Below are some of the most common questions raised by the general public regarding gene therapy and cell therapy. To read more information on each question, simply click on the button to the left to expand the text.

How do I find a clinical trial?

The most complete listing of clinical trials on gene therapy and cell therapy based in the U.S.A. is www.clinicaltrials.gov. To view a list of clinical trials for gene therapy trials for a specific disease, visit www.clinicaltrials.gov and search for specific disease and “gene therapy.”  Similarly, a list of cell therapy trials for a specific disease can be obtained at www.clinicaltrials.gov by searching for the specific disease and “cell therapy.”  The list of clinical trials indicates whether each clinical trial is pending, recruiting (looking for patients), or ongoing (have enrolled sufficient patients). 

In addition, several foundations which provide information and research support for a specific disease such as the National Hemophilia Foundation, Juvenile Diabetes Research Foundation, Blindness.org, Retinal International.org, Leukemia and Lymphoma Society, Leukemia Research Foundation, and American Diabetes Association,have a webpage which lists clinical trials.

Patients with several different genetic diseases and their families have started internet-based chat rooms where they can discuss current trials and upcoming trials. 

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What are some of the challenges gene and cell therapists face?

The challenges of gene and cell therapists can be divided into 3 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 insults. Note that there are many susceptibility genes and additional mutations yet to be discovered.  Gene replacement therapy for single gene defects is the most straightforward conceptually. 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, such as cystic fibrosis which affects lung cells and the digestive track. Thus, 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” summary in the Gene and Cell Therapy for Diseases 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 compared with 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, requiring the animals to be immune suppressed.

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. For oligonucleotide-based therapies, chemical modifications of the oligonucleotides are often performed to attenuate an undesired non-specific immune response.  

All clinical trials are carefully monitored by the NIH, FDA and Institutional Review Boards based on preclinical studies using clinical grade reagents. Trials occur in three phases. Phase I studies usually involve a relatively small number of patients and are designed to evaluate the safety and potential toxicity of the procedure in a dose escalation series. Once a dose is selected that is considered relatively safe, a larger Phase 2 study can be undertaken to evaluate potential benefit of the treatment. If some benefit is indicated and the safety profile is good, a Phase 3 study will be taken with a large patient cohort to determine the statistical significance of therapeutic benefit. A critical component of clinical trials is patient consent to assure that the participating individuals understand the potential risk of the procedure weighed against any potential benefit to themselves or future patients.  

Challenges in development of gene and cell therapy agents:

Scientific challenges include development of gene therapy agents that express the gene in the relevant tissue at the appropriate level for the desired duration of time. While these issues are easy to state, each issue involves extensive research to identify the best means of delivery to the optimal tissue, 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/cell therapy being undertaken.  For example, in gene/cell therapy for cancer, one aim is to selectively boost the immune response to cancer cells. In contrast, in treating genetic diseases like hemophilia and cystic fibrosis the goal is for the therapeutic protein to be accepted by the immune system as “self”.

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 which can be expanded in number in culture and 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 or migrate to 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 and while maintaining their ability to produce 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 become tumorigenic.  

Challenges in funding:

In most fields, funding for basic or applied research for testing innovative ideas in tissue culture and animal models 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 potential benefit from a particular gene/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.  NIH and biotechnology companies are trying meet the demand for this large expenditure, but many promising therapies are slowed down by lack of funding for this critical next phase.

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What is gene therapy?

Gene therapy is the transfer of genetic material into a host (human or animal) with the intention of alleviating a disease state. Gene therapy uses genetic material to change the expression of a protein(s) critical to the development and/or progression of the disease. In gene replacement therapy typically used for diseases of loss of protein function (inherited in an autosomal recessive manner), scientists first identify a gene that is strongly associated with the onset of disease or its progression. They show that correcting its information content or replacing it with expression of a normal gene counterpart corrects the defect in cultured cells and improves the disease in animal models, and is not associated with adverse outcomes. Scientists and clinicians then develop strategies to replace the gene or provide its function by administering genetic material into the patient. The relevant genetic material or gene usually is engineered into a “gene cassette” and prepared for introduction into humans according to stringent guidelines for clinical use. The cassette can be delivered directly as DNA, or engineered into a disabled viral vector, packaged into a type of membrane vesicles (termed liposome) so it is efficiently taken up by the appropriate cells of the body or used to genetically modify cells for implantation into patients.

