Gene therapy

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Originally released December 16, 1999; last updated August 30, 2020; expires August 30, 2023

Key points


• Gene therapy is the transfer of genetic material to target cells in a patient for therapeutic purposes.


• The term “gene therapy” covers strategies for modification or suppression of gene function as well as transplantation of genetically modified cells for in vivo production of therapeutic substances.


• Gene therapy is in clinical trials for treatment of several CNS disorders.


• One gene therapy, nusinersen, has been approved by the FDA for treatment of spinal muscular atrophy.

Historical note and terminology

Gene therapy can be broadly defined as the transfer of defined genetic material to specific target cells of a patient for the ultimate purpose of preventing or altering a particular disease state. Carriers, or delivery vehicles, for therapeutic genetic material are called vectors, which are usually viral, but several nonviral techniques are being used as well. Gene therapy can be broadly classified as follows:


• Somatic line gene transfer for the treatment of genetic as well as nongenetic disorders.
• Therapeutic modification or suppression of gene function.
• Implantation of genetically engineered cells for production of therapeutic substances in vivo.
• Therapeutic DNA vaccines, eg, for cancer.

Gene therapy usually implies the introduction of altered genes into the body of a patient, instead of just the products of cells with altered genes. Gene therapy overlaps with cell therapy. The term "genetic engineering" applies to genetic manipulation of living cells and implantation of genetically engineered cells into the living body and can be considered as a form of gene therapy. Gene therapy can be defined as a treatment that exerts its effects using molecules of DNA or RNA within cells in contrast to most other medicines, which act by mechanisms that include binding to cell surface receptors, inhibiting enzymes in intracellular pathways, or by modifying transcription. Neurosurgeons sometimes refer to gene therapy of neurologic disorders as "cellular and molecular" neurosurgery. Pharmacologists may refer to delivery of therapeutic substances (mostly proteins) by gene therapy as “gene medicines”.

Landmarks in the historical development of gene therapy and its application to neurologic disorders are shown in Table 1. Major developments in gene therapy are currently taking place in the industrial sector, and the technologies of various companies have been reviewed elsewhere (Jain 2020).

Table 1. Historical Landmarks in the Development of Gene Therapy



Discovery or Development


(Watson and Crick 1953)

Identification of the double-stranded structure of the DNA


(Lederberg 1968)

Possibility of gene therapy is speculated


(Rogers and Pfuderer 1968)

Early attempts at use of viral vectors


(Baltimore 1970)

Discovery of reverse transcriptase. Copying of RNA into DNA


(Friedman and Robin 1972)

Suggestion that transforming viruses be used for therapeutic gene transfer


(Graham and van der Erb 1973)

Calcium phosphate transfection


(Zamecnik and Stephenson 1978)

First use of an oligonucleotide to act as inhibitor of translation


(Izant and Weintraub 1984)

First demonstration that antisense nucleic acid can be used to downregulate gene expression


(Hoffman et al 1987)

Identification of dystrophin, the protein product of Duchenne muscular dystrophy gene (basis of future gene therapy of this disorder)


(Blaese et al 1990)

First human gene therapy experiment. Correction of adenosine deaminase deficiency in T-lymphocytes using retroviral-mediated gene transfer


(Hazinski et al 1991)

Use of cationic liposome for gene transfer in experimental animals


(Wells et al 1992)

Correction of myopathy in transgenic mice model of Duchenne muscular dystrophy by germline gene transfer of human dystrophin using a retroviral vector


(Oldfield and Ram 1993)

First clinical trial of herpes simplex virus/thymidine kinase/ganciclovir gene therapy system in glioblastoma multiforme


(Aebischer and Kato 1995)

Treatment of amyotrophic lateral sclerosis using a gene therapy approach involving implantation of genetically engineered microencapsulated cells releasing neurotrophic factors.


(Fire et al 1998)

RNA interference demonstrated: injection of double stranded RNA shown to inhibit genes.


(Collins 2000)

Completion of sequencing phase of human genome project. Further developments in next-generation sequencing in the following years had considerable impact on personalized medicine. For neurologic disorders, it led to improved diagnostics, identification of gene mutations, and development of therapies targeting these (Yuan et al 2015).


(Garneau et al 2010)

Definition of critical components of the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system, which later formed the basis of gene editing.

Classification. A simplified classification of various methods of gene therapy is shown in Table 2.

Table 2. A Simplified Classification of Gene Therapy Techniques

Gene transfer


• chemical: calcium phosphate transfection
• physical
• electroporation
• gene gun

Recombinant virus vectors


• transduction

Viral vectors


• Retroviruses, eg, Moloney murine leukemia virus
• adenoviruses
• adeno-associated virus
• Herpes simplex viruses
• lentiviruses
• vaccinia virus
• other viruses

Nonviral vectors for gene therapy


• liposomes
• ligand-polylysine-DNA complexes
nanoparticles, eg, dendrimers
• synthetic peptide complexes
• artificial viral vectors
• artificial chromosomes

Use of genetically modified microorganisms as oncolytic agents


• genetically modified viruses
• genetically modified bacteria

Cell/gene therapy


• administration of cells modified ex vivo to secrete therapeutic proteins in vivo
• implantation of genetically engineered cells to produce therapeutic substances
• genetic modification of stem cells—stem cell therapy

Gene/DNA administration


• direct injection of naked DNA or genes: systemic or at target site
• receptor-mediated endocytosis
• use of refined methods of drug delivery: eg, microspheres, nanoparticles

Gene regulation


• regulation of expression of delivered genes in target cells by locus control region technology
• molecular switch to control expression of genes in vivo
• promoter element-triggered gene therapy

Repair/editing of genes


• correction of the defective gene in situ


• transcription activator-like effector nucleases (TALENs): restriction enzymes that can be engineered to cut specific sequences of DNA for gene editing


• zinc finger nucleases (ZFNs): engineered DNA-binding proteins for targeted editing of the genome by creating double-strand breaks in DNA at user-specified locations


• gene editing, ie, altering the genomes of living cells by adding or deleting genes


• clustered regularly interspaced short palindromic repeats (CRISPR)

Gene replacement


• excision or replacement of the defective gene by a normal gene

RNA gene therapy


• RNA trans-splicing

Inhibition of gene expression


• antisense oligodeoxynucleotides
• RNA interference
• ribozymes

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