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Originally, monogenic inherited diseases (those caused by inherited single gene defects), such as cystic fibrosis, were considered primary targets for gene therapy. While the positive therapeutic outcome was celebrated as a breakthrough for gene therapy, a serious drawback subsequently became evident. A small number of more recent gene therapy clinical trials, however, are concerned with monogenic disorders.
Gene therapy relies on similar principles as traditional pharmacologic therapy; specifically, regional specificity for the targeted tissue, specificity of the introduced gene function in relation to disease, and stability and controllability of expression of the introduced gene.
Gene therapy can be performed either by direct transfer of genes into the patient or by using living cells as vehicles to transport the genes of interest. A major disadvantage, however, is the additional biological complexity brought into systems by living cells. After in vitro manipulation, these cells may be retransplanted into patients by injection into the bloodstream, where they travel automatically to the place in the bone marrow in which they are functionally active.
The traditional method to introduce a therapeutic gene into hematopoietic stem cells from bone marrow or peripheral blood involves the use of a vector derived from a certain class of virus, called a retrovirus. The major drawback of these methods is that the therapeutic gene frequently integrates more or less randomly into the chromosomes of the target cell.
Another major limitation of using adult stem cells is that it is relatively difficult to maintain the stem cell state during ex vivo manipulations.
Embryonic stem cells are capable of unlimited self-renewal while maintaining the potential to differentiate into derivatives of all three germ layers. Murine (mouse) embryonic stem cells were isolated over 20 years ago,12,13 and paved the way for the isolation of nonhuman primate, and finally human embryonic stem cells.14 Much of the anticipated potential surrounding human embryonic stem cells is an extrapolation from pioneering experiments in the mouse system. Following derivation, human embryonic stem cells are easily accessible for controlled and specific genetic manipulation. First, human embryonic stem cells could be genetically manipulated to introduce the therapeutic gene. An important parameter that must be carefully monitored is the random integration into the host genome, since this process can induce mutations that lead to malignant transformation or serious gene dysfunction. Homologous recombination is a very rare event in cells, and thus a powerful selection strategy is necessary to identify the cells in which it occurs. Gene targeting by homologous recombination has recently been applied to human embryonic stem cells.22 This is important for studying gene functions in vitro for lineage selection and marking.
Despite promising scientific results with genetically modified stem cells, some major problems remain to be overcome.
The addition of human embryonic stem cells to the experimental gene therapy arsenal offers great promise in overcoming many of the existing problems of cellular based gene therapy that have been encountered in clinic trials (see Figure 4.3). There is a lot of controversy about the use of embrionic stem cells to treat a miriad of diseases, but now patients are being treated with their own stem cells and a recent case invlolves a Dallas man having been treated for back pain. Traditional spine surgery to treat backpain has an extremely poor success rate and has often left patients in a worse condition than before, but this type of surgery claims to be much more effective, and a lot less evasive. Though I still think surgery should be a last resort, for people in manual jobs who don’t respond to any other treatments, this could be suitable for them. Hematopoietic cell transplantation (HCT) is the intravenous infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with a variety of acquired and inherited malignant and nonmalignant disorders. Since the advent of HCT in the 1960s, several different methods of transplantation have evolved. This method involves procurement of bone marrow from a human leukocyte antigen (HLA)-identical sibling of the patient. Given that there are a limited number of alleles of the HLA system, typing of large numbers of individuals has led to the observation that full molecular matches for patients exist in the general population. This technique usually involves the transplant of large numbers of T-cell–depleted stem cells from a donor, usually a sibling or a parent, who is half matched to the patient. The blood in the umbilical cord of newborn babies contains large numbers of stem cells, which have been shown to be capable of long-term engraftment in children and some adults after transplant. Autologous HCT allows a delivery of myeloablative high-dose chemoradiotherapy, since the infused hematopoietic progenitor cells provide hematopoiesis and immune reconstitution.
