The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. The literature searches used the following search terms with acronyms, synonyms, and closely related words. Integrations associated with adverse events in hsc hematopoietic. 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.
Gene therapy is an experimental technique that uses genes to treat or prevent disease. Development and clinical translation of approved gene. The ongoing challenge of hematopoietic stem cellbased. Gene therapy, the delivery of a gene into hematopoietic stem cells hscs, has. 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. Lentiviral hematopoietic stem cell gene therapy benefits. The field of gene therapy is striving more than ever to define a path to the clinic and the market. It is a technique for correcting defective genes that are responsible for disease development. 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. 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. Until now, gene therapy has been used to treat patients with scid secondary to adenosine deaminase ada deficiency, xlinked scid, cgd and was.
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. The safety and efficacy of lentiglobin for scd is being evaluated in the ongoing phase 12 hgb206 study nct02140554. The role of conditioning in hematopoietic stemcell gene therapy. 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 this chapter, advances in the technology of hsc gene therapy, e. Download table integrations associated with adverse events in hsc hematopoietic stem cells gene therapy clinical trials. 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. 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.
Initial clinical trials using firstgeneration gammaretroviral vectors to transfer corrective dna demonstrated clinical benefit for patients, but were associated with. Gene therapy for adenosine deaminase deficiency annual. Gene therapy through autologous transplantation of gene. This hspc gene therapy approach has potential for clinical translation. From a clinical perspective, gene therapy has the potential to reverse the clinical sequelae of a condition. 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. Development and clinical translation of approved gene therapy. Ppt gene therapy powerpoint presentation free to download. Abstracthematopoietic stem cell hsc therapy using replicationincompetent. The technique was first developed in 1972 but has, so far, had limited success in treating human diseases. Here, we discuss the current status of gene therapy of hematopoietic stem cells hscs for.
Gene therapy introduces a normal, functional copy of a gene into a cell in which that gene is defective. Lentiviral haemopoietic stemcell gene therapy in earlyonset. Haematopoietic stem cell hsc gene therapy has been successfully employed as a therapeutic option to treat specific inherited immune deficiencies, including. The ongoing challenge of hematopoietic stem cellbased gene. These advances raise great hope to treat devastating rare and inherited diseases as well as incurable illnesses. Hematopoietic stem cells hscs and lentiviral globin vectors. This therapy adds dna containing a functional version of the lost gene back into the cell. Abstractmucopolysaccharidosis type iiia mpsiiia is a lysosomal storage disorder caused by mutations in. Gene therapy using autologous hematopoietic stem cells hsc that are corrected with the normal gene may have a beneficial effect on blood.
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 has shown promise in scid infants but failed in older scidx1 children. Recoding the stories of peoples lives requires a different way of treating disease. 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. From early hsc gene therapy testing to the development of lentiviral vectors.
We demonstrated a strong potential for the clinical translation of hsc gene therapy for brm by demonstrating the brmhoming capacity of. 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. 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. Im working at the san raffaele telethon institute for gene therapy in milano, italy.
We also reported a preliminary assessment12 of the safety and potential bene. Original article from the new england journal of medicine gene therapy in a patient with sickle cell disease. Hematopoietic stem cell gene therapy for brain metastases. The central hypothesis of gene therapy for genetic blood. 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. 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 expansion and gene therapy ncbi nih. 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. Magnetic resonance mr images of the brain of a patient mld01 before and after 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. Apr 20, 2016 gene therapy has shown promise in scid infants but failed in older scidx1 children.
Number of gene therapy clinical trails approved worldwide 19892009 12 two examples of gene therapy for hematologic diseases. In contrast, the clinical utility of replacement gene therapy for sickle cell disease remains unproven. Cts stempro hsc expansion medium for cell and gene therapies. 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. 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. Recently, hsc gene therapy has emerged as an alternative treatment. Therapeutic efficacy of hsc gene therapy approaches in controlling.
Application of retroviralbased gene transfer approaches to mouse hematopoietic stem cells hscs has led to a sophisticated. Prophylactic in vivo hematopoietic stem cell gene therapy. Gene therapy promises to cure the disease at the root and is therefore. 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. Stem cell and gene therapy immune deficiency foundation. In summary, our study establishes a novel approach for targeting of brm with hsc gene therapy. Oct 01, 2017 hematopoietic stem celldirected gene therapy hscgt provides an innovative treatment option for hematological disorders. Lentiviral haemopoietic stemcell gene therapy in early. Wasp is a cytosolic adaptor protein mediating the rearrangement of the actin cytoskeleton upon surface receptor signaling. 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.
