Release date: 2018-01-12
There have been some major events in medical history that have changed the treatment paradigm of diseases, such as the invention of surgery, the discovery of antibiotics, and the next big event may be mature gene therapy.
After 30 years of repeated setbacks, gene therapy has finally ushered in the dawn: in the past 2017, the US FDA approved for the first time two kinds of CAR-T cell immunotherapy for blood diseases and a treatment for ophthalmological diseases Luxturna .
In the near future, more gene therapy methods will move from the laboratory to the clinic, setting off a new medical revolution. In the two days of the JP Morgan Health Industry Conference, many medical companies are eager to try in the field of gene therapy.
On January 11th, the United States "Science" magazine published a joint article "Gene therapy comes of age" of six well-known scientists in the field, systematically reviewed the history of gene therapy, and looked forward to the future of gene therapy.
As early as 45 years ago, therapeutic therapist Theodore Friedmann suggested that a single genetic disease can be treated by providing the patient with the right genes. In principle, protein-based therapies require repeated dosing (eg, diabetics need to always inject insulin), and if the patient's wrong gene can be repaired or the correct gene is directly provided, a single treatment may have a sustained therapeutic effect. .
With the advancement of basic research in the genetic field, gene therapy began to enter clinical trials since the early 1990s. However, the results of clinical trials continue to repeat the cycle of “optimism-disappointmentâ€, either without the expected efficacy or with serious side effects. In 1996, the National Institutes of Health (NIH) Advisory Committee concluded that humans' research on the underlying mechanisms behind gene therapy is still incomplete and calls on researchers to return their attention to laboratory and basic research.
Introduction to three gene therapy
After nearly three decades of hard work, scientists have made great progress in basic research. In particular, new gene vectors, new gene editing technologies, and advances in cell biology and immunology provide theoretical and instrumental support for the safety and efficacy of gene therapy. These advances have led to many breakthroughs in clinical trials of gene therapy in the past decade.
There are several forms of gene therapy: the first is to introduce the correct gene into the cell to replace the wrong mutant gene; the second is to directly repair the wrong gene, which is often referred to as gene editing; the third is to pass in vitro Gene technology modifies cells and then puts the modified cells back into the body to function, such as activating the body's immune system.
For the first approach, a vector is first required to bring the gene into the cell. The most common method is to use a virus that has not been proliferated after modification. This is because the virus is born with the ability to integrate gene sequences into the host genome. Currently, two major types of viral vectors are most commonly used, one is retroviral vectors and the other is Adeno-associated viral vectors. In the early (1980s to early 1990s) retroviral vectors, γ-retroviruses and C-type retroviruses were used, and later scientists developed Lentivirus and spumaviruses vectors. These viruses not only infect non-dividing cells, but also carry larger fragments of genes.
By genetic engineering, such as removal of enhancers, these viruses are engineered to be more gentle, thereby greatly reducing genotoxicity. The adeno-associated virus vector is not easy to integrate into the host genome, so it is safer, especially its infection efficiency to nerve cells is high, so it has become the preferred gene carrier for nervous system and ophthalmic genetic disease.
Directly repairing mutant genes is a safer alternative to exogenously introduced genes. By cutting the gene fragments that need to be modified, and then using the cell's own DNA repair mechanism, scientists can change the cell's original DNA sequence as needed, which is the gene editing technique. Early scientists used zinc finger nucleases (ZFNs) to engineer DNA, but this technique requires different enzymes for different sequences, and requires strong expertise and cumbersome genetic manipulation, making it difficult to use. In 2009, scientists developed transcriptional activator-like effector nuclease technology (TALENs), which greatly reduced the threshold for gene editing. Then the development of the field exceeded everyone's expectations. In just three years, scientists were inspired by the microbial immune system and developed the CRISPR editing system, which made the gene editing technology truly popular. For gene therapy, the issue of gene editing technology, such as safety and efficiency, remains to be solved, but the rapid development of this field has made the biomedical community full of confidence.
We have introduced genetically engineered cells into the human body and are the third form of gene therapy, currently represented by chimeric antigen receptor T cell immunotherapy (CAR-T) technology. This technique separates the patient's T cells from the blood and integrates the designed antigen receptor gene into the T cell gene sequence using a lentivirus. After amplification, it is injected back into the patient to activate the body's immune system. The reaction of the antigen.
In the past 2017, the US FDA officially approved two CAR-T therapies, namely Kymriah from Novartis and Yescarta from Kite Pharmaceuticals, for the treatment of refractory or relapsed acute lymphoblastic leukemia and relapsed or difficult Treatment of invasive non-Hodgkin's lymphoma. In clinical trials, these two drugs have achieved amazing results, and the medical community is full of expectations for this therapy.
Prospects for the future of gene therapy
2017 is the beginning of the official clinical progress of gene therapy, which can be seen as the first year of gene therapy. Beginning this year, gene therapy will welcome more commercial development and clinical trials. Gene therapy is probably the most complex "drug" ever developed by humans, and there are hopes for solving some of the diseases that have so far made the medical community helpless.
From the experience and lessons of the past three decades, it is not difficult to find that the depth of basic research largely determines the success or failure of clinical applications. When conducting large-scale clinical trials, we must not forget to put our eyes back on basic research.
Compared with other treatments in history, gene therapy also involves ethical issues, especially the fact that genetic editing may be used in non-therapeutic fields, raising academic concerns. While gene therapy technology is advancing, it also needs policy follow-up to ensure that this revolutionary technology is not abused.
Source: Intellectuals
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