Gene and Cell Therapy FAQ's

For a more detailed answer, we recommend Gene Therapy Basics in our Patient Education program.

In the broadest sense, gene therapy is the use of genetic material in the treatment or prevention of disease. The transferred genetic material changes how a single protein or group of proteins is produced by the cell. Gene therapy can be used to reduce levels of a disease-causing version of a protein, increase production of disease-fighting proteins, or to produce new/modified proteins. 

Cell therapy is the transfer of intact, live cells into a patient to help lessen or cure a disease. The cells may originate from the patient (autologous cells) or a donor (allogeneic cells). The cells used in cell therapy can be classified by their potential to transform into different cell types. Pluripotent cells can transform into any cell type in the body and multipotent cells can transform into other cell types, but their repertoire is more limited than that of pluripotent cells. Differentiated or primary cells are of a fixed type. The type of cells administered depends on the treatment.

Yes!

In May 2019, the FDA approved Zolgensma to treat spinal muscular atrophy in children under two years old.

The first virally-delivered gene therapy to be approved for clinical usage in the United States, Luxturna (Spark Therapeutics), was approved in December 2017 by the FDA. Luxturna is a one-time gene therapy treatment used to improve vision in patients with established genetic vision loss due to Leber congenital amaurosis or retinitis pigmentosa, both inherited retinal diseases.

CAR T-cell therapy is FDA-approved to treat aggressive B-cell lymphomas in adults (Yescarta and Kymriah), B-cell leukemia in children and young adults (Kymriah), and most recently, relapsed or refractory mantle cell lymphoma (MCL) in adults (Tecartus).

For a more detailed answer, we recommend CAR T Basics in our Patient Education program.

CAR T cell stands for chimeric antigen receptor (CAR) T cell therapy. This a way of modifying the patient’s own immune cells (T-cells) to express a receptor on their surface that recognizes structures (antigens) on the surface of malignant cells. Once the receptor binds to a tumor antigen, the T-cell is stimulated to attack the malignant cells.

For more in-depth learning, we recommend Different Approaches in our Patient Education program.

Gene therapy involves the transfer of genetic material, usually in a carrier or vector, and the uptake of the gene into the appropriate cells of the body. Cell therapy involves the transfer of cells with the relevant function into the patient.

Some protocols utilize both gene therapy and cell therapy. In this case, stem cells are isolated from the patient, genetically modified in tissue culture to express a new gene, expanded to sufficient numbers, and then returned to the patient. 

Yes! At the time of writing, ClinicalTrials.gov lists more than 1000 different types of gene therapy in clinical trials. Additionally, almost any gene in the human genome can be targeted, so the potential for new therapies is immense. The five main therapeutic strategies are presented below. Currently, these techniques are mainly used to target specific populations of somatic cells. 

Gene addition involves inserting a new copy of a gene into the target cells to produce more of a protein. Most often, a modified virus such as adeno-associated virus (AAV) is used to carry the gene into the cells. Therapies based on gene addition are being developed to treat many diseases, including adenosine deaminase severe combined immunodeficiency (ADA- SCID), congenital blindness, hemophilia, Leber’s congenital amaurosis, lysosomal storage diseases, X-linked chronic granulomatous disease, and many others.

Gene correction can be achieved by modifying part of a gene using recently-developed gene editing technology (e.g. CRISPR/cas9, TALEN or ZFN) to remove repeated or faulty elements of a gene, or to replace a damaged or dysfunctional region of DNA. The goal of gene correction is to produce a protein that functions in a normal manner instead of in a way that contributes to disease. It may be possible to use gene correction in the treatment of a wide range of diseases; recent experimental work has used gene editing technologies to extract HIV from the genome of affected laboratory mice and to excise the expanded region responsible for Huntington’s disease from the human gene.

