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Gene therapy is designed to treat diseases by introducing exogenous DNA or RNA into human target cells, which may be achieved by a few different methods. It is used to treat inherited genetic disorders: to correct or compensate for the patient’s abnormal gene, or to silence or inhibit the abnormal expression of genes. In addition to the treatment of genetic diseases, gene therapy is also widely used in the treatment of acquired diseases, such as tumors, autoimmune diseases, organ transplantation, and more.


In this article, we have collected some insights on gene therapy research progress, development trends, applications, and challenges, aiming to inspire even more innovations in gene therapies.


What Is the Background of Gene Therapy Research?

The development of gene therapy can be divided into three historical stages.

Gene Therapy Research Begins: 1980-1989

In 1974, the National Institute of Health (NIH) began to lead the research of recombinant DNA regulation and established the recombinant DNA Advisory Committee (RAC), which approved all the laboratory research projects involving recombinant DNA. Together with the U.S. Food and Drug Administration (FDA), they began to review the human gene therapy program, and formulated a series of rules and regulations pointing out that gene therapy is only applicable to somatic cells, not germ cells - officially putting gene therapy on the national research agenda.

In 1989, the FDA agreed to introduce vectors into clinical trials as "gene markers". In February 1990, the clinical gene therapy protocol presented by Michael Blaese from NIH to RAC was approved. On September 14, the first approved gene therapy in human history which was led by the Blease team was successfully launched. The subjects were 4-year-old children with severe combined immunodeficiency (SCID), which was mainly caused by adenosine deaminase (ADA) deficiency. During the treatment, the patients were placed in the immune isolation state, and a certain amount of white blood cells were extracted from the patients. Those patient cells were processed in the laboratory, inserted with the normal human ADA gene, and then introduced into the patients' body. After treatment, the patient's immunity was significantly enhanced and could live normally. This successful case brought confidence for the research of gene therapy.【1,2】


The Rapid Rise of Gene Therapy Research:1990-1999

The success of the first gene therapy application brought on a feverous period of related research in the field of medical biology. Taking the United States as an example, more than 100 clinical programs have been approved by FDA to enter clinical trials in just a few years. The first transgenic treatment of hemophilia B was implemented on December 2, 1991. As of August 5, 1999, there were 332 approved clinical gene therapy programs in the United States and 36 in other countries, including one clinical trial in Fudan University, Shanghai, China.【2】


Broad Applications of Gene Therapy & Potential Risks: 1999 to Present

In 1999, Jesse Gelsinger, an 18-year-old patient with congenital enzyme deficiency, died of severe hepatitis and multiple organ failure after receiving experimental adenovirus gene therapy led by the James Wilson Laboratory of the University of Pennsylvania. This was the first death to occur from gene therapy.【3】 Thereafter, the development of gene therapy began to slow down as people began to reflect on the prospective challenges and risks of gene therapy.


What is Gene Therapy Used For?

Gene therapy research involves multiple disciplines and technologies. With the development of molecular biology, molecular genetics, and clinical medicine, gene therapy has been widely used in clinical practice. At present, the scope of gene therapy has expanded from genetic diseases to tumors, infectious diseases, and cardiovascular diseases.


Gene Therapy in Malignant Tumors

In the research and treatment of malignant tumors, the more widely used gene therapy strategies are: immune gene, suicide gene, and tumor gene suppression. For example, in 2004, the China Food and Drug Administration approved the first production of gene therapy products - recombinant human p53 anti-cancer injection; In 2007, echinoderm microtubule associated protein like 4-anaplastic lymphoma kinane (4-alk) was found in lung cancer patients, which has greatly promoted the development of its specific inhibitor crizotinib.


Gene Therapy in Monogenic Disease

Monogenic genetic disease refers to a genetic disease controlled by one allele. There are more than 6600 kinds of monogenic diseases identified so far – this figure is increasing at an alarming rate of 10-50 every year and poses a great threat to human health. Green color blindness, hemophilia, and albinism are most common monogenic disorders.

The first case of gene therapy in history was used for a monogenic disease. The patient was a 4-year-old girl from the United States and had a congenital deficiency in the adenosine deaminase (ADA) gene. By using a retroviral vector, the ADA gene was transferred into hematopoietic stem cells and then injected into patient's body. Severe complex immunodeficiency (SCID) caused by gene deficiency was successfully cured. The subsequent hemophilia B gene therapy research carried out by Xue Jinglun and others in China, as well as the AAV2 hFIX injection developed in the experiment, also brought a breakthrough in gene therapy for hemophilia.


Gene Therapy in Cardiovascular System

At present, gene therapy in the field of cardiovascular disease mainly includes: promoting angiogenesis of myocardial and lower limb ischemia, preventing acute stenosis, preventing restenosis after angioplasty or vascular transplantation, vascular repair, and anastomosis, preventing thrombosis, etc. For example, Isner et al, pioneers of cardiovascular gene therapy, injected the vascular endothelial growth factor (VEGF) gene phvegp165 into the lower limbs of patients with dorsalis pedis ulcer and claudication, to promote the angiogenesis and blood circulation of the lower limbs, and greatly improved the clinical symptoms.


Gene Therapy in Infectious Diseases

At present, gene therapy for infectious diseases mainly includes: human immunodeficiency virus (HIV), hepatitis B virus (HBV), cytomegalovirus, etc. This offers a potentially rapid treatment approach for newly-discovered viruses, which is of demonstrable importance in light of the COVID-19 pandemic.


Gene Therapy: Challenges and Future Trends

With the implementation of the human genome project, the discovery of new genes and the advancement of new technology, the applications of gene therapy have been greatly expanded. Gene therapy provides a new treatment option for some diseases that cannot be cured by traditional medicine. However, the low efficiency of gene vector transfection, improper gene integration, and immune response caused by foreign genes have restricted breakthroughs in gene therapy. There are still some key technical problems to be solved in gene therapy: for example, how to efficiently introduce targeting gene into a vector? How to enhance the controllability of foreign gene expression? How to evaluate its effectiveness in clinical practice, while accounting for safety and ethicality.

The main trends of future gene therapy research and development includes two main avenues:

(1) Non-viral vector system: The biological safety of non-viral vector is better, especially the emergence of new products such as targeted liposomes and targeted polymers. In the future, we can improve efficiency and targeting by combining electrical pulse, ultrasound, and other new technologies.

(2) Viral vector system: Viral vector are the most widely used in the field of gene therapy, as about 70% of the treatments use viral vectors - mainly including various retroviruses, adenoviruses, adeno-associated viruses, etc. Each viral vector has their own characteristics. The selection of a viral vector should be based on the disease mechanism, considering safety and efficiency.

As the development of therapeutic genes, vectors and delivery methods continues, there will be improvements in the stability, effectiveness and safety of gene therapy. It is believed that these new technologies will surely trigger a fundamental medical revolution, as the frontier of gene therapies treatments and applications proceeds to expand.


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