Other types of gene therapy include delivery of RNA or DNA sequences (oligonucleotide therapy) that can be used either to depress function of an unwanted gene, such as one responsible for a mutant protein which acts in a negative way to reduce normal protein function (usually inherited in an autosomal dominant manner), to try to correct a defective gene through stimulation of DNA repair within cells, or to suppress an oncogene which acts as a driver in a cancer cell.

In other strategies for diseases and cancer, the gene/RNA/DNA delivered is a novel agent intended to change the metabolic state of the cells, for example to make cancer cells more susceptible to drug treatment, to keep dying cells alive by delivery of growth factors, to suppress or activate formation of new blood vessels or to increase production of a critical metabolite, such as a neurotransmitter critical to brain function. Vectors and cells can also be used to promote an immune response to tumor cells and pathogens by expressing theses antigens in immune responsive cells in combination with factors which enhance the immune response.

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How does gene therapy work?

Scientists focus on identifying genes that affect the progression of diseases. Depending on the disease, the identified gene may be mutated so it doesn’t work. The mutation may shorten the protein, lengthen the protein, or cause it to fold into an odd shape. The mutation may also change how much protein is made (change its expression level). After identification of the relevant gene(s), scientists and clinicians choose the best current strategy to return cells to a normal state, or in the case of cancer cells, to eliminate them. 

Thus, one aim of gene therapy can be to provide a correct copy of its protein in sufficient quantity so that the patient’s disease improves or disappears. Five main strategies are used in gene therapy for different diseases and cancer: gene addition, gene correction, gene silencing, reprogramming, and cell elimination. In some common diseases, such as Parkinson’s disease and Alzheimer’s disease, different genes and non-genetic causes can underlie the condition. In these cases, gene/cell therapy can be directed at the symptoms, rather than the cause, such as providing growth factors or neutralizing toxic proteins.

Gene addition involves inserting a new copy of the relevant gene into the nucleus of appropriate cells. The new gene has its own control signals including start and stop signals. The new gene with its control signals is usually packaged into either viral vectors or non-viral vectors. The gene-carrying vector may be administered into the affected tissue directly, into a surrogate tissue, or into the blood stream or intraperitoneal cavity. Alternatively, the gene-carrying vector can be used in tissue culture to alter some of the patients’ cells which are then re-administered into the patient. 

Gene therapy agents based on gene addition are being developed to treat many diseases, including adenosine deaminase severe combined immunodeficiency (ADA- SCID), alpha-antitrypsin deficiency, Batten’s disease, congenital blindness, cystic fibrosis, Gaucher’s disease, hemophilia, HIV infections, Leber’s congenital amaurosis, lysosomal storage diseases, muscular dystrophy, type I diabetes, X linked chronic granulomatous disease, and many others. 

Gene correction involves delivering a corrected portion of the gene with or without supplemental recombinant machinery that efficiently recombines with the defective gene in the chromosome and corrects the mutation in the genome of targeted cells. This can also be carried out by providing DNA/RNA sequences that allow the mutated portion of the messenger RNA to be spliced out and replaced with a corrected sequences or, when available in the genome, increasing expression of a normal counterpart of the defective gene which can replace its function.

Gene silencing reduces the expression of the target gene, typical by disrupting translation of the messenger RNA encoded in it through interfering RNA molecules. In some cases, the diseased tissue produces too much protein from a specific gene and this overly abundant production is associated with symptoms of the disease. The interfering RNA binds to the normal RNA of the gene and blocks its translation into protein. These interfering RNAs can be synthetic (oligonucleotide therapy) or encoded in novel genes that make sequences that are the inverse of the normal sequence (antisense) and can thus hybridize to the message and prevent its translation. Cells normally make microRNAs which perform this function as a normal form of regulation of gene expression, sometimes resulting in degradation of the targeted message. By changing levels of specific microRNAs in cells, one can also achieve downregulation of gene expression. Thus, interfering RNAs reduce protein production of the corresponding gene.   

For example, too much tumor necrosis factor (TNF) alpha is often expressed in the afflicted joints of rheumatoid arthritis patients. Since the protein is needed in small amounts in the rest of the body, gene silencing aims to reduce TNF alpha only in the afflicted tissue. Another example would be oncoproteins, such as c-myc or EGFR that are upregulated or amplified in some cancers. Lowering expression of these oncoproteins in cancer cells can inhibit tumor growth.