Gene silencing prevents the production of a specific protein by targeting messenger RNA (mRNA; an intermediate required for protein expression from a gene) for degradation so that no protein is produced. mRNA exists in a single-stranded form in human and animal cells, whereas viruses have double-stranded RNA. Human and animal cells recognize double-stranded RNA as being viral in origin and destroy it to prevent its spread. Gene silencing uses small sequences of RNA to bind unique sequences in the target mRNA and make it double-stranded. This triggers the destruction of the mRNA using the cellular machinery that destroys viral RNA. Gene silencing is an appropriate gene therapy for the treatment of diseases where too much of a protein is produced. For example, too much tumor necrosis factor (TNF) alpha is often observed in the afflicted joints of rheumatoid arthritis patients. As TNF alpha is needed in small amounts in the rest of the body, gene silencing is used to reduce TNF alpha levels only in the affected tissue.

Reprogramming involves adding one or more genes to cells of a specific type to change the characteristics of those cells. This technique is particularly powerful in tissues where multiple cell types exist and the disease is caused by dysfunction in one type of cells. For example, type I diabetes occurs because many of the insulin-producing islet cells of the pancreas are damaged. At the same time, the cells of the pancreas that produce digestive enzymes are not damaged. Reprogramming these cells so that they can produce insulin would help heal type I diabetic patients.

Cell elimination strategies are typically used to destroy malignant (cancerous) tumor cells, but can also be used to target overgrowth of benign (non-cancerous) tumor cells. Tumor cells can be eliminated via the introduction of “suicide genes,” which enter the tumor cells and release a prodrug that induces cell death in those cells. Viruses can be engineered to have an affinity for tumor cells. These oncotropic viruses can carry therapeutic genes to increase toxicity to tumor cells, stimulate the immune system to attack the tumor, or inhibit the growth of blood vessels that supply the tumor with nutrients.

Yes! At the time of writing, ClinicalTrials.gov listed more than 8000 active, or actively recruiting, clinical trials for cell therapies being developed for diverse diseases.

The most common type of cell therapy is blood transfusion, and the transfusion of red blood cells, white blood cells, and platelets from a donor. Another common cell therapy is the transplantation of hematopoietic stem cells to create bone marrow which has been performed for over 40 years. As with gene therapy, cell therapy subtypes can be classified in different ways. This is currently no formal classification system for cell therapies. Here the different types of cells used for cell therapy have been classified by cell potency. Four types of pluripotent stem cells and four types of multipotent stem cells obtained from adult tissue are described.

Embryonic stem cells (ESCs). These are pluripotent stem cells derived from embryos. Generally, the embryos used to isolate stem cells are unused embryos generated from in vitro fertilization (IVF) for assisted reproduction. As ESCs are pluripotent they retain the ability to self-renew and to form any cell in the body. ESCs have the advantage of versatility due to their pluripotency, but the use of embryos in the development of therapeutic strategies raises some ethical concerns. In addition, stem cell lines generated from embryos are not genetically matched to the patient which can increase the chance that the transplanted cell is rejected by the patient’s immune system.

Induced pluripotent stem cells (iPSCs). A differentiated adult (somatic) cell, such as a skin cell is reprogrammed to return to a pluripotent state. These cells offer the advantage of pluripotency but without the ethical concerns of embryonic stem cells. iPSCs may also be derived from the patient and thus avoid the problem of immune rejection. iPSCs are produced by transforming the adult cell with a cocktail of genes usually delivered via a viral vector. While the efficiency of the process has been greatly improved since inception, the relatively low rate of reprogramming remains a concern. Another concern is that iPSCs are derived from adult cells and are therefore “older” than embryonic stem cells as evidenced by a higher rate of programmed cell death, lower rates of DNA damage repair and increased incidence of point mutations.

Nuclear transfer embryonic stem cells (ntESCs). These pluripotent cells are produced by transferring the nucleus from an adult cell obtained from the patient to an oocyte (egg cell) obtained from a donor. The process of transferring the nucleus reprograms the egg cell to pluripotency. As with iPSCs, the derived cells match the nuclear genome of the patient and are unlikely to be rejected by the body. However, the major advantage of this technique is that the resulting ntESCs carry the nuclear DNA of the patient alongside mitochondria from the donor, making this technique particularly appropriate for diseases where the mitochondria are damaged or dysfunctional. A drawback of ntESCs is that the process of generation is cumbersome and requires a donor oocyte. At the time of writing stem cell production using this technique has only been shown in lower mammals.

