Virology and Gene Therapy

Gene Therapy for Cancer

• Suicide gene therapy can be achieved through two strategies: indirect form using an enzyme-activated prodrug, and direct form using proapoptotic genes.
• Oncolytic gene therapy involves applying viruses directly into the tumor to induce tumor cell lysis.
• Immunomodulatory gene therapy introduces a gene to stimulate or enhance antitumor immunity.
• Tumor-suppressor gene therapy introduces tumor-suppressor genes to prevent uncontrolled cellular growth.

Viral Vectors for Oncolytic Gene Therapy

• Herpes Simplex Virus (HSV) is attractive as a vector due to its natural tropism to neurons, and ability to replicate only in tumor or dividing cells.
• HSV maintains its genome as an episomal element, reducing the risk of insertional mutagenesis.
• Vaccinia virus is attractive as a vector due to its rapid and efficient cycle, ability to shut down host cell functions, and induce strong immune responses.

Suicide Gene Therapy

• The herpes simplex virus thymidine kinase gene (HSV-tk) converts the antiviral drug ganciclovir (GCV) to monophosphate, leading to cell death.
• Other systems employ the cytochrome P450 and the prodrugs cyclophosphamide (CPA).

Oncolytic Gene Therapy

• Imlygic is a gene therapy that uses a weakened form of herpes simplex virus type 1 to infect and multiply inside melanoma cells, killing them.
• Imlygic also makes the infected cells produce the human cytokine granulocyte macrophage colony stimulating factor gene, which stimulates the patient's immune system to destroy cancer cells.

Immunomodulatory Gene Therapy

• This strategy can take advantage of the enhancement of the immune response through the delivery of proinflammatory genes.
• The combination of an immunological checkpoint blockade with CAVTAK led to a good response and disease control rates in a phase Ib clinical trial for advanced melanoma.

Tumor-Suppressor Gene Therapy

• Gendicine is a gene therapy medication used to treat patients with squamous cell carcinoma linked to mutations in the P53 gene.

Candidate Conditions for Gene Therapy

• Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and others.

Alzheimer's Disease

• Alzheimer's disease is the most common neurodegenerative disorder worldwide, characterized by impairments in memory and behavior.
• The disease is characterized by the accumulation of abnormal protein deposits in the brain, particularly beta-amyloid plaques and tau tangles.
• Gene therapy strategies have been tested in preclinical studies, focusing on the expression of neurotrophic factors, especially the nerve growth factor (NGF).

Parkinson's Disease

• Parkinson's disease is a progressive neurodegenerative disorder that affects movement, coordination, and balance.
• It is caused by the degeneration of dopamine-producing neurons in the brain and the formation of intracellular inclusions of α-synuclein.
• A viral vector delivering a gene that produces the enzyme glutamic acid decarboxylase (GAD) to the brain enhanced disease symptoms.