Gene therapy

Gene therapy represents a significant branch of modern health technology that seeks to achieve therapeutic benefit by modifying gene expression or altering the biological characteristics of living cells. It encompasses a range of strategies aimed at correcting, replacing or regulating genetic material to address disease at its molecular source. Since its conceptual origins in the mid-twentieth century, the field has evolved from theoretical proposals to a sophisticated clinical and commercial discipline, supported by decades of research, clinical trials and regulatory development.

Early scientific background

The scientific foundations of gene therapy were established during the 1960s, when researchers began to explore methods of introducing new genetic functions into mammalian cells. Early experimentation involved microinjection of DNA directly into living cells and the use of DNA precipitates to facilitate cellular uptake. A key conceptual breakthrough came with the recognition that viruses could serve as vectors for delivering therapeutic genes, capitalising on their natural ability to enter cells and insert genetic material.
Important early contributions included work by Dr Lorraine Marquardt Kraus in 1961, who altered haemoglobin characteristics in bone-marrow cells of a patient with sickle-cell disease by incubating them with DNA from a healthy donor. In 1968, researchers at the National Institutes of Health corrected cellular defects associated with Lesch–Nyhan syndrome by introducing foreign DNA into cultured patient cells. These investigations demonstrated the possibility of targeted genetic manipulation in mammalian tissues and laid the foundation for later clinical attempts.

Pioneering attempts and early trials

The first attempt to modify human DNA in a clinical context occurred in 1980, undertaken by Martin Cline in the United States. Although unsuccessful and not formally validated, it marked the beginning of human interventions aimed at genetic modification. During the 1980s, extensive animal studies and gene-tagging experiments refined delivery techniques and safety considerations.
The first widely recognised successful example of human gene therapy occurred in September 1990, when a child with adenosine deaminase deficiency, a form of severe combined immunodeficiency, received modified cells engineered to express a functional version of the missing enzyme. This case became a landmark in the clinical application of genetic technologies.
A further milestone was achieved in 1993 with the initiation of the first somatic treatment designed to produce a permanent genetic change. This approach involved introducing a gene into tumour cells to render them sensitive to a drug that would subsequently induce tumour cell death, illustrating the potential of gene therapy in oncology.

Evolution of techniques and therapeutic strategies

Gene therapy strategies have traditionally focused on replacing defective genes with functional equivalents. These therapeutic genes are typically delivered using vectors—most commonly viruses—that transport the genetic material into target cells. Widely used vectors include adeno-associated viruses (AAVs) for in vivo delivery and lentiviruses for ex vivo applications. AAVs are favoured for their stable capsid, lower immunogenicity, ability to transduce both dividing and non-dividing cells and potential for long-term expression.
Non-viral delivery systems have also been developed, particularly for allele-specific oligonucleotide and small interfering RNA therapies. These approaches rely on chemical carriers rather than viral vectors and are often used for targeting liver cells via GalNAc transport mechanisms. Non-viral systems allow manipulation of gene expression without permanent integration into the genome.
Beyond classical gene addition, advances in molecular biology have introduced genome-editing techniques using zinc-finger nucleases, CRISPR-based systems and other engineered nucleases. These methods permit precise modification, replacement or disruption of DNA sequences. They may involve ex vivo removal of patient cells, editing in laboratory conditions and reinfusion of modified cells. This has expanded therapeutic possibilities to include gene disruption, correction of point mutations and modulation of regulatory DNA.

Clinical development and regulatory milestones

Between 1989 and 2018, more than 2,900 clinical trials were undertaken, many of which progressed through early-phase safety and efficacy evaluations. These trials covered a wide array of conditions, including inherited metabolic disorders, blindness due to retinal degeneration, immune deficiencies, haematological malignancies, neurodegenerative diseases and haematological genetic disorders.
The first regulatory approval of a gene therapy product occurred in 2003 with the release of Gendicine in China for certain cancer treatments. Subsequent approvals expanded globally, including alipogene tiparvovec in 2012 for lipoprotein lipase deficiency, Strimvelis in 2016 for ADA-SCID, tisagenlecleucel in 2017 for certain leukaemias and voretigene neparvovec in 2017 for inherited retinal dystrophy. Between 2018 and 2022, several further therapies received approval, including products for spinal muscular atrophy, haemophilia and bladder cancer. Together, these marked gene therapy’s transition from experimental science to mainstream clinical practice.
Clinical successes have included significant progress in treating retinal diseases such as Leber’s congenital amaurosis and choroideremia, X-linked immune deficiencies, adrenoleukodystrophy, chronic lymphocytic and acute lymphocytic leukaemias, multiple myeloma, haemophilia and Parkinson’s disease. Investment in the field increased correspondingly, with substantial financial commitments from biotechnology companies and venture capital groups in the early 2010s.

Applications, mechanisms and delivery modalities

Gene therapy applications can be broadly grouped into several categories:

• Gene supplementation, replacing defective alleles with functional variants.
• Gene inhibition, blocking harmful gene expression through antisense or RNA interference mechanisms.
• Gene editing, correcting mutations within the genome itself.
• Cell-based therapies, modifying cells ex vivo before reintroducing them to the patient.

Delivery systems fall into two primary categories:

• Viral vectors, such as AAVs and lentiviruses, offering efficient delivery and long-term expression.
• Non-viral carriers, including nanoparticles, lipid complexes and conjugated oligonucleotides, used particularly where transient or reversible modulation is required.

Many therapies remain somatic, affecting only the treated individual rather than producing heritable changes. Somatic therapies have been used to produce lasting modifications in targeted cell populations, especially in oncology, immunodeficiencies and metabolic disorders.

Classification and evolving definitions

Debates surrounding the scope and definition of gene therapy have persisted since the mid-1980s. Early definitions by the Institute of Medicine characterised it as the addition or replacement of a gene in a specific cell type. Over time, regulatory agencies such as the United States Food and Drug Administration proposed broader definitions encompassing any intervention that modified genetic expression or cellular properties.
By 2018, refinements suggested restricting definitions to therapies that produced intentional and permanent genomic changes, excluding temporary episomal activity and standard transplantation procedures. Scholarly discussions have highlighted the practical and ethical implications of these definitions, particularly as technologies such as mRNA therapeutics blur the boundaries between genetic modulation and traditional pharmacology.
The COVID-19 pandemic renewed public debates on the meaning of gene therapy, especially concerning mRNA vaccine technology, which uses genetic instructions to stimulate transient protein production without altering DNA or producing permanent genomic change. Academic commentary and independent fact-checking emphasised the need for clarity in scientific communication to prevent misconceptions about genetic technologies.

Significance and contemporary context

Gene therapy has become a central pillar of personalised medicine, offering treatments tailored to individual molecular defects rather than symptomatic management. Its success has been particularly notable in rare diseases with well-defined genetic origins but is increasingly expanding into complex diseases and oncology. Continued advances in vector engineering, genome editing and regulatory frameworks are expected to broaden clinical applications further.