In this form of transplantation, marrow or peripheral blood stem cells are procured from an individual who is a genetic identical twin to the patient.
As noted previously, matched related allogeneic HCT involves a donor who is an HLA-matched sibling of the recipient. HLA typing is performed on blood samples or from buccal smears obtained from the patient and potential donor. In cases in which the patient needs an allogeneic transplant and a donor cannot be found within the family, the identification of a matched unrelated donor is accomplished by searching the computer files of the National Marrow Donor Program as well as other, international registries.
The disadvantages of an allogeneic transplant include the difficulty in finding an appropriate HLA-matched donor and the development of GVHD after HCT, which contributes to the morbidity and mortality of the procedure.
Reduced-intensity transplant has allowed older patients (up to 75 to 80 years of age) to undergo transplant to treat their disease when clinically indicated. In autologous transplant, the reinfused stem cells come from either the patient’s own bone marrow or peripheral blood.
This is the first time researchers have shown that bone marrow stem cells can home to the skin and upper gastrointestinal tract and alter the natural course of the disease.
Family Research Council’s mission is to advance faith, family and freedom in public policy and the culture from a Christian worldview. In this photo taken June 10, 2009, Carol Fischman plays with Lucy the Labradoodle, as the dog sits in her stroller at their Vero Beach, Fla. At only 5 years old, she's unable to walk, crippled by rheumatoid arthritis that has rendered her back limbs unusable.
Lucy's owners credit a costly stem cell treatment, despite what experts say is a lack of evidence such treatments work. Thousands of dogs and horses with degenerative arthritis have had stem cell treatments, costing around $2,500 to $3,000 per procedure.
University of Florida veterinarian Kristin Kirkby, who performed Lucy's procedure, said that the outcomes on five similar treatments have all been positive. Owners tell her their dogs have an easier time getting around the house and getting into position to urinate.
To get hard results, Kirkby says the university plans to start taking a pain inventory of each animal at the beginning of the process, followed by an evaluation and checkups afterward to measure changes. Vet-Stem, a Poway, Calif.-based company, is developing the stem cell therapy and began treating horses in 2003.
The procedure has been used mainly to treat osteoarthritis, which involves loss of cartilage in the joints, but Vet-Stem is researching treatments for other diseases. Since 2003, the privately held company has treated 3,500 horses and 1,500 dogs and plans to begin treating cats later this year.
Adam Gassel has used stem cells to treat almost 40 dogs at his Irvine, Calif., veterinary clinic during the past two years. But for about 25 percent of dogs, their owners report they are like puppies again, able to get back to normal activities, he said.
One peer-reviewed study by researchers at Cornell University, published in the American Journal of Veterinary Research and sponsored in part by Vet-Stem, found that tendinitis in horses was improved by injection of the adult stem cells. Two other studies published in Veterinary Therapeutics found that dogs with osteoarthritis showed improvements in lameness after stem cell injections. Jonathan Slack, director of the University of Minnesota's Stem Cell Research Institute, said adult stem cells from fat can become cartilage in a laboratory cell culture. Whatever the scientific merits of the therapies, Lucy's owners say they would do it again for her. She's had her stem cell treatments through an IV three times, and the Fischmans want to give her a fourth one soon, despite the $3,000-per-procedure cost. University of Minnesota scientists, in groundbreaking research, say they have used human embryonic stem cells to kill cancer cells. Expanding waistlines, unsightly bulges: people will gladly remove excess body fat to improve their looks.
After years of working toward this goal, scientists at the OU Cancer Institute have found a way to isolate cancer stem cells in tumors so they can target the cells and kill them, keeping cancer from returning. In a potential breakthrough for the performance horse industry (such as racing and polo), Melbourne scientists are aiming to harness stem cells to repair tendon, ligament, cartilage and bone damage in horses. Supercomputers have helped scientists find a surprising link between cross-shaped (or cruciform) pieces of DNA and human cancer, according to a study at The University of Texas at Austin (UT Austin). Like top musicians, songbirds train from a young age to weed out errors and trim variability from their songs, ultimately becoming consistent and reliable performers. A biomedical breakthrough published today in the journal Nature reveals never-before-seen details of the human body's cellular switchboard that regulates sensory and hormonal responses.

