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  • Updated 08.24.2021
  • Released 12.16.1999
  • Expires For CME 08.24.2024

Gene therapy



Gene therapy is the transfer of genetic material to target cells in a patient for therapeutic purposes. The term “gene therapy” also 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.

Key points

• Gene therapy, by acting at the level of genes, modifies a disease or even cures it.

• A wide variety of technologies are available in the broad category of gene therapy, including gene transfer, gene suppression, and gene editing.

• Genetically engineered cells can be transplanted for delivery of therapeutic proteins in vivo.

• Besides neurogenetic and neurodegenerative disorders, cerebral vascular disease, CNS trauma, and glioblastoma are amenable to gene therapy.

Historical note and terminology

Gene therapy was originally defined as the transfer of defined genetic material to specific target cells of a patient, instead of just the products of cells with altered genes, 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 now 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 and RNA vaccines, eg, for cancer.

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 (35).

Table 1. Historical Landmarks in the Development of Gene Therapy


Discovery or Development


Identification of the double-stranded structure of the DNA (54)


Possibility of gene therapy is speculated (39)


Early attempts at use of viral vectors (51)


Discovery of reverse transcriptase: copying of RNA into DNA (04)


Suggestion that transforming viruses be used for therapeutic gene transfer (23)


Calcium phosphate transfection (27)


First use of an oligonucleotide to act as inhibitor of translation (60)


First demonstration that antisense nucleic acid can be used to downregulate gene expression (33)


Identification of dystrophin, the protein product of Duchenne muscular dystrophy gene, which is the basis of gene therapy of this disorder (31)


The first authorized human gene therapy clinical trial for the treatment of Gaucher disease ( identifier number: NCT00001234).


Correction of adenosine deaminase deficiency in T-lymphocytes using retroviral-mediated gene transfer (08)


Use of cationic liposome for gene transfer in experimental animals (29)


Correction of myopathy in transgenic mice model of Duchenne muscular dystrophy by germline gene transfer of human dystrophin using a retroviral vector (55)


First clinical trial of herpes simplex virus/thymidine kinase/ganciclovir gene therapy system in glioblastoma (44)


Treatment of amyotrophic lateral sclerosis using a gene therapy approach involving implantation of genetically engineered microencapsulated cells releasing neurotrophic factors (02).


RNA interference demonstrated: injection of double stranded RNA shown to inhibit genes (21).


First death in a clinical trial of gene therapy: adenoviral vector-mediated transfer to replace a defect in the ornithine transcarbamylase gene causing a rare liver disorder (36). This led to a setback in the development of gene therapy.


Completion of sequencing phase of human genome project (11). 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 (59).


Definition of critical components of the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system, which later formed the basis of gene editing (24).


Publication of radically new gene editing method that harnessed the CRISPR-Cas9 system, invented by Doudna and Charpentier (37).


UK’s Human Fertilization and Embryo Authority approved use of CRISPR in a human embryo.


EU approval of first ex vivo stem cell gene therapy in the world: Strimvelis for deficiency of the enzyme adenosine deaminase resulting in severe combined immunodeficiency.


FDA approval of splice-modulating antisense agents: eteplirsen for Duchenne muscular atrophy and nusinersen for spinal muscular atrophy.


FDA approved CAR (chimeric antigen receptor)-T cell CTL019 (Kymriah), a cell/gene therapy, for B cell acute lymphoid leukemia.


FDA approved voretigene neparvovec (Luxturna): first U.S. approval of an AAV vector-delivered gene therapy for treating biallelic RPE65-mediated Leber hereditary optic neuropathy causing blindness.


FDA approval of patisiran (Onpattro), a siRNA, for polyneuropathy of hereditary transthyretin mediated amyloidosis in adults.

Approximately 2106 clinical trials of gene therapy conducted worldwide from 1988 to 2020 have been reviewed from 17 clinical trial database providers to show the clinical development of gene therapy as well as approval by regulatory authorities and acceptance by payors (03).

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