Gene Therapy and Pharmacogenomics

Gene therapy is the treatment of disease by introducing functional genes into a patient's cells. Pharmacogenomics is the use of an individual's genetic information to tailor drug treatment. Both are central to 21st-century personalised medicine. OCR A-Level Biology A specification 6.1.3 (j)–(k) requires you to distinguish somatic from germline therapy, describe the vectors used, and give named examples of diseases treated.

Key Definitions:

• Gene therapy — the introduction of a functional allele into cells to correct a genetic disorder.
• Somatic cell gene therapy — genetic modification of body cells; changes are not passed to offspring.
• Germline gene therapy — genetic modification of gametes or embryos; changes are heritable.
• Pharmacogenomics — the study of how genetic variation affects response to drugs.
• Personalised medicine — tailoring medical treatment to an individual's genotype.

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Why Gene Therapy?

Genetic disorders caused by a single faulty gene (monogenic diseases) are in principle curable by replacing the faulty allele with a functional one. Over 10,000 monogenic disorders are known, from cystic fibrosis (CF) and sickle cell anaemia to the lysosomal storage diseases and severe combined immunodeficiency (SCID). Many are recessive, so a single functional copy is enough to produce normal phenotype — ideal targets for gene therapy.

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Somatic vs Germline Gene Therapy

Somatic Cell Gene Therapy

Only body (somatic) cells are modified, so the change affects the individual but is not passed to offspring. All gene therapy trials in humans to date are somatic. The modified cells may be:

• Removed, modified, and returned (ex vivo) — e.g. bone marrow stem cells for SCID.
• Treated inside the body (in vivo) — e.g. delivering a vector directly into the lungs of a CF patient.

Somatic therapy typically needs repeated treatment because modified cells are eventually replaced by the body.

Germline Gene Therapy

Modification of gametes, fertilised eggs or early embryos means every cell of the resulting individual — and all their descendants — carries the change. This is currently illegal for humans in the UK, EU and most other countries because of ethical concerns: unknown long-term effects, the inability of unborn people to consent, and fears of "designer babies". The only reported case (He Jiankui, China, 2018) who edited two embryos to resist HIV sparked international condemnation and led to his imprisonment.

Feature	Somatic	Germline
Cells treated	Body cells	Gametes or embryos
Heritable	No	Yes
Consent from future generations	Not needed	Impossible
Currently permitted in humans	Yes (clinical trials)	No (banned)
Permanence	Lost as cells die	Permanent in lineage

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Vectors for Gene Therapy

Getting a gene into a patient's cells requires a vector. The ideal vector is safe, specific, efficient and persistent. Different vectors suit different tissues.

Viral Vectors

Viruses are natural gene delivery machines. Their virulence genes are removed and replaced with the therapeutic gene.

• Retroviruses — integrate into the host genome. Used for SCID therapy but caused leukaemia in some early trials by disrupting oncogenes.
• Lentiviruses (e.g. HIV-derived) — integrate into non-dividing cells; safer than other retroviruses.
• Adenoviruses — do not integrate, so expression is transient. Used for CF and some cancers.
• Adeno-associated viruses (AAV) — small, low immunogenicity, can give long-lasting expression. Used in the first FDA-approved gene therapy, Luxturna (RPE65 for inherited blindness, 2017).

Non-Viral Vectors

• Liposomes — lipid vesicles that fuse with target cell membranes. Used in aerosol form for CF lungs.
• Naked DNA injected directly into tissue — inefficient but safe.
• Electroporation — electrical pulses open transient pores.
• Nanoparticles — increasingly used in mRNA vaccines and therapies.

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Named Examples of Gene Therapy

Severe Combined Immunodeficiency (SCID)

Children born with SCID ("bubble boy disease") lack functioning T and B lymphocytes and die young without treatment. A common form is ADA-SCID, caused by mutation of the adenosine deaminase gene.