Imagine you wanted to know how much energy it took to bike up a mountain, but couldn't finish the ride to the peak yourself.
Its emergence is a direct consequence of the revolution heralded by the introduction of recombinant DNA methodology in the 1970s. For instance, in pioneering studies on the correction of adenosine deaminase deficiency, a lymphocyte-associated severe combined immunodeficiency (SCID), was attempted.1 Although no modulation of immune function was observed, data from this study, together with other early clinical trials, demonstrated the potential feasibility of gene transfer approaches as effective therapeutic strategies. Out of the approximately 1000 recorded clinical trials (January 2005), fewer than 10% target these diseases (see Figure 4.1).
To integrate all these aspects into a successful therapy is an exceedingly complex process that requires expertise from many disciplines, including molecular and cell biology, genetics and virology, in addition to bioprocess manufacturing capability and clinical laboratory infrastructure.
In this scenario, genes are delivered directly into a patient's tissues or bloodstream by packaging into liposomes (spherical vessels composed of the molecules that form the membranes of cells) or other biological microparticles.
In many cases, direct gene transfer does not allow very sophisticated control over the therapeutic gene. This procedure is relatively complex in comparison to direct gene transfer, and can be divided into three major steps. Isolation of a specific cell type requires not only extensive knowledge of biological markers, but also insight into the requirements for that cell type to stay alive in vitro and continue to divide.
The role of adult stem cells is to sustain an established repertoire of mature cell types in essentially steady-state numbers over the lifetime of the organism.
One type of retroviral vector was initially employed to show proof-of-principle that a foreign gene (in that instance the gene was not therapeutic, but was used as a molecular tag to genetically mark the cells) introduced into bone marrow cells may be stably maintained for several months.9 However, these particular retroviral vectors were only capable of transferring the therapeutic gene into actively dividing cells.
In principle, this is dangerous, because the gene therapy vector can potentially modify the activity of neighboring genes (positively or negatively) in close proximity to the insertion site or even inactivate host genes by integrating into them. Even after months and years of growth in the laboratory, they retain the ability to form any cell type in the body. Experiments performed with human embryonic stem cells in the last couple of years indicate that these cells have the potential to make an important impact on medical science, at least in certain fields. When this facility is combined with their rapid growth, remarkable stability, and ability to mature in vitro into multiple cell types of the body, human embryonic stem cells are attractive potential tools for gene therapy. This gene may either be active or awaiting later activation, once the modified embryonic stem cell has differentiated into the desired cell type. The levels of immune system reconstitution observed in the mice were quite modest (<1% of normal), while the methodology employed to achieve hematopoietic engraftment is not clinically feasible. Since these cells can be differentiated in vitro into many cell types, including presumably tissue-specific stem cells, they may provide a constant in vitro source of cellular material.
However, several copies of the therapeutic gene may also be integrated into the genome, helping to bypass positional effects and gene silencing. Specific proteins stabilizing these episomal DNA molecules have been identified as well as viruses (adenovirus) that persist stably for some time in an episomal condition. Recombinant DNA is altered in vitro, and the therapeutic gene is introduced into a copy of the genomic DNA that is targeted during this process. Usually, the introduced construct has an additional gene coding for antibiotic resistance (referred to as a selectable marker), allowing cells that have incorporated the recombinant DNA to be positively selected in culture. For therapeutic applications in transplantation medicine, the controlled modification of specific genes should be useful for purifying specific embryonic stem cell-derived, differentiated cell types from a mixed population, altering the antigenicity of embryonic stem cell derivatives, and adding defined markers that allow the identification of transplanted cells. The more specific and extensive the genetic modification, the longer the stem cells have to remain in vitro. Transgenic genes, as well as vectors introducing these genes (such as those derived from viruses), potentially trigger immune system responses.
