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.
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 with the first gene therapy death see also video 5.
Whereas in , 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 , China approved Oncorine H , an oncolytic adenovirus, to be used in combination with chemotherapy as a treatment for patients with late stage refractory nasopharyngeal cancer.
In , 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 first operation was carried out on a 23 year-old British male in early 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 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia. 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 viral vector that delivered the gene to their T cells had also activated an oncogene, triggering leukemia. The U. In his case, the viral vector caused a fatal immune response. In the early s, gene therapy experienced a renaissance. Scientists developed better viral vectors to deliver genetic therapies.
These elements specified where and when the gene should turn on, and at what level. Some deliver genes meant to work for a short while and then inactivate themselves. Others carry genes that remain active long-term and pass to daughter cells as the cells divide. Popular viruses for gene therapy include adenoviruses, adeno-associated virus, and lentiviruses. The vector silences a gene called BCL11A , leading to production of fetal hemoglobin that is not affected by the sickle cell mutation.
Traditional gene therapy uses viruses to carry healthy genes into cells, compensating for a faulty or missing gene. While 9 out of 10 were treated, 4 of the 9 patients developed leukemia.
This study demonstrated the need for improved viral vectors in gene therapy 11 ,12 Necker Hospital for Sick Children The FDA approved the first clinical trial in humans using an LVV to test the safety and tolerability of a single infusion in patients with HIV.
When the bacterium reproduced, it replicated the foreign DNA and maintained the genetic material from the original organism. Stanley N. Cohen and Herbert W. Boyer US-Japan joint meeting on plasmids, Hawaii. The results were mixed, with 1 modest response and 1 limited response. Additional patient protection caused delays in research at the time, but has led to greater emphasis on safety and data sharing in gene therapy research efforts since 10 Jesse Gelsinger, an year-old boy with a relatively mild form of ornithine transcarbamylase OTC deficiency, died while participating in an adenoviral gene therapy trial due to a severe immune reaction to the vector.
A clinical trial of gene therapy using a gamma retrovirus raised concern about the safety of gene insertion 11,12 Ten patients with X-linked severe combined immunodeficiency SCID were treated with gene therapy.
This study demonstrated the need for improved viral vectors in gene therapy 11, National Medical Products Administration China. Jean Bennett University of Pennsylvania. Philippe Leboulch Paris Descartes University. Explore Genehome Learn more about how gene therapies work. Types of gene therapy. Keep learning with Genehome Expand your knowledge with gene therapy and content sent directly to your inbox. Stay Informed. References 1. Back to Top.
The structure of DNA was characterized by a double helix 3. Researchers discovered a genetic engineering technique that allows genetic material from 1 organism to be artificially introduced, replicated, and expressed in another 5 DNA was spliced into a plasmid carrier a DNA structure that can replicate without a chromosome , which then inserted genetic material into an E. US-Japan joint meeting on plasmids, Hawaii.
The University of California, Los Angeles. The first gene therapy clinical trial was conducted using new viral vector technology 7 2 patients with severe combined immunodeficiency SCID received treatment using novel gamma retrovirus vector technology. The results were mixed, 1 modest response and 1 limited response. John Hopkins University. The first generation of lentiviral vectors LVVs was created using 3 different plasmids A DNA structure that can replicate without a chromosome containing a large deactivated portion of the HIV genome, making it unlikely for HIV to replicate in human cells 9 Second and third generation LVVs followed a couple years later containing further reduction of the original HIV genome less than two-thirds.
Salk Institute. A clinical trial of gene therapy using a gamma retrovirus raised concern about the safety of gene insertion 11 ,12 Ten patients with X-linked severe combined immunodeficiency SCID were treated with gene therapy.
This study demonstrated the need for improved viral vectors in gene therapy 11 , Necker Hospital for Sick Children. In particular, a class of viral vectors called adeno-associated viruses AAVs has emerged as a leading platform for developing gene therapies. They can be engineered and targeted towards specific cell or tissue types. All these features make them ideal tools for modern gene therapy applications, and the rise in interest in this technology has been steep.
Targeting the eye has become particularly attractive, as its anatomy is well suited to gene therapy approaches. The approval of Luxturna in the EU was the first for any gene therapy for the eye. The treatment consists of a n AAV-based gene therapy to stop the progression of vision loss caused by a genetic mutation. In Europe, companies such as Nightstar Therapeutics, Horama, Eyevensys, and MeiraGTx are developing multiple gene therapies targeting different genetic mutations that cause blindness.
This technique has immense potential and could broaden the concept of genetic treatment beyond conventional gene therapy approaches. As a result, gene editing has the potential to address a vast array of genetic disorders. As of last year, preliminary results seem to indicate the treatment works.
We have laid a careful groundwork with our preclinical research and are very optimistic about what the next phase means for science and for patients. Gene therapy has overcome immense challenges to become a medical reality, and its evolution is still far from over.
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