Sep 25, 2019 the field of gene therapy is striving more than ever to define a path to the clinic and the market. Selection and expansion of genecorrected hscs has now been accomplished for the first time using hsc from large animals dogs and humans. Gene and cell therapy research recently reached a fundamental milestone toward the goal to deliver new medicines for orphan diseases. Hematopoietic stem cell gene therapy progress and lessons. Nov 15, 2003 hematopoietic stem cell hsc gene therapy can potentially cure a variety of human hematopoietic diseases, such as sickle cell disease.
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. The role of conditioning in hematopoietic stemcell gene. Application of retroviralbased gene transfer approaches to mouse hematopoietic stem cells hscs has led to a sophisticated understanding of. There is tremendous potential for hematopoietic stem cell hsc and. 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. This is used to treat diseases caused by a mutation that stops a gene from producing a functioning product, such as a protein. 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. Allogenic hematopoietic stem cell hsc transplantation represents a curative approach but remains problematic in light of severe risks and side effects. 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. Nearly 50 years after the concept was first proposed, gene therapy is now considered a promising treatment option for several human diseases. 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. Gene therapy is the insertion, alteration, or removal of genes within an individuals cells and biological tissues to treat diseases. 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. Milestones in hsct are highlighted in light blue whereas major contributions in the field of gene transfer are.
View larger image or click on image download as powerpoint. Gene therapy gt approaches based on autologous hematopoietic stem cell hsc corrected ex vivo have shown therapeutic benefit in a number of inherited disorders. Lentiviral gene transfer demonstrated an excellent safety record 41,42, with promising results in patients. Lentiviral hematopoietic stem cell gene therapy for x. Development of hematopoietic stem cell gene therapy for. Hematopoietic stem celldirected gene therapy hscgt provides an innovative treatment option for hematological disorders. Pdf lentiviral hematopoietic stem cell gene therapy in. Pdf hematopoietic stem cell gene therapy for inherited. 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. Number of hsc transplants in the us from 20102015, by source. Treating immunodeficiency through hsc gene therapy. Lentiviral hematopoietic stem cell gene therapy for xlinked. 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. Cts stempro hsc expansion medium for cell and gene.
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. Hematopoietic stem cell gene therapy for storage disease. There are several techniques for carrying out gene therapy. 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. 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. Hematopoietic stem cell hsc gene therapy remains a highly attractive treatment option for many disorders including hematologic conditions. 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. The basic concept of gene therapy is to introduce a gene with the capacity to cure or prevent the progression of a disease. Hematopoietic stem cell hscbased gene therapy is being explored for gld. Hematopoietic stem cell gene therapy for the treatment of. Recent advances in hematopoietic stem cell gene therapy. Lentiglobin for sickle cell disease scd gene therapy contains exvivo lentiviral vector lvvmediated addition of a modified. Graphic1 hsc gene therapy can prevent progression of metachromatic leukodystrophy.
The relationships between target gene transduction. 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. 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. Thats why were allin on building integrated product platforms that encompass gene therapy, cancer immunotherapy and gene editing. 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.
Serious adverse effects were encountered in early clinical studies, but this fueled basic research that led to safer and more efficient gene transfer vectors. Hematopoietic stem cell hsc gene therapy can potentially cure a variety of human hematopoietic diseases, such as sickle cell disease. Zhao h, pestina ti, nasimuzzaman m, mehta p, hargrove pw, persons da. Identification of hematopoietic stem cellspecific mirnas. The potential application of an in vivo gene therapy approach may open a door to a novel approach for disease treatment. Promises and challenges in hematopoietic stem cell gene. Review treating immunodeficiency through hsc gene therapy. 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. Selection and expansion of gene corrected hscs has now been accomplished for the first time using hsc from large animals. Scid arrives 25 years after the first gene therapy attempt in humans. A schematic representation of the hscbased gene therapy for. Hematopoietic stem cell hsc gene therapy remains a highly attractive. Reduced intensity conditioning ric regimens are thought to be appropriate for hematopoietic stem cell hsctargeted gene therapy, as autologous hscs are utilized in. 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.
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