Further research is essential to determine the full potential of both adult and embryonic stem cells in this exciting new field.
Molecular analysis of T lymphocyte-directed gene therapy for adenosine deaminase deficiency: long-term expression in vivo of genes introduced with a retroviral vector. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency.
Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.
Non-hematopoietic bone marrow stem cells: molecular control of expansion and differentiation. Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients.
Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Lack of expression from a retroviral vector after transduction of murine hematopoietic stem cells is associated with methylation in vivo.
High-level sustained transgene expression in human embryonic stem cells using lentiviral vectors. Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. People are having their wisdom teeth taken out while young and getting them put on ice in case they need the stem cells for the future.
These include hematologic malignancies (eg, leukemia, lymphoma, and myeloma), nonmalignant acquired bone marrow disorders (eg, aplastic anemia), and genetic diseases associated with abnormal hematopoiesis and function (thalassemia, sickle cell anemia, and severe combined immunodeficiency). At present, the hematopoietic progenitor cells used for HCT are obtained from either bone marrow or peripheral blood. In some cases, a partially matched sibling or family donor (one antigen mismatch) can be used for HCT. Tissue typing is performed on the patient’s blood, and a search of the computer files of various international registries is made to determine whether a patient has a match with an unrelated individual. Although these are the most difficult transplants to perform successfully, there is great interest in this approach, because most patients will have a donor in their family who is at least a 50% HLA match. Similar to unrelated-donor registries, cord blood banks have been developed to store cord blood cells that can be used for unrelated-donor transplant. This method is essentially the same as autologous HCT, with no concerns about potential tumor contamination within the graft.
The formula for calculating the chances of a particular person having an HLA-matched sibling is 1 ? (0.75)N, where N denotes the number of potential sibling donors. Molecular methods are now used for more refined matching of both class I (A, B, C loci) and class II (DR, DQ, DP loci) antigens. Through international connections, the National Marrow Donor Program searches more than 18.5 million potential donors.
These cells do not cause GVHD, and thus, autologous transplant is associated with less morbidity and mortality than is allogeneic HCT and increases in the number of patients who can undergo the procedure in the upper age limit.
If this post has been helpful to you, please consider a gift to help us continue to advance Faith, Family, and Freedom. There are no independent studies verifying their effectiveness, and some experts say such studies are needed to assess their potential. Bob Harman, veterinarian and Vet-Stem founder, said it made sense to use these fat-based adult stem cells, which the body uses to create scar tissue and repair damage, to treat chronic disease in animals. Those studies also were sponsored by Vet-Stem and conducted by Vet-Stem researchers and other veterinarians. Conclusive results on whether the stem-cell injection process actually makes new bone cells in animals don't exist, to his knowledge.
But unwanted fat also contains stem cells with the potential to repair defects and heal injuries in the body.
Gene therapy is still highly experimental, but has the potential to become an important treatment regimen. The majority of current clinical trials (66% of all trials) focus on polygenic diseases, particularly cancer. Alternately, the genes are packaged into genetically-engineered viruses, such as retroviruses or adenoviruses.
This is because the transferred gene either randomly integrates into the patient's chromosomes or persists unintegrated for a relatively short period of time in the targeted tissue.
In the first step, cells from the patient or other sources are isolated and propagated in the laboratory. Unfortunately, specific biological markers are not known for many cell types, and the majority of normal human cells cannot be maintained for long periods of time in vitro without acquiring deleterious mutations.
Although adult tissues with a high turnover rate, such as blood, skin, and intestinal epithelium, are maintained by tissue-specific stem cells, the stem cells themselves rarely divide.

These properties reflect their origin from cells of the early embryo at a stage during which the cellular machinery is geared toward the rapid expansion and diversification of cell types.