Parthenogenetic embryonic stem cells (pES). The final option for obtaining pluripotent cells is from unfertilized oocytes. Here the oocyte is treated with chemicals that induce embryo generation without the addition of sperm (parthenogenesis) and ESCs are harvested from the developing embryo. This technique generates ESCs that are genetically identical to the female patient. However, this method is in the early stages of development and it is not known if cells and tissues derived from parthenogenesis develop normally.

Hematopoietic stem cells (HSCs) are multipotent blood stem cells that give rise to all types of blood cells. HSCs can be found in adult bone marrow, peripheral blood, and umbilical cord blood.

Mesenchymal stem cells (MSCs) are multipotent cells present in multiple tissues including umbilical cord, bone marrow, and fat tissue. MSCs give rise to bone, cartilage, muscle, and adipocytes (fat cells) which promotes marrow adipose tissue.

Neural stem cells (NSCs). Adult neural stem cells are present in small number in defined regions of the mammalian brain. These multipotent cells replenish neurons and supporting cells of the brain. However, adult neural stem cells cannot be obtained from patients due to their location in the brain. Therefore, neural stem cells used for cell therapies are obtained from iPSCs or ESCs.

Epithelial stem cells. Epithelial cells are those that form the surfaces and linings of the body including the epidermis and the lining of the gastro-intestinal tract. Multipotent epithelial stem cells are found in these areas along with unipolar stem cells that only differentiate into one type of cell. Epithelial stem cells have been successfully used to regenerate the corneal epithelium of the eye.

Immune cell therapy. Cells that rapidly reproduce in the body such as immune cells, blood cells or skin cells can usually do so ex vivo given the right conditions. This allows differentiated, adult immune cells to be used for cell therapy. The cells can be removed from the body, isolated from a mixed cell population, modified and then expanded before return to the body. A recently developed cell therapy involves the transfer of adult self-renewing T lymphocytes which are genetically modified to increase their immune potency to kill disease-causing cells. 

Risks of any medical treatment depend on the exact composition of the therapeutic agent and its route of administration. Different types of administration, whether intravenous, intradermal or surgical, have inherent risks.

Risks include the outcome that gene therapy or cell therapy will not be as effective as expected, possibly prolonging or worsening symptoms, or complicating the condition with adverse effects of the therapy. The expression of the genetic material or the survival of the stem cells may be inadequate and/or may be too short-lived to fully heal or improve the disease. Their administration may induce a strong immune response to the protein in the case of replacing proteins from genetic diseases. This immune response may become uncontrolled and lead to normal proteins or cells being attacked, as in autoimmune diseases. On the other hand, in the case of cancer or viral/fungal/bacterial infections, there may be an insufficient immune response, or the targeted cell or microorganism may develop resistance to the therapy. With the current generation of vectors in clinical trials, there is no way to “turn off” gene expression, if it seems to be producing unwanted effects.

In the case of retroviral or lentiviral vectors, integration of the genetic material into the patients’ DNA may occur next to a gene involved in cell growth regulation and the insertion may induce a tumor over time by the process called insertional mutagenesis. 

High doses of some viruses can be toxic to some individuals or specific tissues, especially if the individuals are immune compromised.

Gene therapy evaluation is generally carried out after birth. There is little data on what effects this therapeutic approach might have on embryos, and so pregnant women are usually excluded from clinical trials. 

Risks of cell therapy also include the loss of tight control over cell division in the stem cells. Theoretically, the transplanted stem cells may gain a growth advantage and progress to a type of cancer or teratomas. Since each therapy has potential risks, patients are strongly encouraged to ask questions of their investigators and clinicians until they fully understand the risks.   

Get more detail from Vectors 101 in our Patient Education program.

