Table of Contents
With the rapid development of basic research and technology development in gene transduction and modification technology, delivery vector system, and cell culture technology, gene therapy has made breakthroughs, providing new opportunities and treatment concepts for refractory diseases (Especially rare hereditary diseases).
Since the emergence of gene therapy technology, safety has always been one of the most concerned issues in gene therapy research and development. This is related to the orderly development of technology research and development and industrial applications in the entire field.
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Gene therapy products should conduct systematic nonclinical research, assess safety risks, and verify effectiveness mechanisms so as to support relevant clinical trials and marketing. Gene therapy products are diverse, and their mechanism of action and mode of action are different from small and large-molecule drugs.
The type, timing, and flexibility of trials in nonclinical trial design, conduct, and study design may differ from nonclinical studies of other drugs.
For the past few decades, the scientific community has been trying to use viruses to modify human DNA to potentially cure diseases such as cancer, rare genetic diseases, and more.
The virus can introduce its genetic material into the host cell and use the host’s “cell factory” for continuous expression. So gene therapy ushered in a vital breakthrough from concept to reality. However, this work is highly challenging, and progress has been made, but safe and effective gene therapy has not yet appeared.
The concept of gene therapy first emerged in the 1960s and early 1970s. With the advent of recombinant DNA technology, cloned genes became available. They were used to demonstrate that exogenous genes can indeed correct genetic defects and disease phenotypes in mammalian cells in-vitro.
Highly efficient retroviral vectors and other gene transfer methods have allowed efficient phenotypic correction in-vitro and in-vivo with convincing results, and gene therapy is now a widely accepted treatment and has proven beneficial to patients—rationality for clinical application research.
In a narrow sense, gene therapy refers to directly introducing a correct gene fragment into the patient’s body to realize the increase and modification of the gene to treat the disease. However, due to the inability to effectively deliver gene fragments or gene editing tools in the body, the development of gene therapy in the early years has been slow.
Gene therapy broadly refers to a treatment method that corrects or compensates for abnormal gene defects to treat diseases. As the basic unit of genetic material, the gene controls the expression of genetic traits and regulates activity.
Infections often occur when human genes are abnormal. Gene therapy can introduce therapeutic genes into patients through methods such as gene transfer or gene regulation so that they can be expressed commonly to obtain therapeutic effects.
History of Gene Therapy
Gene therapy has a very long history of development. After the DNA double helix structure was published in the 1970s and 1980s, restriction endonucleases, DNA ligases, and reverse transcriptases were discovered one after another, genetic recombination engineering technology was developed, viral vectors appeared, and the technical system of gene therapy was initially established.
In 1972, the famous American biologist Theodore Friedmann and others published an epoch-making forward-looking commentary, “Can gene therapy be used for human genetic diseases?” in Science, and raised the question of whether gene therapy can treat human diseases.
The attitude of society toward this brand-new treatment method at that time was more questionable. It was not until 1989 that the FDA approved the introduction of vectors into clinical trials as “gene markers.” It was not officially approved to enter clinical trials until 1990.
The first clinical trial of gene therapy in history was gene therapy for severe combined immunodeficiency disease (SCID), led by Dr. William French Anderson.
They first extracted white blood cells from the body of a 4-year-old girl, Ashanti DeSilva, then used retroviral vectors to insert the ADA gene that can correctly encode adenosine deaminase into the genome of Ashanti DeSilva’s white blood cells, and finally, these genetically engineered white blood cells reinfusion into Ashanti DeSilva’s body. This is undoubtedly a significant milestone in the history of gene therapy development.
However, by the end of the 1990s, a series of adverse cases and even deaths caused by gene therapy occurred. This led to gene therapy’s cold winter, and people began to think calmly about gene therapy.
On Oct 16, 2003, Gendicine successfully obtained the new drug certificate, production approval document, and drug GMP certificate issued by CFDA. Gendicine is a recombinant human p53 adenovirus injection approved for treating patients with squamous cell carcinoma of the head and neck.
In 2012, the European Union approved Glybera from UniQure in the Netherlands for the treatment of familial lipoprotein lipase deficiency (LPLD). Its marketing approval opened a new era of gene therapy.
In 2016, Strimvelis, a gene therapy developed in collaboration with the San Raffaele Telethon Institute in Italy and GlaxoSmithKline (GSK), achieved a complete cure for 18 children with Adenosine deaminase – severe combined immunodeficiency (ADA-SCID).
In the same year, Strimvelis obtained the marketing authorization of the European Union, making a significant step forward in the commercialization of gene therapy technology. In December 2017, the gene therapy Luxturna of the American company Spark Therapeutics was approved for marketing, becoming the first “direct administration” gene therapy approved in the United States to target specific gene mutations.
In May 2019, Novartis Zolgensma was approved by the FDA for marketing, becoming the first gene therapy approved by the FDA for the treatment of SMA (spinal muscular atrophy). According to FDA predictions, by 2025, about 20 gene or cell therapies will enter the market each year.
