Integration:
    • Permanent integration could lead to long-term expression but carries risks of damaging host genome (insertional mutagenesis).
    • Non-Integration:
    • Temporary gene presence without risks to the host genome, likely requiring repeated therapy over time.

  • Examples of Gene Therapy in Practice

    • Bubble Baby Syndrome (SCID):
    • ADA deficiency: mutation leads to severe immune deficiencies.
    • Early trials involved transducing patient T-cells with wild-type ADA genes leading to improved immune function.
    • Risk of Gene Therapy:
    • Highlighted by cases like Jesse Gelsinger's death during a clinical trial due to severe immune reactions.
    • Other cases where therapies caused unexpected cancerous growth.

  • Cost and Accessibility of Gene Therapy

    • Therapies can be prohibitively expensive, raising ethical concerns about accessibility.
    • Example: SMA (Spinal Muscular Atrophy) gene therapies demonstrate significant financial costs yet improve life quality for patients.

  • RNA Interference (RNAi)

    • An alternative therapeutic approach aimed at silencing genes.
    • Mechanism involves Dicer protein cutting double-stranded RNA that matches target mRNA.
    • Potentially useful for conditions involving overexpression of oncogenes or pathogenic genes.

  • Conclusion:

    • Gene therapy is a promising field with ongoing developments and challenges.
    • Future directions may involve both improving delivery mechanisms and expanding the range of treatable conditions.