Utilizing specialized adeno-associated viral (AAV) vectors to deliver functional human FMR1 directly into the central nervous system, the team successfully restored FMRP production within key cortical and subcortical regions of Fmr1 knockout mice. The genetic replacement effectively reversed severe, translationally relevant traits, even when administered well after major stages of brain development had already occurred……Continue reading….
By: Tim Bonfield
Source: Neuroscience News
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Critics:
Gene therapy was first conceptualized in the 1960s, when the feasibility of adding new genetic functions to mammalian cells began to be researched. Several methods to do so were tested, including injecting genes with a micropipette directly into a living mammalian cell, and exposing cells to a precipitate of DNA that contained the desired genes. Scientists theorized that a virus could also be used as a vehicle, or vector, to deliver new genes into cells.
One of the first scientists to report the successful direct incorporation of functional DNA into a mammalian cell was biochemist Dr. Lorraine Marquardt Kraus (6 September 1922 – 1 July 2016) at the University of Tennessee Health Science Center in Memphis, Tennessee. In 1961, she managed to genetically alter the hemoglobin of cells from bone marrow taken from a patient with sickle cell anaemia.
She did this by incubating the patient’s cells in tissue culture with DNA extracted from a donor with normal hemoglobin. In 1968, researchers Theodore Friedmann, Jay Seegmiller, and John Subak-Sharpe at the National Institutes of Health (NIH), Bethesda, in the United States successfully corrected genetic defects associated with Lesch-Nyhan syndrome, a debilitating neurological disease, by adding foreign DNA to cultured cells collected from patients suffering from the disease.
The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by geneticist Martin Cline of the University of California, Los Angeles in California, United States on 10 July 1980.[11][12] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified.
After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashanthi DeSilva was treated for ADA-SCID. The first somatic treatment that produced a permanent genetic change was initiated in 1993.
The goal was to cure malignant brain tumors by using recombinant DNA to transfer a gene making the tumor cells sensitive to a drug that in turn would cause the tumor cells to die. The polymers are either translated into proteins, interfere with target gene 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. 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 diseases Leber’s congenital amaurosis and choroideremia, 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 2011, Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia. In 2012, alipogene tiparvovec, a treatment for a rare inherited disorder, lipoprotein lipase deficiency, became the first treatment to be approved for clinical use in either the European Union 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. alipogene tiparvovec treats one such disease, caused by a defect in lipoprotein lipase.
DNA must be administered, reach the damaged cells, enter the cell and either express or 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 knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.
Gene editing is a potential approach to alter the human genome to treat genetic diseases, viral diseases, and cancer. As of 2020 these approaches are being studied in clinical trials.Gene therapy encapsulates many forms of adding different nucleic acids to a cell. Gene augmentation adds a new protein coding gene to a cell.
One form of gene augmentation is gene replacement therapy, a treatment for monogenic recessive disorders where a single gene is not functional; an additional functional gene is added. For diseases caused by multiple genes or a dominant gene, gene silencing or gene editing approaches are more appropriate but gene addition, a form of gene augmentation where new gene is added, may improve a cell’s function without modifying the genes that cause a disorder.
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