Reprogramming involves the addition of one or more genes into cells of the same tissue which causes the altered cells to have a new set of desired characteristics. For example, type I diabetes occurs because many of the islet cells of the pancreas are damaged. But the exocrine cells of the pancreas are not damaged. Several groups are deciphering which genes to add to some of the exocrine cells of the pancreas to change them into islet cells, so these modified exocrine cells make insulin and help heal type I diabetic patients.

This is also the strategy in the use of induced pluripotent stem cells (iPS) where skin cells or bone marrow cells are removed from the patient and reprogrammed by transitory expression of transcription factors which turn on developmentally programmed genes, thereby steering the cells to become the specific cell types needed for cell replacement in the affected tissue.

Cell elimination strategies are typically used for cancer (malignant tumors) but can also be used for overgrowth of certain cell types (benign tumors). Typical strategies involve suicide genes, anti-angiogenesis agents, oncolytic viruses, toxic proteins or mounting an immune response to the unwanted cells. Suicide gene therapy involves expression of a new gene, for example an enzyme that can convert a pro-drug (non-harmful drug precursor) into an active chemotherapeutic drug. Expression of this suicide gene in the target cancer cells can only cause their death upon administration of a prodrug, and since the drug is generated within the tumor, its concentration is higher there and is lower in normal tissues, thus reducing toxicity to the rest of the body. Since tumors depend on new blood vessels to supply their ever increasing volume, both oligonucleotides and genes aimed at suppressing angiogenesis have been developed. In another approach, a number of different types of viruses have been harnessed through mutations such that they can selectively grow in and kill tumor cells (oncolysis), releasing new virus on site, while sparing normal cells. In some cases toxic proteins, such as those that produce apoptosis (death) of cells are delivered to tumor cells, typically under a promoter that limits expression to the tumor cells. Other approaches involve vaccination against tumor antigens using genetically modified cells which express the tumor antigens, activation of immune cells or facilitation of the ability of immune cells to home to tumors. 

Cancer therapy has been limited to some extent by the difficulty in efficient delivery of the therapeutic genes or oligonucleotides to sufficient numbers of tumor cells, which can be distributed throughout tissues and within the body. To compensate for this insufficient delivery, killing mechanisms are sought which have a “bystander effect” such that the genetically modified cells release factors that can kill non-modified tumor cells in their vicinity. Recent studies have found that certain cell types, such as neuroprecursor cells and mesenchymal cells, are naturally attracted to tumor cells, in part due to factors released by the tumor cells. These delivery cells can then be armed with latent oncolytic viruses or therapeutic genes which they can carry over substantial distances to the tumor cells.

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How are genes delivered?

Scientists and clinicians use the following four basic ways to carry genetically modifying factors (DNA or RNA and/or their interacting proteins) into the relevant cells. 

First, naked DNA or RNA can be pushed into cells by using high voltage (electroporation) or through uptake through invaginating vesicles (endocytosis) or by sheer mechanical forces with an instrument called a “gene gun.”

Second, DNA or RNA can be packaged into liposomes (membrane bound vesicles) that are taken up into cells more easily than naked DNA/RNA. Different types of liposomes are being developed to preferentially bind to specific tissues, and to modify protein or RNA at different levels. Recent work has also electroporated interfering RNA oligonucleotides into membrane vesicles normally released by cells (exosomes) to carry them to specific tissues.

Third, DNA or RNA can be packaged into virus-like particles using a modified viral vector. Basically, in one format, the gene(s) of interest and control signals replace most or all of the essential viral genes in the vector so the viral vector does not replicate (can’t make more viruses) in cells, as in the case of adeno associated virus (AAV) vectors andretrovirus/lentivirus vectors. In another format, one of more viral genes are replace with therapeutic genes so that the virus is still able to replicate in a restricted number of cell types, as for oncolytic viruses, such asadenovirus and herpes simplex virus. A number of different viruses are being developed as gene therapy vectors because they each preferentially enter a subset of different tissues, express genes at different levels, and interact with the immune system differently.

