Gene therapy – Wikipedia, the free encyclopedia

Gene therapy is the use of DNA as a drug to treat disease by delivering therapeutic DNA into a patient's cells. The most common form of gene therapy involves using DNA that encodes a functional, therapeutic gene to replace a mutated gene. Other forms involve directly correcting a mutation, or using DNA that encodes a therapeutic protein drug (rather than a natural human gene) to provide treatment. In gene therapy, DNA that encodes a therapeutic protein is packaged within a "vector", which is used to get the DNA inside cells within the body. Once inside, the DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patient's disease.

Gene therapy was first conceptualized in 1972, with the authors urging caution before commencing gene therapy studies in humans. The first FDA-approved gene therapy experiment in the United States occurred in 1990, when Ashanti DeSilva was treated for ADA-SCID.[1] Since then, over 1,700 clinical trials have been conducted using a number of techniques for gene therapy.[2]

Although early clinical failures led many to dismiss gene therapy as over-hyped, clinical successes since 2006 have bolstered new optimism in the promise of gene therapy. These include successful treatment of patients with the retinal disease Leber's congenital amaurosis,[3][4][5][6]X-linked SCID,[7] ADA-SCID,[8][9]adrenoleukodystrophy,[10]chronic lymphocytic leukemia (CLL),[11]acute lymphocytic leukemia (ALL),[12]multiple myeloma,[13]haemophilia[9] and Parkinson's disease.[14] These recent clinical successes have led to a renewed interest in gene therapy, with several articles in scientific and popular publications calling for continued investment in the field.[15][16]

In 2012, Glybera became the first gene therapy treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[17][18]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how this technique could be applied to medicine; could human chromosomes be modified to treat disease? Two main approaches have been considered - adding a gene to replace a gene that wasn't working properly, or disrupting genes that were not working properly.[19] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. As of 2014, gene therapy was still generally an experimental technique, although in 2012 Glybera became the first gene therapy treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission, as a treatment for a disease caused by a defect in a single gene, lipoprotein lipase.[17][18]

In gene therapy, DNA must be administered to the patient, get to the cells that need repair, enter the cell, and express a protein.[20] Generally the DNA is incorporated into an engineered virus that serves as a vector, to get the DNA through the bloodstream, into cells, and incorporated into a chromosome.[21][22] However, so-called naked DNA approaches have also been explored, especially in the context of vaccine development.[23]

Generally, efforts have focused on administering a gene that causes a protein to be expressed, that the patient directly needs. However, with development of our understanding of the function of nucleases such as zinc finger nucleases in humans, efforts have begun to incorporate genes encoding nucleases into chromosomes; the expressed nucleases then "edit" the chromosome, disrupting genes causing disease. As of 2014 these approaches have been limited to taking cells from patients, delivering the nuclease gene to the cells, and then administering the transformed cells to patients.[24]

There are other technologies in which nucleic acids are being developed as drugs, such as antisense, small interfering RNA, and others. To the extent that these technologies do not seek to alter the chromosome, but instead are intended to directly interact with other biomolecules such as RNA, they are generally not considered "gene therapy" per se.

Gene therapy may be classified into the two following types, only one of which has been used in humans:

As the name suggests, in somatic gene therapy, the therapeutic genes are transferred into the somatic cells (non sex-cells), or body, of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring or later generations. Somatic gene therapy represents the mainstream line of current basic and clinical research, where the therapeutic DNA transgene (either integrated in the genome or as an external episome or plasmid) is used to treat a disease in an individual.

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Gene therapy - Wikipedia, the free encyclopedia