Gene Therapy--New Challenges Ahead

  title={Gene Therapy--New Challenges Ahead},
  author={David Alan Williams and Christopher Baum},
  pages={400 - 401}
The successful use of retroviral gene transfer to treat 10 patients with X-linked severe combined immunodeficiency (SCID-X1) has been welcomed as evidence of the therapeutic potential of gene therapy. However, as [Williams and Baum][1] suggest in their Perspective, the discovery that 2 of the 10 patients developed leukemia within 3 years of gene therapy ([ Hacein-Bey-Abina et al .][2]) reinforces the need to develop even more specific gene therapy interventions. [1]:… Expand
[Development and application of gene therapy technologies].
To cope with this serious problem, basic studies are required to improve the safety of retroviral vectors and to develop the method for site-specific integration of transgenes, in order to obtain therapeutic efficacy of hematopoietic stem cell gene therapy in many other disorders. Expand
Safety and efficacy in retrovirally modified haematopoietic cell therapy.
This review summarizes the current state of the debate, proposing future research directions towards understanding the complex interplay of risk factors related to random transgene insertion, unphysiological transgenes expression and additional contributory factors of the specific therapeutic setting. Expand
Overview of Gene Therapy and Viral Vectors for CNS Applications
This trial underscores the tremendous opportunity that gene therapy approaches provide, but it also clearly elucidates the need to understand how different viral vectors and the transgenes that they deliver interact with host cells. Expand
Towards hematopoietic stem cell-mediated protection against infection with human immunodeficiency virus
This work tested whether HSCs and their progeny can be modified to express therapeutic levels of M87o, a gammaretroviral vector encoding an artificial transmembrane molecule that blocks fusion-mediated uptake of HIV. Expand
Live and let die: in vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection.
Expression of mutant forms of O(6)-methyguanine-DNA-methytransferase coupled with the simultaneous use of pharmacologic inhibitors and chemotherapeutic agents has been shown to provide a powerful method to select HSC in vivo. Expand
The Status and Promise of Cancer Gene Therapy
With new approaches undergoing clinical testing, it is anticipated that over the next five years the authors will see registration of a number of efficacious therapeutic gene medicines that will have equal or greater efficacy than conventional approaches. Expand
Targeting site-specific chromosome integration.
Experiments with hybrid vectors incorporating the adeno-associated virus and phage integrases are encouraging, but extensive research should be directed towards the safety and efficacy of this approach before it will be available for gene therapy. Expand
Polymer Design for Nonviral Gene Delivery
Non-viral vectors, although achieving only transient and lower gene expression level, may be able to compete on potential advantages of ease of synthesis, low immune response, and unrestricted plasmid size and satisfy many of the pharmaceutical issues better than the viral vectors. Expand
Gene therapy: regulations, ethics and its practicalities in liver disease.
It is hoped to be widely used in the treatment of liver disease, especially hepatic tumors by using different vectors encoding the aim gene for anti-tumor activity by activating primary and adaptive immunity, inhibiting oncogene and angiogenesis. Expand
Vascular-targeted cancer gene therapy
Targeting gene therapy, not to the malignant population, but instead to the vasculature upon which the survival and growth of a tumour depends constitutes an alternative approach that overcomes some of the delivery problems associated with established tumour cell-directed strategies. Expand


American Society of Gene Therapy (ASGT) ad hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells.
This study reports the report of clinically significant restoration of immunity in patients with the X-linked form of severe combined immune deficiency (XSCID) and provides incontrovertible proof that gene therapy can ameliorate genetic diseases. Expand
Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning
Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions, and lower toxic metabolites, indicating the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID. Expand
LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1
Retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter. Expand
Side effects of retroviral gene transfer into hematopoietic stem cells.
It is the intention to emphasize the need for a critical and hypothesis-driven analysis of "transgene toxicology," in order to improve safety, efficiency, and prognosis for the yet small but expanding group of patients that could benefit from gene therapy. Expand
Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.
Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency and allow patients to have a normal life. Expand
Murine Leukemia Induced by Retroviral Gene Marking
Somatic gene transfer is a promising therapeutic strategy, but it may also evoke new types of side effects related to genetic damage or transgene activity. Retroviral vectors, the best tool currentlyExpand
Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration
Map of retroviral integrations in the human genome showed that MLV preferred integration near the start of transcriptional units (either upstream or downstream) whereas HIV-1 preferred integration anywhere in the transcriptional unit but not upstream of a transcriptional start. Expand
HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots
Global analysis of cellular transcription indicated that active genes were preferential integration targets, particularly genes that were activated in cells after infection by HIV-1, and this data suggests how selective targeting promotes aggressive HIV replication. Expand
Polyclonal long-term repopulating stem cell clones in a primate model.
This study provides direct molecular evidence for a polyclonal, multilineage, and sustained contribution of individual stem cells to primate hematopoiesis and demonstrates the derivation of circulating peripheral blood cells from individual stem cell clones. Expand