Viral vectors and oncolytic viruses are designed to reduce the risk of adverse effects, and each viral vector is rigorously tested in cells and animals before it is considered for human use. The viral vectors used in human trials are prepared under strict guidelines to ensure purity and integrity. However, every medicine has risks. Thus, it is essential that patients thoroughly discuss the potential risks of any new therapy with their physicians, patient advocate, family, and investigators of a clinical trial.

For more in-depth learning, we recommend Different Approaches in our Patient Education program.

Both approaches have the potential to alleviate the underlying cause of genetic diseases and acquired diseases by replacing the missing protein(s) or cells causing the disease symptoms, suppressing expression of proteins which are toxic to cells, or eliminating cancerous cells.

Gene therapy involves the transfer of genetic material into the appropriate cells. In genetic diseases, the stem cells of the afflicted tissue are often targeted. The adult stem cells of the tissue can replenish the specialized cells. Expressing the appropriate gene in the stem cells ensures that the subsequent specialized cells will contain the therapeutic protein. However, in some cases, it’s technically easier to express a gene in a long-lived tissue cell and the secreted protein travels through the blood to its target organs. Introduction of genes into cells can be carried out in culture with subsequent administration to the patient, or by direct injection of vectors into the body.

Cell therapy is the transfer of cells to a patient. For treatment of most diseases by cell therapy, stem cells are chosen because their establishment in the patient leads to continual production of the appropriate specialized cells. 

As mentioned previously, gene therapy and cell therapy are often combined to treat various genetic diseases, such as ADA-SCID. Stem cells from the patient are altered by gene therapy in culture to express the relevant functional protein. The improved stem cells are administered or returned to the patient.

Get more detail from Vectors 101 in our Patient Education program.

Scientists and clinicians use the following four methods to carry genetic material into the targeted cells. 

Non-vector methods such as electroporation, passive delivery, and ballistic delivery. Simple strands of naked DNA or RNA can be pushed into cells using high voltage electroporation. This is a common technique in the lab. Naked DNA or RNA may also be taken up by target cells using a normal cellular process called endocytosis after addition to the medium surrounding the cells. Finally, sheer mechanical force can be utilized to introduce genetic material with an instrument called a “gene gun.”

Membrane-bound vesicles. Genetic material can be packaged into artificially-created liposomes (sacs of fluid surrounded by a fatty membrane) that are more easily taken up into cells than naked DNA/RNA. Different types of liposomes are being developed to preferentially bind to specific tissues. Recent work has utilized a subtype of membrane vesicles that are endogenously produced and released by cells (extracellular vesicles or “exosomes”) to carry small sequences of RNA into specific tissues.

Viral vectors. Viruses have an innate ability to invade cells. The symptoms of a cold are triggered by a cold virus entering the cells of the upper respiratory tract and hijacking the cell’s machinery to manufacture more virus. Viral vectors for gene therapy are modified to utilize the ability of viruses to enter cells after disabling the capability of the virus to divide. Different types of viruses have been engineered to function as gene therapy vectors. In the case of adeno-associated virus (AAV) and retrovirus/lentivirus vectors, the gene(s) of interest and control signals replace all or most of the essential viral genes in the vector so the viral vector does not replicate. For oncolytic viruses, such as adenovirus and herpes simplex virus, fewer viral genes are replaced and the virus is still able to replicate in a restricted number of cell types. Different types of viral vector preferentially enter a subset of different tissues, express genes at different levels, and interact with the immune system differently.

Gene therapy can be combined with cell therapy protocols. Cells are collected from the patient or matched donor and then purified and expanded in vitro. Scientists and clinicians then deliver the gene to the cells using one of the three methods described above. Those cells that express the therapeutic gene are then re-administered to the patient.

Get more detail from Vectors 101 in our Patient Education program.

Viruses are used in gene therapy as gene delivery vectors and as oncolytic viruses:

Viruses as gene delivery vectors. Modified viruses are used as carriers in gene therapy. These viral vectors protect the new gene from enzymes in the blood that can degrade it, and deliver it to the relevant cells. Viral vectors efficiently coerce the cells to take up the new gene, uncoat the gene from the virus particle, and transport it, usually to the cell nucleus. The transduced cells begin using the new gene to perform its function, such as synthesis of a new protein. Viral vectors are genetically engineered so that most of their essential genes are missing, which prevents uncontrolled replication of the virus and makes room for insertion of the gene to be delivered.

