Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient’s cells as a drug to treat disease. Gene therapy could be a way to fix a genetic problem at its source. The polymers are either expressed as proteins, interfere with protein expression, or possibly correct genetic mutations.
The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.
Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies. The first gene therapy experiment approved by the US Food and Drug Administration (FDA) occurred in 1990, when Ashanti DeSilva was treated for ADA-SCID. By January 2014, some 2,000 clinical trials had been conducted or approved.
Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014, it was still largely an experimental technique. These include treatment of retinal disease Leber’s congenital amaurosis,X-linked SCID, ADA-SCID,adrenoleukodystrophy,chronic lymphocytic leukemia (CLL),acute lymphocytic leukemia (ALL),multiple myeloma,haemophilia and Parkinson’s disease. Between 2013 and April 2014, US companies invested over $600 million in the field.
The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers. In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.
Following early advances in genetic engineering of bacteria, cells and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes. Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.
DNA must be administered, reach the damaged cells, enter the cell and express/disrupt a protein. Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.Naked DNA approaches have also been explored, especially in the context of vaccine development.
Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then “edit” the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.
Other technologies employ antisense, small interfering RNA and other DNA. To the extent that these technologies do not alter DNA, but instead directly interact with molecules such as RNA, they are not considered “gene therapy” per se.
Gene therapy may be classified into two types:
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