Fourth, gene therapy can be combined with cell therapy protocols. The relevant cells from the patient or matched donor are collected and purified, and when possible, expanded in culture to achieve substantial numbers. Scientists and clinicians treat the patient’s cells with the gene therapy vector using one of the three methods described above. Some of the treated cells express the desired, inserted gene or carry the virus in a latent state. These gene-expressing cells are then re-administered to the patient.

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How are viruses and cells used in gene therapy and can they make me sick?

Viruses are used in gene therapy in two basic ways: as gene delivery vectors and as oncolytic viruses. First, modified viruses are used as viral vectors or carriers in gene therapy. Viral vectors protect the new gene from enzymes in the blood that can degrade it, and they deliver the new gene in the “gene cassette” to the relevant cells. Viral vectors efficiently coerce the cells to take up the new gene, uncoat the gene from the virus particle (virions), 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.  These viral vectors have been genetically engineered so that most of their essential genes are missing. Removal of these viral genes makes room for the “gene cassette” and reduces viral toxicity. Viral vectors typically have to be grown in special cells in culture that provide the missing viral proteins in order to package the therapeutic gene(s) into virus particles. 

Many different kinds of viral vectors are being developed because the requirements of gene therapy agents for specific diseases vary depending on what tissue is affected, how stringent control of gene expression needs to be, and how long the gene needs to be expressed. Scientists examine at least the following characteristics while choosing or developing an appropriate viral vector:  (i) size of DNA or gene that can be packaged, (ii) tropism to 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.   

Second, oncolytic viruses are engineered to replicate only or predominantly in cancer cells and not in normal human cells. These viruses grow in cancer cells and cause the cancer cells to burst, releasing more oncolytic viruses to infect surrounding cancer cells. These viruses can also carry therapeutic genes to increase toxicity to tumor cells, stimulate the immune system or inhibit angiogenesis of the tumor.

Can they make me sick? Viral vectors and oncolytic viruses are designed to reduce their risk of causing human disease. The viral vectors and oncolytic viruses are tested in tissue culture in many cell types of humans and animals to ensure their selective toxicity to tumor cells as compared to normal cells. They  also need to be shown to improve various aspects of the disease and have low toxicity in animal studies performed in mice and sometimes in rats, dogs, and/or non human primates before they are considered for human use. Formal toxicology and biodistribution studies of the gene therapy agent are performed and the doses for humans are estimated from these studies. Vectors used in human trials are prepared under strict guidelines to insure 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. The National Institutes of Health has a website, the Office of Biotechnology Activities (http://oba.od.nih.gov/oba/), where adverse events from clinical trials of gene therapy vectors are posted to provide additional insights into possible risks with certain vectors.

Several types of human cells have been removed from patients, genetically modified in culture and then readministered to the patient. This includes skin fibroblasts modified to produce a nerve growth factor and then introduced into the brains of Alzheimer’s patients. More typically bone marrow stem cells and mesenchymal precursor cells are used. In the case of bone marrow stem cells replacement of a deficient gene can lead to repopulation of blood cells with that lineage. Gene insertion into certain sites in the genome can lead to overproliferation of blood cells, for example causing leukemia. This situation has led to extensive efforts to control sites of insertion into the genome into safe zones. Use of iPSCs and other pluripotent cells in clinical trials is still early, with the greatest concern being overgrowth of the cells producing benign or malignant tumors.

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What are the ethical issues associated with gene and cell therapy?

Several ethical issues can arise during development of novel therapeutics. The development of genetic and cellular therapies shares many of those same ethical issues with other types of therapy, such as prosthetics, drugs, organ transplantation and protein replacement. In all cases, scientists, clinicians, regulatory committees and concerned citizens take an active role in addressing these issues.

One issue that often arises in the development of new therapies is balancing any risks associated with the new therapy and the potential therapeutic benefit to the patient. Regulatory committees often request that the trials of a new gene therapy or cell therapy agent begin in late stage disease patients.  These patients already have significant disease symptoms at the beginning of the clinical trial. Gene therapy and cell therapy agents may be less able to reverse a set of severe symptoms than prevent their development. Ethical issues especially arise when the disease symptoms occur early in a child’s life as the parents are weighing the risks and the potential benefits for their child. Most gene therapy trials are Phase I trials, which means that safety of the vector and delivery mode are being evaluated. Therefore, no direct benefit to the participant is expected, with the anticipation that if the approach is safe it may then be tested in a Phase II/III trial to assess potential benefit.