Many different viral vectors are being developed because the requirements of gene therapy agents for specific diseases vary depending on the affected tissue, the level of gene expression, and the required duration of expression. Scientists examine the following characteristics while choosing or developing an appropriate viral vector: (i) size of DNA or gene that can be packaged, (ii) efficiency of uptake by the desired cells for therapy, (iii) duration of gene expression, (iv) effect on immune response, (v) ease of manufacturing, (vi) ease of integration into the cell’s DNA or ability to exist as a stable DNA element in the cell nucleus without genomic integration, and (vii) chance that the patients have previously been exposed to the virus and thus might have antibodies against it which would reduce its efficiency of gene delivery.

Oncolytic Viruses. Oncolytic viruses are engineered to replicate only or predominantly in cancer cells and not in normal human cells. Once oncolytic viruses replicate in cancer cells they cause the cancer cells to burst, releasing more oncolytic viruses to infect surrounding cancer cells.

For a more detailed answer, we recommend Gene Therapy Basics in our Patient Education program.

Put simply, gene therapy works by changing the genetic information of a population of cells in a way that alleviates or combats the cause or symptoms of a disease. 

For more in-depth learning, we recommend Different Approaches in our Patient Education program.

The challenges of gene and cell therapists can be divided into three broad categories based on disease, development of therapy, and funding.

Challenges based on the disease characteristics: Disease symptoms of most genetic diseases, such as Fabry’s, hemophilia, cystic fibrosis, muscular dystrophy, Huntington’s, and lysosomal storage diseases are caused by distinct mutations in single genes. Other diseases with a hereditary predisposition, such as Parkinson’s disease, Alzheimer’s disease, cancer, and dystonia may be caused by variations/mutations in several different genes combined with environmental causes. Note that there are many susceptible genes and additional mutations yet to be discovered. Gene replacement therapy for single gene defects is the most conceptually straightforward. However, even then the gene therapy agent may not equally reduce symptoms in patients with the same disease caused by different mutations, and even the same mutation can be associated with different degrees of disease severity. Gene therapists often screen their patients to determine the type of mutation causing the disease before enrollment into a clinical trial. 

The mutated gene may cause symptoms in more than one cell type. Cystic fibrosis, for example, affects lung cells and the digestive tract, so the gene therapy agent may need to replace the defective gene or compensate for its consequences in more than one tissue for maximum benefit. Alternatively, cell therapy can utilize stem cells with the potential to mature into the multiple cell types to replace defective cells in different tissues.

In diseases like muscular dystrophy, for example, the high number of cells in muscles throughout the body that need to be corrected in order to substantially improve the symptoms makes delivery of genes and cells a challenging problem.

Some diseases, like cancer, are caused by mutations in multiple genes. Although different types of cancers have some common mutations, every tumor from a single type of cancer does not contain the same mutations. This phenomenon complicates the choice of a single gene therapy tactic and has led to the use of combination therapies and cell elimination strategies. For more information on gene and cell therapy strategies to treat cancer, please refer to the Cancer and Immunotherapy summary in the Disease Treatment section.

Disease models in animals do not completely mimic the human diseases and viral vectors may infect various species differently. The testing of vectors in animal models often resemble the responses obtained in humans, but the larger size of humans in comparison to rodents presents additional challenges in the efficiency of delivery and penetration of tissue. Gene therapy, cell therapy, and oligonucleotide-based therapy agents are often tested in larger animal models, including rabbit, dog, pig and nonhuman primate models. Testing human cell therapy in animal models is complicated by immune rejections. Furthermore, humans are a very heterogeneous population. Their immune responses to the vectors, altered cells, or cell therapy products may differ or be similar to results obtained in animal models.

