Gene Therapy: Approaches, Benefits and Concerns – Explained, pointwise

Introduction

Scientists in the United Kingdom had been testing a technique of Gene Therapy on a girl suffering from a form of cancer (T-cell acute lymphoblastic leukaemia). The doctors had tried several standard treatments including chemotherapy and radiation but with limited success. The Scientists have reported some success in the treatment of the disease through Gene Therapy. Gene Therapy has the potential to revolutionize the curative care and treat diseases not treatable by standard methods. However there are several concerns associated with Gene Therapy that must be addressed before widespread application.

What is Gene Therapy?

Gene therapy is the introduction, removal or change in genetic material (typically means DNA and RNA) in the cells of a patient to treat an inherited or developed disease. Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve human body’s ability to fight disease.

Typically, genetic material, such as a working copy of a gene, is transferred into the target cell. It is difficult to insert a new gene into cells, so a vector is used to insert the genes. The vector is often a virus (other options are using liposomes, electroporation etc.), but the viral genes that could cause disease are removed. Once in the cell, the working copy of the gene will help make functioning proteins despite the presence of a faulty gene. The production of proteins helps in overcoming the defect/disease. Achieving the normal expression and function of proteins makes a big impact on the overall health of the individual.

Source: University of Utah

Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS etc.

What are the various approaches to Gene Therapy?

Various approaches are available for Gene Therapy. For instance, for treatment of Sickle Cell disease, the approaches used are:

Gene Addition: The stem cells from the patient are collected and taken to a lab for modification. An extra copy of a haemoglobin A gene (missing in patient) is added to the stem cell, which allows the cells to produce haemoglobin A (non-sickling haemoglobin).

Gene Addition, Source: NHGRI.

Gene Editing: The goal of gene editing is to remove, disrupt or correct faulty elements of DNA within the gene rather than replace the gene. Gene editing uses systems that are highly precise to make this change inside the cell. The cells can be from the patient or donor. There are two types of Gene Editing: Gene Silencing and Gene Correction.

Gene Silencing: In this method, the faulty segment of the gene (e.g., that inhibits the production of haemoglobin) is silenced. By silencing this gene, the correct gene (e.g., that makes haemoglobin) can be activated. Methods like CRISPR are used to silence genes.

Gene Silencing, Source: NHGRI.

Gene Correction: The variant in the gene that is faulty (e.g., that causes sickle cell disease) is corrected so that it codes for correct function (e.g., produce haemoglobin).

Gene Correction, Source: NHGRI.

Cell-based Gene Therapy: This type of treatment combines both Gene Therapy and Cell (Cellular) Therapy techniques. Cell therapy (CT) is the transplantation of human cells to replace or repair damaged tissue and/or cells. It introduces cells to the body that have a particular function to help treat a disease. CAR T Cell Therapy (or chimeric antigen receptor T cell therapy) is an example of cell-based gene therapy.

In cell-based gene therapy, the cells have been genetically altered to give them the special function. CAR T cell therapy introduces a gene to a person’s T cells (a type of immune cell). This gene provides instructions for making a protein, called the chimeric antigen receptor (CAR), that attaches to cancer cells. The modified immune cells can specifically attack cancer cells.

RNA Therapy: It uses pieces of RNA to help treat a disorder. In many of these techniques, the pieces of RNA interact with a molecule called messenger RNA (mRNA). In cells, mRNA uses the information in genes to create a blueprint for making proteins. By interacting with mRNA, these therapies influence how much protein is produced from a gene, which can compensate for the effects of a genetic alteration. Examples of these RNA therapies include antisense oligonucleotide (ASO), small interfering RNA (siRNA), and microRNA (miRNA) therapies. An RNA therapy called RNA aptamer therapy introduces small pieces of RNA that attach directly to proteins to alter their function.

Epigenetic Therapy: It affects epigenetic changes in cells. Epigenetic changes are specific modifications (often called “tags”) attached to DNA that control whether genes are turned on or off. Abnormal patterns of epigenetic modifications alter gene activity and, thus protein production. Epigenetic therapies are used to correct epigenetic errors that underlie genetic disorders.

What are the benefits of Gene Therapy?

Treatment of Rare Diseases: Gene and cell-base gene therapy can help treat rare and debilitating diseases that have limited treatment options. Often, these rare inherited diseases result in disability or premature death. Studies have shown that Gene and Cell-based Gene Therapies have slowed or completely stopped the progression of rare diseases.