However, multiple issues still need to be resolved before gene therapy products can enter routine clinical use to provide safe treatment. Improving scientific research, safety, and further maturity of gene transfer efficiency and infusion of gene therapy has finally promoted numerous clinical advances. The current research direction of gene therapy mainly focuses on gene delivery vectors and gene editing.
Classification of Gene Therapy
Gene therapy can be divided into in-vitro (ex-vivo) therapy and in-vivo therapy. The research and development pipelines for in-vivo and in-vitro gene therapy are divided equally, and viruses are still the most commonly used gene carriers.
The in-vivo or in-vitro method is determined by many factors, such as the location of the disease, the difficulty of obtaining cells in the body, etc. Generally speaking, there is no significant difference between in-vivo and in-vitro methods.
Whether it is in-vivo or in-vitro therapy, the vast majority of R&D pipelines use viral vectors. The most widely used platforms are adeno-associated viruses, lentivirus, and adenovirus.
Among them, adeno-associated virus (AAV) is a non-enveloped virus with a size of about 26nm, containing only a single-stranded linear DNA gene and a protein capsid. AAV is widely used in gene therapy due to its low toxicity, high transduction rate, controllable cost, and low risk of insertion.
Gene Therapy Market Overview
With the maturity of medical technology and related regulations, the global gene therapy market will see an order of magnitude growth. Evaluate Pharma predicts that sales of gene therapy products will grow from $10 million in 2017 to $13.6 billion in 2024.
Currently, gene therapy is still in the development stage. As the market’s demand for innovation and optimization continues to increase, the division of labor in gene therapy will be more refined, which will drive major pharmaceutical companies to seek professional CRO and CDMO services to reduce costs.
And compared with traditional drug research and development, gene therapy requires higher research and development investment. Therefore, in the field of gene therapy research and development, there is a high demand for the use of professional outsourcing of R&D and production teams to reduce costs. Therefore, the multi-faceted cooperation of enterprises has played a role that cannot be ignored in promoting the pipeline research of gene therapy.
Prospects and Challenges
Gene therapy promises to be an essential treatment of this century, as it reaches far beyond traditional medicines. Gene therapy can facilitate biologics’ stable, sustained, and regulated expression.
Furthermore, when combined with cell therapy, gene therapy turns cells into innovative vehicles for targeted gene delivery. Gene therapy can direct robust biological processes toward disease correction, tissue repair, and regeneration.
And the information can be transmitted through the genetic mechanism to ensure the treatment’s stability, fidelity, and amplification. The homing tools of human stem cells can be used to target gene therapy to specific tissues and disease sites.
Gene therapy also exploits the regenerative potential of stem cells and transplantation and the biological weapons of immunity for the particular elimination of transformed or infected cells.
By harnessing these intrinsic physical capabilities, gene therapy has the potential to address significant unmet medical needs for both rare and common serious diseases, which will benefit patients more broadly.
However, several significant challenges must be faced before this beautiful vision can be realized. For example, the effectiveness and safety of gene transfer vectors should be improved by further design and composition, which may need to be assessed by combining the biological characteristics of different viruses with synthetic molecules.
These advances will enable vectors to precisely target tissues and cell types, overcome cellular limitations for gene transduction, and bypass exogenous nucleic acid sensors. It will also help the carrier avoid activating the innate and adaptive immune systems.
These changes will also ensure that transgene expression is reproducible, robust, occurs over extended periods, and is consistent with endogenous expression patterns.
In addition, ethical, religious, management, and social issues caused by the specificity of genes will follow. How to make a comprehensive, scientific, and reasonable evaluation of the research and development of gene therapy technology has become a significant problem to be solved in this field. Therefore, long-term monitoring of the safety and effectiveness of gene therapy is required.
Nonclinical research of gene therapy products provides supporting information for clinical trials. The research content is pharmacology, pharmacokinetics, and toxicology, which are used to provide evidence of the effectiveness of the mechanism of action, clarify the characteristics of biodistribution, determine the characteristics of pharmacological effects, and toxicology (determination of target organs, exposure-response relationship, and reversibility, etc.), determination of safe dose levels for first-in-human trials, suggested clinical administration routes and dose escalation plans, support for patient inclusion criteria, determination of physiological parameters that can guide clinical monitoring parameters, prompting clinical trial risks, etc.
Medicilon’s preclinical research services cover pharmacodynamics research, drug safety evaluation, pharmacokinetics research, biological analysis, etc. Medicilon has established a complete gene therapy product research and development platform, which can provide cell and gene therapy products with a one-stop shop pharmacological efficacy, distribution and safety evaluation research.
Service Qualification
Medicilon’s animal facilities have been certified by AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care) and the NMPA GLP certificate and successfully passed the GLP audit of the US FDA.
Service Module
- Pharmacological effects
- Biodistribution
- Immunogenicity
- Safety evaluation
Type of Drugs
- Cell therapy products
- Oncolytic virus products
- mRNA products
- Oligonucleotide products
- Gene editing products