Challenges in the development of gene and cell therapy agents: Scientific challenges include the development of gene therapy agents that express the gene in the relevant tissue at the appropriate level for the desired duration of time. There are a lot of issues in that once sentence, and while these issues are easy to state, each one requires extensive research to identify the best means of delivery, how to control sufficient levels or numbers of cells, and factors that influence duration of gene expression or cell survival. After the delivery modalities are determined, identification and engineering of a promoter and control elements (on/off switch and dimmer switch) that will produce the appropriate amount of protein in the target cell can be combined with the relevant gene. This “gene cassette” is engineered into a vector or introduced into the genome of a cell and the properties of the delivery vehicle are tested in different types of cells in tissue culture. Sometimes things go as planned and then studies can be moved onto examination in animal models. In most cases, the gene/cell therapy agent may need to be improved further by adding new control elements to obtain the desired responses in cells and animal models. 

Furthermore, the response of the immune system needs to be considered based on the type of gene or cell therapy being undertaken. For example, in gene or cell therapy for cancer, one aim is to selectively boost the existing immune response to cancer cells. In contrast, to treat genetic diseases like hemophilia and cystic fibrosis the goal is for the therapeutic protein to be accepted as an addition to the patient’s immune system.

If the new gene is inserted into the patient’s cellular DNA, the intrinsic sequences surrounding the new gene can affect its expression and vice versa. Scientists are now examining short DNA segments that may insulate the new gene from surrounding control elements. Theoretically, these “insulator” sequences would also reduce the effect of vector control signals in the gene cassette on adjacent cellular genes. Studies are also focusing on means to target insertion of the new gene into “safe” areas of the genome, to avoid influence on surrounding genes and to reduce the risk of insertional mutagenesis.

Challenges of cell therapy include the harvesting of the appropriate cell populations and expansion or isolation of sufficient cells for one or multiple patients. Cell harvesting may require specific media to maintain the stem cells ability to self-renew and mature into the appropriate cells. Ideally “extra” cells are taken from the individual receiving therapy. Those additional cells can expand in culture and can be induced to become pluripotent stem cells (iPS), thus allowing them to assume a wide variety of cell types and avoiding immune rejection by the patient. The long term benefit of stem cell administration requires that the cells be introduced into the correct target tissue and become established functioning cells within the tissue. Several approaches are being investigated to increase the number of stem cells that become established in the relevant tissue.

Another challenge is developing methods that allow manipulation of the stem cells outside the body while maintaining the ability of those cells to produce more cells that mature into the desired specialized cell type. They need to provide the correct number of specialized cells and maintain their normal control of growth and cell division, otherwise there is the risk that these new cells may grow into tumors.

Challenges in funding: In most fields, funding for basic or applied research for gene and cell therapy is available through the National Institutes of Health (NIH) and private foundations. These are usually sufficient to cover the preclinical studies that suggest a potential benefit from a particular gene and cell therapy. Moving into clinical trials remains a huge challenge as it requires additional funding for manufacturing of clinical grade reagents, formal toxicology studies in animals, preparation of extensive regulatory documents, and costs of clinical trials. Biotechnology companies and the NIH are trying to meet the demand for this large expenditure, but many promising therapies are slowed down by lack of funding for this critical next phase.

Stem cells are cells that can self-renew and can mature into at least one type of specialized cell. Stem cells can be isolated from many types of tissues. Embryonic stem cells are isolated from the inner mass of the blastocyst, an early stage of the embryo. Umbilical cord stem cells, often called cord blood stem cells, are isolated from the umbilical cord at the time of a baby’s birth. 

Adult stem cells can be isolated from any type of adult tissue. The ease of isolation of adult stem cells depends on the accessibility of the tissue, the prevalence of stem cells in the tissue, the age of the patient, the presence of markers that aid stem cell isolation, and developed protocols for isolation and culture. It is also possible to convert a mature adult cell into a stem cell by introducing a mixture of transcription factors; these cells are referred to as induced pluripotent stem (iPS) cells.

Embryonic stem cells are pluripotent stem cells isolated from an early stage embryo. They can self-renew and can differentiate into all cells of the body. 

