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Historic Overview of Gene Therapy

On September 14, 1990, the first approved gene therapy procedure was performed on four-year old patient (see video 1). Born with a rare genetic disease called (SCID), she lacked a healthy immune system, and was vulnerable to every passing germ or infection. Children with this illness usually develop overwhelming infections and rarely survive to adulthood; a common childhood illness is life-threatening. She led a cloistered existence; avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics.

In her gene therapy procedure, doctors removed white blood cells from the child's body, let the cells grow in the lab, inserted the missing gene into the cells, and then infused the genetically modified blood cells back into the patient's bloodstream. Laboratory tests have shown that the therapy strengthened her immune system by 40%; she no longer has recurrent colds, she has been allowed to attend school, and she was immunized against whooping cough. This procedure was not a cure; the white blood cells treated genetically only work for a few months, after which, the process must be repeated. As of early 2007, she was still in good health, and she was attending college.

Video 1: First gene therapy trial for
SCID patient (YouTube, 1:15)
Video 2: Gene therapy for Muscular Dystrophy (YouTube, 1:29)

The reasons for selecting this disease for the first approved human clinical gene therapy trial is that the disease is caused by a defect in a single gene, which increases the likelihood that gene therapy will succeed. In addition, the gene is regulated in a simple, “always-on” fashion, unlike many genes whose regulation is complex, and the amount of ADA present does not need to be precisely regulated. Even small amounts of the enzyme are known to be beneficial, while larger amounts are also tolerated well.

Although this simplified explanation of a gene therapy procedure sounds like a happy ending, it is little more than an optimistic first chapter in a long story; the road to the first approved gene therapy procedure was rocky and fraught with controversy. Gene therapy actually started around 1984 when Gluzman, Carter & Muzyczka developed a gene delivery system derived from adenoviruses and adeno-associated viruses. Soon it became clear that the biology of human gene therapy is very complex, and there are many techniques that still need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. A major drawback came in 1999 with the first gene therapy death (see also video 5).

In 2001, the 500th gene therapy clinical trial was submitted to the FDA/NIH for approval. Whereas in 2003, the first commercial gene therapy medicine (Gendicine) was available on the market in China. Gendicine is registered for the treatment of head and neck cancers. In November 2005, China approved Oncorine (H101), an oncolytic adenovirus, to be used in combination with chemotherapy as a treatment for patients with late stage refractory nasopharyngeal cancer. See also sections Medical Tourism and Gene Therapy Products on the Market.

In 2008, three groups reported positive results using gene therapy to treat Leber's Congenital Amaurosis (LCA), a rare inherited retinal degenerative disorder that causes blindness in children. The patients had a defect in the RPE65 gene, which was replaced with a functional copy using adeno-associated virus. The LCA trials were conducted independently by groups in the United Kingdom, Florida, and Pennsylvania. The first operation was carried out on a 23 year-old British male in early 2007. In all three clinical trials, patients recovered functional vision without apparent side-effects. These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.

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. Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.

In November 2012, the European Commission approved the gene therapy Glybera® (alipogene tiparvovec), a treatment for patients with lipoprotein lipase deficiency (LPLD, also called familial hyperchylomicronemia) suffering from recurring acute pancreatitis. Patients with LPLD, a very rare, inherited disease, are unable to metabolize the fat particles carried in their blood, which leads to inflammation of the pancreas (pancreatitis), an extremely serious, painful, and potentially lethal condition. The approval makes Glybera the first gene therapy approved by regulatory authorities in the Western world. The commercial rollout of Glybera began in late 2014. See alsoGene Therapy Products on the Market.

In February 2015 LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease. In March of 2015, scientists, including an inventor of CRISPR, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans until the full implications are discussed among scientific and governmental organizations. In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies, but that basic research including embryo gene editing should continue.

n April 2016 the European Medicines Agency and the European Commission endorsed a gene therapy treatment called Strimvelis. This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe. In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.

In 2017 Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma. In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease. In August 2017, the FDA approved Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia. This is the first form of gene therapy to be approved in the United States. In October 2017, a similar therapy called Yescarta (axicabtagene ciloleucel) was approved by the FDA for non-Hodgkin lymphoma.