Comprehensive Notes on Gene Therapy

Gene Therapy

• Gene therapy is a treatment or prevention method for diseases that involves:
  • Replacing a faulty gene.
  • Inactivating a malfunctioning gene.
  • Introducing a new or modified gene.

Types of Gene Therapy

• Somatic Gene Therapy
  • Targets non-reproductive cells.
  • Effects are not heritable (i.e., not passed on to future generations).
  • Most current gene therapy treatments fall under this category.
• Germline Gene Therapy (not approved for use in humans)
  • Targets sperm or egg cells.
  • Changes are heritable, meaning they can be passed on to future generations.
  • Raises significant ethical and safety concerns.
• In vivo Gene Therapy
  • Therapeutic genetic material is delivered directly into a patient's tissues or bloodstream.
  • This is done using vectors without removing cells from the body.
• Ex vivo Gene Therapy
  • Patient-derived cells are genetically modified outside the body.
  • These genetically modified cells are then reintroduced back into the patient.

Delivery Methods (Vectors)

• Viral Vectors
  • Delivery Efficiency: High
  • Duration of Expression: Long-term, especially with integrating vectors
  • Examples: Adenovirus, AAV (adeno-associated virus), and lentivirus
  • Immune Response: Often triggers an immune response
• Non-Viral Methods
  • Delivery Efficiency: Generally low to moderate
  • Duration of Expression: Mostly transient
  • Examples: Plasmids, liposomes, and nanoparticles
  • Immune Response: Minimal immune reaction

Case Study: Spinal Muscular Atrophy (SMA) Type 1

• Overview:
  • Definition: A severe neuromuscular disorder.
  • Pathophysiology: Loss of the SMN1 gene causes motor neuron degeneration, leading to muscle weakness and wasting. SMA Type 1 is the leading genetic cause of infant death.
  • Onset: Typically occurs before 6 months of age. Without treatment, it has high mortality by age 2.
• Genetic Cause:
  • Patients usually have a homozygous deletion or mutation in the SMN1 gene.
  • SMN2 is a backup gene that produces only a small amount of functional SMN protein due to alternative splicing.
  • Prevalence: Occurs in approximately 1 in 6,000 to 1 in 10,000 live births.
  • Carrier frequency: 1 in 40 to 1 in 60
• Mechanism of SMA Type 1:
  • SMN1 deficiency leads to splicing defects.
  • This results in motor neuron degeneration, causing muscle weakness and wasting.
• SMN1 Gene Details:
  • Location: Chromosome 5q13.2
  • Inheritance: Autosomal recessive

Gene Therapy for Spinal Muscular Atrophy Type 1 (SMA1)

• Why AAV (Adeno-Associated Virus)?
  • AAV crosses the blood-brain barrier, making it effective for targeting the central nervous system (CNS).
  • AAV can target motor neurons.
• Mechanism:
  • An AAV-based viral vector is used to deliver a functional copy of the SMN1 gene to motor neurons.
  • Administered via a single-dose intravenous injection.
• Key Features:
  • One-time systemic administration is sufficient.
  • The SMN1 gene is delivered episomally (non-integrating).
  • Episomal delivery reduces the risk of insertional mutagenesis.