Adult stem cells are present in adult tissues. Each tissue has a reservoir of stem cells (sometimes called somatic stem cells). They can mature or differentiate into cells from that tissue. Adult stem cells can also be isolated from adipose tissue, gut, liver, brain, and muscle.

iPS stands for induced pluripotent stem cells. Specialized cells, such as skin cells, are isolated from adult tissues and treated with agents that change their protein expression pattern to mimic the proteins expressed by pluripotent stem cells. This process of reprogramming changes a cell with a specialized function to a cell with unlimited ability to self-renew and produce cells that can mature into all of the different types of specialized cells in the body. The process involves using gene delivery to express the relevant 3-4 genes that can convert the specialized cells into iPS cells.

The ethical issues facing gene and cell therapy are covered as part of the ASGCT Patient Education program in Ethical Issues: Germline Gene Editing and Ethical Issues: Illegitimate Clinical Trials.

Several ethical issues can arise during the development of any novel therapeutic. The development of genetic and cellular therapies share many ethical issues with other types of therapy, such as prosthetics, drugs, organ transplantation, and protein replacement. In addition, there are ethical issues unique to gene and cell therapy. In all cases, scientists, clinicians, regulatory committees, and concerned citizens take an active role in addressing these issues.

Balancing risk and benefit to the patient is important to any developing therapeutic. This is complicated by the fact that most gene therapy trials are Phase I trials, which means that safety of the vector and delivery mode are being evaluated and no direct benefit to the participant is expected. To assess potential benefit, regulatory committees often request that investigators administer a range of doses of the agent for the initial patients to determine whether higher doses do have adverse effects—even during Phase II/III trials. Thus, the dosage tested in a particular patient may be insufficient to induce a therapeutic response or may be so high as to cause toxicity. 

High costs associated with gene and cell therapy raise the ethical question of whether these treatments will only be utilized by the wealthy. Biotechnology companies such as Novartis, who developed the leukemia treatment Kymriah, are aware of this and are developing programs to provide financial help to patients in the USA who are uninsured or underinsured. Another factor to consider is that gene and cell therapies are designed to be curative, and so the cost of therapy can be weighed against that of lifetime treatment. In the long-term, costs will likely be reduced by optimized production of cell and gene therapies and the development of therapies that do not need to be tailored to the individual. In the meantime, patient groups, clinicians, regulators and manufacturers all have a role to play in addressing the issue of cost.

Contamination of the human genome with novel DNA sequences is a concern that may be considered in two ways. First, there is the issue of accidental contamination of the genome while conducting gene or cell therapy on somatic (adult) cells. To minimize the possibility of this, all vectors are tested to make sure they do not enter the germ line in experimental animals, and sperm from human males in clinical studies are tested to make sure the gene has not inserted in the genome. Second, there is the issue of intentional manipulation of the germline to alleviate disease. As new gene editing technologies have now made this much easier, there is currently much debate between scientists, clinicians, patient groups, and regulators regarding the ethics of editing, or not editing the human genome.

Use of embryonic stem cells, or human fetal tissue, as a source of stem cells remains an ethical issue. The development of stem cells from other sources such as iPSCs has somewhat reduced the dependence on ESCs. 

Clinicians and scientists may classify gene therapy according to whether the therapy is administered to cells in the body or out of the body. In vivo gene therapy means that therapy is administered directly the patient. The targeted cells remain in the body of the patient. With ex vivo gene/cell therapy the targeted cells are removed from the patient and gene therapy is administered to the cells in vitro before they are returned to the patient’s body.

A cell line is a group of related cells grown in culture vessels in a laboratory. A stem cell line is originally isolated from a single source, such as the inner mass of a blastocyst, an early stage of the embryo. The isolated cells are grown in the laboratory in medium that contains appropriate growth factors so that the cells can divide indefinitely while maintaining their ability to mature into specialized cells in alternate media. Stem cell lines are easily characterized for protein expression and gene status. Stem cells can also be manipulated in tissue culture to help scientists understand how cells mature into different types of cells.  

