outline how genetic diseases can be treated with gene therapy, using the examples severe combined immunodeficiency (SCID) and inherited eye diseases

Genetic Technology Applied to Medicine

Objective: Outline how genetic diseases can be treated with gene therapy, using the examples of severe combined immunodeficiency (SCID) and inherited eye diseases.

1. What is Gene Therapy?

Gene therapy involves the introduction, removal, or alteration of genetic material within a patient’s cells to treat or prevent disease. The main strategies are:

• Gene addition – delivering a functional copy of a defective gene.
• Gene editing – correcting the mutation in situ (e.g., CRISPR‑Cas9).
• RNA‑based approaches – silencing a mutant allele with RNA interference.

2. Severe Combined Immunodeficiency (SCID)

SCID is a group of inherited disorders characterised by a lack of functional T‑cells (and sometimes B‑cells), leaving patients highly susceptible to infections. The most common form is X‑linked SCID, caused by mutations in the IL2RG gene that encodes the common γ‑chain of several interleukin receptors.

2.1 Gene‑addition therapy for X‑linked SCID

1. Harvest hematopoietic stem cells (HSCs) from the patient’s bone marrow or cord blood.
2. Use a viral vector (commonly a γ‑retrovirus or a self‑inactivating lentivirus) to insert a functional copy of IL2RG into the HSC genome.
3. Condition the patient with low‑dose chemotherapy to create space in the bone marrow.
4. Re‑infuse the genetically corrected HSCs; they home to the marrow, differentiate into T‑cells, and restore immune function.

Clinical outcomes have shown long‑term immune reconstitution in many treated children, reducing the need for bone‑marrow transplantation.

3. Inherited Eye Diseases

Inherited retinal dystrophies (IRDs) such as Leber congenital amaurosis (LCA) and retinitis pigmentosa are caused by mutations in genes essential for photoreceptor function. Gene therapy aims to restore vision by delivering a normal copy of the defective gene directly to retinal cells.

3.1 In‑vivo gene addition for LCA caused by RPE65 mutations

1. Design an adeno‑associated virus (AAV) vector carrying a functional RPE65 cDNA.
2. Perform a sub‑retinal injection, placing the vector between the retinal pigment epithelium (RPE) and the photoreceptor layer.
3. The AA \cdot transduces RPE cells, leading to expression of functional RPE65 protein and restoration of the visual cycle.
4. Patients experience improved light sensitivity and visual acuity, often within weeks of treatment.

Other IRDs (e.g., those caused by mutations in CHM, MYO7A, or ABCA4) are currently in clinical trials using similar AAV‑mediated approaches.

4. Comparison of Gene‑Therapy Approaches

5. Ethical and Practical Issues

• Long‑term safety: insertional mutagenesis (especially with integrating vectors) and potential oncogenesis.
• Germ‑line vs. somatic therapy: current clinical work is limited to somatic cells to avoid heritable changes.
• Access and cost: treatments such as Luxturna cost > $400 000 per patient, raising equity concerns.
• Informed consent, especially for paediatric patients, and the need for robust post‑treatment monitoring.

6. Summary

Gene therapy offers a powerful means of treating genetic diseases by correcting the underlying molecular defect. Ex‑vivo approaches, exemplified by SCID, rely on modifying stem cells outside the body and re‑introducing them, while in‑vivo strategies, such as those for inherited eye diseases, deliver therapeutic genes directly to the affected tissue. Ongoing advances in vector design, genome‑editing tools, and clinical protocols continue to expand the therapeutic horizon, but ethical, safety, and accessibility issues must be addressed alongside scientific progress.