Recent advances in hematopoietic stem cell gene therapy. Gene therapy for adenosine deaminase deficiency annual. We demonstrated a strong potential for the clinical translation of hsc gene therapy for brm by demonstrating the brmhoming capacity of. Abstracthematopoietic stem cell hsc therapy using replicationincompetent. Twenty gene therapy products have already been approved and over two thousand human gene therapy clinical trials have been reported worldwide. In this chapter, advances in the technology of hsc gene therapy, e.
Gene therapy promises to cure the disease at the root and is therefore exceptional in its potential, but also formidable in its challenges, as longterm side effects are hard to predict and clinical experience remains limited. Lentiviral haemopoietic stemcell gene therapy in earlyonset. In contrast, gvhd is not a problem after gene therapy, because in this case the normal copy of the gene is inserted into the patients own hsc, negating the need for a hsc donor. Gene therapy using autologous hematopoietic stem cells hsc that are corrected with the normal gene may have a beneficial effect on blood. Cell and gene therapy get the report with graphs and tables on. Scid arrives 25 years after the first gene therapy attempt in humans. Cts stempro hsc expansion medium for cell and gene. Gene therapy is an emerging medical modality in which genetic diseases will be corrected by transfer of a normal version of the relevant gene into a patients somatic cells. Development of hematopoietic stem cell gene therapy for. When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells hscs, there are only two in which the hsc and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject. Application of retroviralbased gene transfer approaches to mouse hematopoietic stem cells hscs has led to a sophisticated.
Promises and challenges in hematopoietic stem cell gene. Thus, hsc gene therapy for adascid using a lentiviral vector is expected to become the alternative therapy in cases without a suitable donor for hsct. In summary, our study establishes a novel approach for targeting of brm with hsc gene therapy. Wasp is a cytosolic adaptor protein mediating the rearrangement of the actin cytoskeleton upon surface receptor signaling. Jan 15, 2017 when considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells hscs, there are only two in which the hsc and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject. Hematopoietic stem cell gene therapy for the treatment of. Haematopoietic stem cell hsc gene therapy has been successfully employed as a therapeutic option to treat specific inherited immune deficiencies, including. These advances raise great hope to treat devastating rare and inherited diseases as well as incurable illnesses. Metachromatic leukodystrophy combined with therapy or hematopoietic stem cell hsc transplantation, as well as mouse model and metachromatic leukodystrophy and gene therapy or hsc gene therapy. Recently, hsc gene therapy has emerged as an alternative treatment. Sep 25, 2019 the field of gene therapy is striving more than ever to define a path to the clinic and the market. History of gene therapy and the milestones that contributed to the implementation of gene therapy for monogeneic disorders using haematopoietic cells adapted from appelbaum, 2007.
Serious adverse effects were encountered in early clinical studies, but this fueled basic research that led to safer and more efficient gene transfer vectors. Gene therapy, the delivery of a gene into hematopoietic stem cells hscs, has. Apr 20, 2016 gene therapy has shown promise in scid infants but failed in older scidx1 children. Selection and expansion of gene corrected hscs has now been accomplished for the first time using hsc from large animals dogs and humans with a novel drug. Gene therapy gt approaches based on autologous hematopoietic stem cell hsc corrected ex vivo have shown therapeutic benefit in a number of inherited disorders. Nearly 50 years after the concept was first proposed, gene therapy is now considered a promising treatment option for several human diseases. Gene and cell therapy research recently reached a fundamental milestone toward the goal to deliver new medicines for orphan diseases. From early hsc gene therapy testing to the development of lentiviral vectors. Considering the limited prophylactic options that are currently offered to women with highrisk germline mutations, the in vivo hspc gene therapy approach is a promising strategy that addresses a major medical problem. Initial clinical trials using firstgeneration gammaretroviral vectors to transfer corrective dna demonstrated clinical benefit for patients, but were associated with. Review treating immunodeficiency through hsc gene therapy. Gene therapy promises to cure the disease at the root and is therefore.
The ongoing challenge of hematopoietic stem cellbased. There are several techniques for carrying out gene therapy. Lentiglobin for sickle cell disease scd gene therapy contains exvivo lentiviral vector lvvmediated addition of a modified. Due to pioneering in vitro investigations on gene modification, gene engineering platforms have incredibly improved to a safer and more powerful tool for the treatment of multiple blood and immune disorders. Selection and expansion of genecorrected hscs has now been accomplished for the first time using hsc from large animals dogs and humans. Transfer of new genetic material to hematopoietic stem cells and expression of the gene product in daughter cells of various lineages is an exciting approach to the treatment of congenital and acquired human diseases. Selection and expansion of genecorrected hscs has now been accomplished for the first time using hsc from large animals dogs and humans with a novel drugresistance gene, mgmt, which is not expressed in normal hscs see the related articles. Development and clinical translation of approved gene therapy. Pdf lentiviral hematopoietic stem cell gene therapy in. The potential application of an in vivo gene therapy approach may open a door to a novel approach for disease treatment.