Another common issue is whether patients in early stage clinical trials will see any therapeutic benefit as a result of the novel treatment. Regulatory committees often request that investigators give a range of doses of the agent for the initial patients in the trials in an effort to determine whether higher doses do have adverse effects. Thus, the dosage tested in a particular patient may be insufficient to induce a therapeutic response or may be so high as to cause some toxicity. 

Two other ethical risks to be considered are possible “contamination” of the human germ line with new DNA sequences and whether a new epidemiologic agent may be generated that could be passed onto other individuals. 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.  Replicating, and even non-replicating viruses have the potential to recombine with other viral elements and generate novel types of viruses that can replicate and spread. Extensive evaluation of vectors is carried out to reduce the chances that this could happen to virtually nil. Patients are also monitored for potential release of virus and may be quarantined for a short period after administration of the virus to make sure there is no shedding into the environment.

Several mechanisms are in place to help the patient, family members, clinicians and scientists openly address any ethical issues associated with development of genes and cells as virtual drugs. Before enrolling a patient in a clinical trial, investigators must ensure the patient understands the potential benefits and risks associated with the trial. The process of educating patients to help them decide whether to enroll in a clinical trial is known as informed consent. For more information on informed consent, please visit http://www.asgct.org/educational_resources/clinical_trials.php. If you or a family member is considering participating in a clinical trial, be sure to consult your physician before making any medical decisions. 

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What is cell therapy? 

Cell therapy is the transfer of cells into a patient or animal to help lessen or cure a disease. The origin of the cells depends on the treatment. The transplanted cells are often a type of adult stem cells which have the ability to divide and self renew as well as provide cells that mature into the relevant specialized cells of the tissue. 

Blood transfusion and transfusion of red blood cells, white blood cells and platelets are a form of cell therapy that is very well accepted. Another common cell therapy is bone marrow transplantation which has been performed for over 40 years. 

Several investigative protocols of cell therapy involve the transfer of adult T lymphocytes which are genetically modified to increase their immune potency and can self renew and kill the disease-causing cells. 

Stem cells from umbilical cord blood and other tissues are being developed to treat many genetic diseases and some acquired diseases. Ethical issues remain about the use of human fetal tissue as a source of stem cells, and other cell sources are being actively explored.

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How are gene therapy and cell therapy related?

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-SCIDs. 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.    

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What is the difference between gene therapy and cell therapy?

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:  stem cells are isolated from the patient, genetically modified in tissue culture to express a new gene, typically using a viral vector, expanded to sufficient numbers, and returned to the patient. 

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What are the risks associated with gene therapy and cell therapy?

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 making symptoms worse and prolonged, 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 “get out of hand” and start attacking normal proteins or cells, 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 in animals/humans 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 its potential risks, patients are strongly encouraged to ask questions of their investigators and clinicians until they fully understand the risks.     

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What kinds of diseases do gene and cell therapy treat?

Characteristics of diseases amenable to gene therapy and cell therapy include those for which there is not current 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.  Such diseases, for 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 gene(s) 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. So 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 under the different diseases. 

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What are stem cells and where do they come from?

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 which is 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.

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What is a stem cell line?

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. The isolated cells are grown in the laboratory in media 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 line can easily be 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.   

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What are the differences between embryonic stem cells, adult stem cells and iPS cells?

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

Adult stem cells are present in adult tissues of adults. Each tissue has a reservoir of stem cells (sometimes called somatic stem cells). They can mature or differentiate into cells from that tissue. For some tissues such as blood, blood stem cells contained in bone marrow have been isolated and transferred into humans for over 40 years in bone marrow transplants. Adult stem cells can also be isolated from mesenchymal tissue marrow stroma, 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 covert the specialized cells into iPS cells. IPS is a relatively new development with immense promise, with mouse iPS and human iPS cells first described in 2006 and 2007, respectively. 

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Why are stem cells so important in gene and cell therapy?

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). Thus, gene and cell therapy that uses stem cells will theoretically improve the disease condition for as long as those modified stem cells live, potentially the lifetime of the patient.   

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What is regenerative medicine?

Regenerative medicine focuses on 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.

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