Effectiveness: The advantage of gene therapy over traditional pharmacological approaches is that therapeutic benefits of Gene Therapy remain effective for a long period of time without the need of repeated interventions. A fundamental aspect of Gene Therapies is that they aim to treat the cause of the disease, not just the symptoms.

Accuracy: It’s difficult to design specific medicines that influence specific proteins. However, with gene therapy it may be possible to design therapeutic agents that can influence any of body’s roughly 20,000 genes.

What are the challenges associated with Gene Therapy?

Complexity of Gene Delivery and Activation: Success with gene therapy requires delivering a healthy gene to a very large number of cells (multiple millions) in a tissue. Moreover the delivery has to be to the right cells, in the right tissue. The gene must be turned on once it reaches its target in order to produce the protein it encodes. Also, once activated, it must stay that way; cells tend to turn off genes that are too active or display other aberrant behaviour.

It is also crucial to prevent the gene from being introduced into the wrong cells. It would be inefficient and potentially harmful to deliver a gene to the wrong tissue.

Immune Response: Human body’s immune systems are designed to fight off ‘intruders’ such as bacteria and viruses or any foreign material. Gene-delivery vectors must be able to avoid the body’s natural surveillance system. An unwelcome immune response to introduced genes (through vectors) could cause serious illness or even death.

Vulnerability to Disrupt Other Cells: A good gene therapy is long-lasting. Ideally, an introduced gene will continue working for the rest of the patient’s life. For this to happen, the introduced gene must become a permanent part of the target cell’s genome, usually by integrating, or ‘stitching’ itself, into the cell’s own DNA. But if the gene stitches itself into an inappropriate location, it will disrupt another genes giving rise to newer problems.

Commercial Viability: Many genetic disorders that can potentially be treated with gene therapy are extremely rare, some affecting just one person out of a million. Gene therapy could be life-saving for these patients, but the high cost of developing a treatment makes it an unappealing prospect for pharmaceutical companies.

What are the ethical concerns related to Gene Therapy?

Most ethical discussions related to genome editing center around human germline because changes made in the germline would be passed down to future generations, thus having long term implications.

Safety: Due to the possibility of off-target effects (edits in the wrong place) and mosaicism (when some cells carry the edit but others do not), safety and unintended consequences are of primary concern.

Informed Consent: Some people worry that it is impossible to obtain informed consent for germline therapy because the patients affected by the edits are the embryo and future generations. Researchers and bioethicists also worry about the possibility of obtaining truly informed consent from prospective parents as long as the risks of germline therapy are unknown.

Justice and Equity: As with many new technologies, there is concern that genome editing will only be accessible to the wealthy and will increase existing disparities in access to health care and other interventions. Some worry that taken to its extreme, germline editing could create classes of individuals defined by the quality of their engineered genome (designer babies).

Use of Embryos: Some scientists have expressed moral and religious objections to the use of human embryos for genome-editing research.

What should be the approach going ahead?

Use as Last Resort: Gene Therapy should be utilized only for rare diseases that cause serious illness/fatality, when no other treatment alternatives are available.

Monitoring: There is a need to have data on the health risks and benefits, as well as the requirement for continuous monitoring throughout clinical trials. In addition, there should be long-term surveillance in the future generations for any unintended side-effects.

Regulation and Scrutiny: Gene Therapy experiments and tests must be subjected to strict regulation and scrutiny to keep any unethical activity (like designer babies) under check and prevent commercial misuse. There is a need to create a multi-sector collaboration to develop an accessible mechanism for confidential reporting of concerns about possibly illegal, unregistered, unethical and unsafe human genome editing research and other activities.

IP Rights and Equitable Access: The WHO should work with all stakeholders to encourage relevant patent holders to help ensure equitable access to human genome editing interventions.

Engagement and Education: The UN/WHO should establish inter-agency working groups on frontier technologies that facilitates global dialogue to formulate ethical frameworks to guide their applications (of frontier technologies like human genome editing). There is a need for an inclusive dialogue on the future of human genome editing, including scientific, ethical and societal aspects.

Conclusion

Gene Therapy has a huge potential to cure rare and untreatable diseases. However, the approach to Gene Therapy requires extreme caution as it can have several long-terms unintended consequences. The field needs appropriate regulation to address the social, equity and ethical concerns. Nevertheless, these concerns should not act as roadblock to the scientific research in this field, that has huge untapped potential.

Syllabus: GS III, Science and Technology: Developments and their applications and effects in everyday life; Awareness in the fields of Bio-technology.

Source: The Hindu, National Human Genome Research Institute, National Library of Medicine