Integrations associated with adverse events in hsc hematopoietic. Gene therapy through autologous transplantation of gene. Hematopoietic stem celldirected gene therapy hscgt provides an innovative treatment option for hematological disorders. Magnetic resonance mr images of the brain of a patient mld01 before and after gene therapy. In contrast, the clinical utility of replacement gene therapy for sickle cell disease remains unproven. The safety and efficacy of lentiglobin for scd is being evaluated in the ongoing phase 12 hgb206 study nct02140554. Lentiviral gene transfer demonstrated an excellent safety record 41,42, with promising results in patients. In these infants, gene therapy was performed without any need for chemotherapy prior to the transfusion of hsc that had been cultured with the virus. To determine whether this gene therapy strategy is safe and can offer therapeutic benefit to patients with earlyonset mld, we designed a phase iii trial.
A schematic representation of the hscbased gene therapy for. Hematopoietic stem cell gene therapy for brain metastases. Scid was considered an ideal candidate for somatic cell gene therapy because of the ubiquitous expression of the ada enzyme in normal conditions and the survival advantage of ada. And my talk is going to be dedicated to the presentation of our recent results in the development of hematopoietic stem cell gene therapy for the treatment of metachromatic leukodystrophy. Gene therapy has shown promise in scid infants but failed in older scidx1 children. Selection and expansion of gene corrected hscs has now been accomplished for the first time using hsc from large animals.
Hematopoietic stem cell hsc gene therapy remains a highly attractive. Milestones in hsct are highlighted in light blue whereas major contributions in the field of gene transfer are. Number of gene therapy clinical trails approved worldwide 19892009 12 two examples of gene therapy for hematologic diseases. This hspc gene therapy approach has potential for clinical translation. Thus, the safety and efficacy of hsc gene therapy for adascid has now been proved over several trials, allowing gene therapy to stand as an alternative treatment even for patients who have a matched unrelated donor available for transplantation, as this treatment is associated with less use of chemotherapy and no risk of graftversushost disease. Development and clinical translation of approved gene. Ppt gene therapy powerpoint presentation free to download. This therapy adds dna containing a functional version of the lost gene back into the cell. Methods this is an adhoc analysis of data from an ongoing, nonrandomised, openlabel, singlearm phase 12 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy. Gene therapy introduces a normal, functional copy of a gene into a cell in which that gene is defective. Nov, 2019 lentiglobin for sickle cell disease scd gene therapy contains exvivo lentiviral vector lvvmediated addition of a modified. Zhao h, pestina ti, nasimuzzaman m, mehta p, hargrove pw, persons da.
Gene therapy in a patient with sickle cell disease nejm. It is a technique for correcting defective genes that are responsible for disease development. Haematopoietic stem cell hsc gene therapy has been successfully employed as a therapeutic option to treat specific inherited immune deficiencies, including severe combined immune deficiencies scid over the past two decades. The ongoing challenge of hematopoietic stem cellbased gene. Hematopoietic stem cell hsc gene therapy can potentially cure a variety of human hematopoietic diseases, such as sickle cell disease.
Gene therapy for childhood immunological diseases bone marrow. Hematopoietic stem cell gene therapy hsc gt is becoming a powerful and versatile strategy to treat a. We also reported a preliminary assessment12 of the safety and potential bene. The central hypothesis of gene therapy for genetic blood. The clinical gene therapy trials for adenosine deaminase ada deficiency have defined both the potential benefits and the present limitations of gene therapy with hematopoietic stem cells hsc. Its challenge is to ensure viral transduction into hematopoietic stem cells hscs and to generate safe, stable, erythroidspecific replacement gene expression at a level that is sufficient to have a clinical effect.
Until now, gene therapy has been used to treat patients with scid secondary to adenosine deaminase ada deficiency, xlinked scid, cgd and was. Abstractmucopolysaccharidosis type iiia mpsiiia is a lysosomal storage disorder caused by mutations in. Here, we discuss the current status of gene therapy of hematopoietic stem cells hscs for. In 2016, the european commission granted market approval to glaxosmithkline gsk for ex vivo hematopoietic stem cell hsc gene therapy for the treatment of adenosine deaminase ada. Prophylactic in vivo hematopoietic stem cell gene therapy. Hscs represent a minor population of the adult bone marrow, accounting for 1 in 2,500 to 1 in 10,000 cells in the adult mouse 25, 26. Allogenic hematopoietic stem cell hsc transplantation represents a curative approach but remains problematic in light of severe risks and side effects. From a clinical perspective, gene therapy has the potential to reverse the clinical sequelae of a condition. Oct 01, 2017 hematopoietic stem celldirected gene therapy hscgt provides an innovative treatment option for hematological disorders. Lentiviral hematopoietic stem cell gene therapy for xlinked. Treating immunodeficiency through hsc gene therapy. The basic concept of gene therapy is to introduce a gene with the capacity to cure or prevent the progression of a disease. There is tremendous potential for hematopoietic stem cell hsc and.
