The Revival of Gene Therapy: Past, Present, Future

Gene therapy is the use of recombinant DNA technology to introduce normal genes and sequences required for their expression into diseased cells or somatic cells to replace or compensate for the function of defective genes, or inhibit gene overexpression, so as to achieve the purpose of the treatment of hereditary or acquired disease. Compared with other methods, the advantage of gene therapy is to solve the problem fundamentally, and it is expected to treat the disease in a one-time way.

In the past few years, gene therapy has been greatly developed. More and more diseases have been controlled and treated through gene therapy. Major pharmaceutical companies and scientists have been committed to research and development in this field. At present, 3 gene therapy drugs using recombinant AAV as the vector have been approved for the market. They are Glybera (AAV1, delisted) developed by UniQure, Luxturna (AAV2) developed by SparkTherapeutics and Zolgensma (AAV9) developed by Novartis. It can be seen that the potential of gene therapy is huge.

• Ill-fated gene therapy

Since 1990, hundreds of laboratories around the world have joined the research of gene therapy. More than 4000 patients participated in approximately 500 clinical trials. The basic research of gene therapy showed the therapeutic effects of various diseases, including diabetes, cancer, and sickle cell anemia, intensifying this decade-long carnival.

In 1999, an 18-year-old American Jesse Gelsinger participated a clinical trial of gene therapy for congenital ornithine transformylase deficiency. He developed a severe immune response in his body and died 4 days later. This experiment caused a young man to lose his life, a top scientist was banned from clinical trials for ten years, and caused the development of gene therapy to stagnate to a certain extent.

"Nowadays, gene therapy is undergoing a revival after a roller coaster trajectory. According to the different gene vectors introduced into cells, gene therapy is mainly divided into two categories, which are divided into non-viral vectors (such as plasmid DNA) and viral vectors (adenovirus, adeno-associated virus, lentivirus, herpes virus)." as introduced by a scientist at Creative Biolabs, a company focusing on gene therapy development services.

The simplest non-viral gene delivery systems are naked DNA and plasmid DNA, and when directly injected into certain tissues, especially muscles, they produce a significant level of gene expression, but it is still lower than the gene expression achieved with viral vectors. Currently, viral vectors are still the most popular delivery method for gene therapy trials, and so far, they have been used in approximately two-thirds of the trials.

• Not Only Gene Corrector

Drug delivery

Gene therapy technology is not only directly used to treat defective parts of polygenic diseases, but can also improve the delivery of proteins for disease treatment. The most typical example is RGX-314 developed by RegenXbio for the treatment of neovascular age-related macular degeneration. The gene therapy uses the NAV AAV8 vector, which encodes a monoclonal antibody fragment that neutralizes vascular endothelial growth factor (VEGF). One subretinal injection of RGX-314 is sufficient to continuously synthesize anti-VEGF therapeutic protein, avoiding repeated intravitreal injections of VEGF neutralizing protein.

Chemotherapy

Continuous positive airway pressure or surgery is the current treatment for obstructive sleep apnea. Obstructive sleep apnea is a disease in which the tongue loses muscle tone and blocks the upper airway of sleeping patients. Researchers at Johns Hopkins School of Medicine are exploring an alternative method. They are evaluating whether DREADDs (designer receptor exclusively activated by designer drugs) can be used to activate the genioglossus muscles to improve breathing during sleep. Researchers are implanting design receptors for synthetic drugs into specific brain cells to keep the airway open. If it is successfully transformed in human clinical trials, it means that one-time injection and night medication will eliminate the risk of death due to obstructive sleep apnea.

• Huge Challenges Faced by Gene Therapy

There are still many challenges in the clinical application of gene therapy, including increasing the efficiency of gene transfer or editing to the level necessary for effective treatment of diseases, dealing with repeated immune responses given to carriers in vivo, and reaching consensus on socially controversial issues. In addition, it is also important to cooperate with medical reimbursement agencies including the government and insurance companies to develop new models. In short, gene therapy has the potential to provide long-term benefits to human health. The scientific progress and clinical achievements in the past few years have shown that this therapy will eventually become an important part of the treatment of serious human diseases.

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