In particular, this impact includes: a) differentiation of human embryonic stem cells into various cell types, such as neurons, cardiac, vascular, hematopoietic, pancreatic, hepatic, and placental cells, b) the derivation of new cell lines under alternative conditions, c) and the establishment of protocols that allow the genetic modification of these cells. Two possible scenarios whereby human embryonic stem cells may benefit the gene therapy field are discussed below.
Recently published reports establish the feasibility of such an approach.15 Skin cells from an immunodeficient mouse were used to generate cellular therapy that partially restored immune function in the mouse. This methodology involved using a more severely immunodeficient mouse as a recipient (which also had the murine equivalent of the human X-linked SCID mutation) and genetically engineering the hematopoietic engrafting cells with a potential oncogene prior to transplantation. Positional effects are caused by certain areas within the genome and directly influence the activity of the introduced gene. Next, recombinant DNA is introduced by transfection into the cell, where it recombines with the homologous part of the cell genome.
However, antibiotic resistance only reveals that the cells have taken up recombinant DNA and incorporated it somewhere in the genome.
Additionally, since the therapeutic gene can now be introduced into defined regions of the human genome, better controlled expression of the therapeutic gene should be possible.
Although human embryonic stem cells in the culture dish remain remarkably stable, the cells may accumulate genetic and epigenetic changes that might harm the patient (epigenetic changes regulate gene activity without altering the genetic blueprint of the cell). If stem cells are not autologous, they eventually cause immuno-rejection of the transplanted cell type. HCT is also used in the support of patients undergoing high-dose chemotherapy for the treatment of certain solid tumors for whom hematologic toxicity would otherwise limit drug administration (germ cell tumors, soft tissue sarcomas, and neuroblastoma).
The decision to use a certain type of HCT is dictated by the patient’s age, disease and condition, and the availability of a donor. Most transplants will engraft, and few patients will have significant graft-vs-host disease (GVHD).
Given the immunologic immaturity of cord blood cells, these transplants can be accomplished even when there are disparities (mismatching) in the HLA typing between the donor and recipient. A match is noted when the major class I antigens, as well as class II antigens, are the same as those of the donor.
Because there are multiple alleles of any given HLA locus, serologic identity does not necessarily imply genotypic identity, such as is the case among sibling donor-recipient pairs.
Lucy can only scoot around the ground to grab a bone_she is unable to walk, crippled by rheumatoid arthritis that has rendered her back limbs unusuable.
In all, Gassel said, all but 20 percent of the animals show some positive response to the therapy, according to their owners and the requests for pain medicine. In principle, it allows the transfer of genetic information into patient tissues and organs. Because of biosafety concerns, the viruses are typically altered so that they are not toxic or infectious (that is, they are replication incompetent). Additionally, the targeted organ or tissue is not always easily accessible for direct application of the therapeutic gene. Second, the therapeutic gene is introduced into these cells, applying methods similar to those used in direct gene transfer. However, in certain situations, such as during tissue repair after injury or following transplantation, stem cell divisions may become more frequent. Vectors derived from other types of retroviruses (lentiviruses) and adenoviruses have the potential to overcome this limitation, since they also target non-dividing cells. In these experiments, embryonic stem cells were generated from an immunodeficient mouse by nuclear transfer technology.
Usually, small molecules, such as liposomes, as well as other cationic-lipid based particles are employed to facilitate the entry of DNA encoding the gene of interest into the cells. Gene silencing refers to the phenomenon whereby over time, most artificially introduced active genes are turned off by the host cell, a mechanism that is not currently well understood.
This in turn results in the replacement of normal genomic DNA with recombinant DNA containing genetic modifications. To select for cells in which homologous recombination has occurred, the end of the recombination construct often includes the thymidine kinase gene from the herpes simplex virus.