Jan 12, 2018 nearly 50 years after the concept was first proposed, gene therapy is now considered a promising treatment option for several human diseases. Reduced intensity conditioning ric regimens are thought to be appropriate for hematopoietic stem cell hsctargeted gene therapy, as autologous hscs are utilized in. This is used to treat diseases caused by a mutation that stops a gene from producing a functioning product, such as a protein. Im working at the san raffaele telethon institute for gene therapy in milano, italy. Recoding the stories of peoples lives requires a different way of treating disease. The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. The dao pan lab is researching in vivo gene transfer into hsc and other organs in order to avoid difficulties encountered by ex vivo hscmediated gene transfer. Nov 21, 20 reduced intensity conditioning ric regimens are thought to be appropriate for hematopoietic stem cell hsc targeted gene therapy, as autologous hscs are utilized in gene therapy and most gene. Thats why were allin on building integrated product platforms that encompass gene therapy, cancer immunotherapy and gene editing. Download table integrations associated with adverse events in hsc hematopoietic stem cells gene therapy clinical trials. The relationships between target gene transduction.
Original article from the new england journal of medicine gene therapy in a patient with sickle cell disease. Pdf hematopoietic stem cell gene therapy for inherited. Hematopoietic stem cell hsc gene therapy remains a highly attractive treatment option for many disorders including hematologic conditions. Hematopoietic stem cell hscbased gene therapy is being explored for gld. Lessons learned from advancing hsc therapies to the clinic may help inform the development of other stem cell therapies. Childhood immunological diseases are highly favorable candidates for responses to gene therapy using hsc. Current clinical results indicate that both umbilical cord blood and neonatal bone marrow hsc can be transduced with murine retroviralbased vectors, the transduced hsc can engraft in nonmyeloablated. Stem cell and gene therapy immune deficiency foundation.
The role of conditioning in hematopoietic stemcell gene. Selection and expansion of genecorrected hscs has now been accomplished for the first time using hsc from large animals dogs and humans with a novel drugresistance gene, mgmt, which is not expressed in normal hscs see the related articles beginning. View larger image or click on image download as powerpoint. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patients cells instead of using drugs or surgery. Gene therapy uses sections of dna usually genes to treat or prevent disease the dna is carefully selected to correct the effect of a mutated gene that is causing disease. Identification of hematopoietic stem cellspecific mirnas. Likewise, several clinical trials have been initiated combining autologous hematopoietic stem cell transplantation autohsct with gene therapy gt tools. Hematopoietic stem cell expansion and gene therapy ncbi nih. Gene therapy is the insertion, alteration, or removal of genes within an individuals cells and biological tissues to treat diseases. Lentiviral hematopoietic stem cell gene therapy benefits. Hematopoietic stem cell gene therapy for storage disease. Number of hsc transplants in the us from 20102015, by source. Lentiviral hematopoietic stem cell gene therapy for x. Hematopoietic stem cell gene therapy progress and lessons.
Cts stempro hsc expansion medium for cell and gene therapies. These variabilities predetermine the success rate of the gene therapy to treat certain diseases. Gene therapy using autologous hematopoietic stem cells hsc that are corrected with the normal gene may have a beneficial effect on blood cell production or function, without the immunologic complications of allogeneic hsc transplantation. As an alternative to hsc based gene therapy, a study using an aav vector has reported ada gene expression in various tissues, including heart, skeletal muscle, and kidney. Lentiviral haemopoietic stemcell gene therapy in early. The field of gene therapy is striving more than ever to define a path to the clinic and the market. Gene therapy encompasses multiple approaches to manipulate genetic material in an effort to treat specific diseases, including replacing a mutated or defective gene with a healthy one, introducing a new gene to help fight disease, or editing an existing gene to change its function 1. Therapeutic efficacy of hsc gene therapy approaches in controlling. For example, lvmediated gene therapy is mostly used to overexpress a transgene, whereas crisprcas9 system is capable of gene disruption, gene correction, and precise transgene integration.
Gene therapy is an experimental technique that uses genes to treat or prevent disease. Hematopoietic stem cells hscs and lentiviral globin vectors. Graphic1 hsc gene therapy can prevent progression of metachromatic leukodystrophy. We believe these approaches will provide the potential to treat a broad range of serious conditions with the goal that. Gene therapy program, danafarberboston childrens cancer and blood disorders center and program for gene therapy in rare diseases, department of medicine, boston childrens hospital, boston, ma 02115, usa. The technique was first developed in 1972 but has, so far, had limited success in treating human diseases. The literature searches used the following search terms with acronyms, synonyms, and closely related words. Nov 15, 2003 hematopoietic stem cell hsc gene therapy can potentially cure a variety of human hematopoietic diseases, such as sickle cell disease. The role of conditioning in hematopoietic stemcell gene therapy. Application of retroviralbased gene transfer approaches to mouse hematopoietic stem cells hscs has led to a sophisticated understanding of. Beginning with a groundbreaking study in paris followed by a similar experience in london, there have been 20 xscid babies around the world that have been treated with gene therapy.
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