Regenerative medicine focuses on the development of strategies to repair the functions of damaged organs or tissues. Recently, the American Medical Association has begun to use the term regenerative medicine for research and protocols involving stem cells in the repair of diseased tissue and organs. Two common approaches include the administration of stem cells for the regeneration of the indicated tissue or the administration of agents that enhance the patient’s resident tissue stem cells to more efficiently rebuild the damaged tissue. Recent advances have also been made in generating specific tissues and organs in the laboratory and safely implanting them into patients.

The goal of gene and cell therapy is to develop a treatment that lasts the lifetime of the patient. Most cells of the body turn over in days, weeks, or months. Changing the protein expression of a cell that lives only a few days, weeks, or months means that the therapy would require multiple administrations. A few cells, such as muscle cells, stem cells, neurons, and memory cells of the immune system, are long lived and may last the lifetime of the individual. 

Stem cells provide two major benefits for gene and cell therapy. First, they provide a cell type that can self-renew and may survive the lifetime of the patient. Second, stem cells provide daughter cells that mature into the specialized cells of each tissue. These differentiated daughter cells can replace the diseased cells of the afflicted tissue(s). Therefore, gene and cell therapy that uses stem cells theoretically improves the disease condition for as long as those modified stem cells live, potentially the lifetime of the patient.  

Learn more from the Disease Treatments section of the ASGCT Patient Education program and ASGCT's Clinical Trials Finder.

Characteristics of diseases amenable to gene therapy and cell therapy include those for which there is no effective treatment, those with a known cause (such as a defective gene), those that have failed to improve or have become resistant to conventional therapy, and/or cases where current therapy involves long term administration of an expensive therapeutic agent or an invasive procedure.  

Gene therapy and cell therapy have the potential for high therapeutic gain for a broad range of diseases. An example would be those caused by a mutation in a single gene where an accessible tissue is available, such as bone marrow, and with the genetically modified cell ideally having a survival advantage. However, patients with similar symptoms may have mutations in different genes involved in the same biological process. For example, patients with hemophilia A have a mutation in blood clotting Factor VIII whereas patients with hemophilia B have a mutation in Factor IX. It is important to know which gene is mutated in a particular patient, as well as whether they produce an inactive protein which can help to avoid immune rejection of the normal protein.  

Gene therapy and cell therapy also offer a promising alternative or adjunct treatment for symptoms of many acquired diseases, such as cancer, rheumatoid arthritis, diabetes, Parkinson’s disease, Alzheimer’s disease, etc. Cancer is the most common disease in gene therapy clinical trials. Cancer gene therapy focuses on eliminating the cancer cells, blocking tumor vascularization and boosting the immune response to tumor antigens. Many gene and cell therapy approaches are being explored for the treatment of a variety of acquired diseases. More details are listed in the ASGCT.org disease information page. 

Please visit Ethical Issues: Illegitimate Clinical Trials, part of  ASGCT's Patient Education program, for additional important safety information.

Probably not. Creams and lotions that contain stem cells effectively contain dead cellular matter as stem cells can only remain intact and alive under defined culture conditions. Procedures that inject stem cells into the skin are largely unregulated and have not been subject to rigorous testing. The FDA provides a list of approved cell therapies.

Please visit Ethical Issues: Germline Gene Editing, part of ASGCT's Patient Education program, to learn more.

Germline gene therapy is an experimental technique that modifies sex cells (eggs or sperm) or the cells of an embryo to create heritable genetic change. In 2015, scientists in China published a report detailing the use of a technique called CRISPR/cas9 to edit the gene responsible for β-thalassemia in embryos. Since then, the possibility of germline gene therapy has been the subject ethical debate as scientists, clinicians, patient groups, and regulators seek to understand its therapeutic potential and to limit any negative or controversial aspects of this type of gene therapy.

Somatic cell gene therapy targets those cells of the body that are not involved in reproduction – the somatic cells. Examples include the cells that make up the retina, liver, or heart. Somatic cell gene therapies are being developed for a wide-range of diseases, but most gene therapies are not yet FDA approved for widespread use. Patients currently receiving somatic gene therapy do so through clinical trials which are subject to FDA oversight.