Indeed, sporadic chromosomal abnormalities in human embryonic stem cell culture have been reported, and these may occur more frequently when the cells are passaged as bulk populations.
However, the relapse rate is high, and the process of immune reconstitution is slow, with patients often having troublesome infections for a long time after transplant.
Cord blood transplants are generally used in situations in which the patient does not have a sibling donor and an unrelated adult donor cannot be identified through the international registries. The average American family size usually limits the success of finding a family donor to approximately 30% of patients. Each sibling receives one set of antigens (A, B, C, DR, DQ, DP) from each parent (chromosome 6). The development of oligonucleotide probes has greatly increased the precision of HLA typing and has allowed for more specific selection of bone marrow donors by matching molecular alleles of the class I and II antigens.
Jakub Tolar, along with international colleagues, have used adult stem cells from donor bone marrow or donor umbilical cord blood to treat EB successfully. These basic tools of gene therapists have been extensively optimized over the past 10 years.
The prototypic example of adult stem cells, the hematopoietic stem cell, has already been demonstrated to be of utility in gene therapy.4,5 Although they are relatively rare in the human body, these cells can be readily isolated from bone marrow or after mobilization into peripheral blood.
The nucleus of an egg cell was replaced with that from a skin cell of an adult mouse with the genetic immunodeficiency. Additionally, some viruses (particularly retroviruses) only infect dividing cells effectively, whereas others (lentiviruses) do not require actively dividing cells. In these cases, integration of several copies may help to achieve stable gene expression, since a subset of the introduced genes may integrate into favorable sites.
Cells that randomly incorporate recombinant DNA usually retain the entire DNA construct, including the herpes virus thymidine kinase gene. This observation reinforces the necessity to optimize culture conditions further, to explore new human embryonic stem cell lines, and to monitor the existing cell lines.23,24 Additionally undifferentiated embryonic stem cells have the potential to form a type of cancer called a teratocarcinoma. Recently, the Johns Hopkins group developed a method of haploidentical HCT using post-HCT cyclophosphamide as prevention of GVHD, which showed promising results.
Genotypic identity can be confirmed by testing the parents and determining the inheritance of each set of antigens. Furthermore, the procedure allows the addition of new functions to cells, such as the production of immune system mediator proteins that help to combat cancer and other diseases. Specific surface markers allow the identification and enrichment of hematopoietic stem cells from a mixed population of bone marrow or peripheral blood cells. All of these techniques have been applied to various stem cells, including human embryonic stem cells. In most cases, the genetic information carried by the viral vector is stably integrated into the host cell genome (the total complement of chromosomes in the cell).
In cells that display homologous recombination between the recombinant construct and cellular DNA, an exchange of homologous DNA sequences is involved, and the non-homologous thymidine kinase gene at the end of the construct is eliminated. Safety precautions are therefore necessary, and currently, protocols are being developed to allow the complete depletion of any remaining undifferentiated embryonic stem cells.25 This may be achieved by rigorous purification of embryonic stem cell derivatives or introducing suicide genes that can be externally controlled.
In the laboratory dish (in vitro), cells can be manipulated much more precisely than in the body (in vivo). However, the destiny of the introduced DNA is relatively poorly controlled using these procedures.
Cells expressing the thymidine kinase gene are killed by the antiviral drug ganciclovir in a process known as negative selection. Some of the cell types that continue to divide under laboratory conditions may be expanded significantly before reintroduction into the patient.
In most cells, the DNA disappears after days or weeks, and in rare cases, integrates randomly into host chromosomal DNA.
Therefore, those cells undergoing homologous recombination are unique in that they are resistant to both the antibiotic and ganciclovir, allowing effective selection with these drugs (see Figure 4.2). Moreover, some cell types are able to localize to particular regions of the human body, such as hematopoietic (blood-forming) stem cells, which return to the bone marrow.
In principle, this approach may be employed for treating human patients with immunodeficiency or other diseases that may be corrected by cell transplantation.

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