Oversight and Review of Clinical Gene Transfer Protocols Assessing the Role of the Recombinant DNA Advisory Committee (2014) / Chapter Skim
Currently Skimming:
2 Gene Transfer Research: The Evolution of the Clinical Science
2 Gene Transfer Research: The Evolution of the Clinical Science
Pages 21-40
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 21... ...
This chapter explores the scientific foundations of gene transfer as well as how the field has advanced over time, outlining recent notable clinical developments in the basic techniques of gene transfer and illustrating the potential of gene transfer as a therapeutic approach. The current chapter also outlines the scientific community's initial understandings of risks involved in clinical gene transfer research and describes how those theoretical risks and uncertainties look today, summarizing how and why many risks and uncertainties have been minimized and noting those that persist today.
|
From page 22... ...
Gene therapy is the clinical application of gene transfer, with the intent to produce beneficial health consequences. In research ethics, the term therapy is generally reserved for a product or intervention with demonstrated safety and efficacy -- it is not applied to interventions that are still being investigated, a distinction that is important, given that all gene transfer products are investigational; none has received a Biologic Licensing Application1 (BLA)
|
From page 23... ...
. EARLY EXPERIENCE IN HUMAN GENE TRANSFER RESEARCH In the 1960s, about one decade after the discovery that viruses could transfer genetic material between bacteria, it became apparent that viruses might be used to deliver genes into cells of interest (Wirth and Ylä-Herttuala, 2013)
|
From page 24... ...
Martin Cline attempted gene therapy in two research subjects who had beta thalassemia, a hereditary blood disorder (Jacobs, 1980)
|
From page 25... ...
. In 1995, as gene transfer research progressed, the National Institutes of Health director convened a multidisciplinary panel, co-chaired by Stuart Orkin and Arno Motulsky, to review the field of gene therapy.
|
From page 26... ...
Understandings of Risk and Uncertainty in Initial Gene Transfer Research In the early years of gene transfer research, the members of the scientific community generally agreed that gene transfer research had new risks and contained many uncertainties. Many concerns were also brought to attention by the public involving the potential social and ethical implications of the idea of gene transfer, while scientists articulated scientific uncertainties and technical and safety concerns.
|
From page 27... ...
Theodore Friedmann and Richard Roblin wrote an opinion piece in 1972 in which they opposed attempts at gene therapy in human patients until technical advances were made and regulatory structures were put into place. Referencing Rogers's failed Shope papilloma experiment, Friedmann and Roblin argued that "our understanding of such basic processes as gene regulation and genetic recombination in human cells is inadequate" (Friedmann and Roblin, 1972)
|
From page 28... ...
Very little was known about what might trigger a host's immune response to vectors or to the transgene products or how researchers might mitigate any potential adverse events. CURRENT UNDERSTANDING OF THE SAFETY OF GENE TRANSFER Since the first RAC-approved gene transfer trial in 1988, hundreds of clinical gene transfer trials have been initiated and completed.
|
From page 29... ...
. These technological advances, along with the ever-growing knowledge of molecular virology and virushost cell interactions, have constantly improved the safety profile of viral vectors that are now used in gene therapy.
|
From page 30... ...
. In 2010, clinical trials were initiated using lentiviral vectors to transfer functional genes to young patients with metachromatic leukodystrophy, and 3 of these patients experienced no further disease progression for up to 24 months.
|
From page 31... ...
Three gene therapy products have been approved outside the United States. Two were approved by China's State Food and Drug Administration: Gendicine, which involves a non-replicative virus for squamous cell carcinoma treatment, was approved in 2003; and Oncorine, which delivers genetic material through a conditionally replicative adenovirus to treat nasopharyngeal carcinoma in combination with chemotherapy, was approved in 2005 (Wirth and YläHerttuala, 2013)
|
From page 32... ...
. REMAINING CONCERNS IN GENE TRANSFER RESEARCH Although dramatic advances have taken place regarding the techniques of human gene transfer and mechanisms of action, some gaps in scientific knowledge remain.
|
From page 33... ...
Several characteristics of gene therapy products (as well as cell therapy products) present increased risk for patients, including researchers' relatively limited clinical experience with these therapies, the persistence of the transgene in humans for an extended period after a single administration, the potential to elicit an immune response (immunogenicity)
|
From page 34... ...
was a predicted risk, and although it is not unique to gene transfer, in some cases it presented more problems than expected in clinical studies. In a 2008 trial involving 12 patients with X-linked severe combined immunodeficiency disorder, 4 patients developed vector-induced T-cell leukemia (Aiuti and Roncarolo, 2009)
|
From page 35... ...
. Non-viral vectors are attractive because of their suitability for pharmaceutical considerations such as scale-up, storage stability, and quality control; however, non-viral gene delivery remains prohibitively inefficient for most therapeutic applications (Grigsby and Leong, 2010)
|
From page 36... ...
Whereas the field of gene transfer research was characterized in its early years by considerable uncertainty and concern about theoretical risks -- on the part of the public as well as the scientific community -- this field has matured to a state in which some of the early concerns about risk, and uncertainty overall, have been minimized. With the experience of more than 40 years of gene transfer trials and nearly 1,700 currently approved clinical trials; much has been learned about potential adverse events and how to ensure the safety of research participants.
|
From page 37... ...
2013. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy.
|
From page 38... ...
2013. Guidance for industry: Considerations for the design of early-phase clinical trials of cellular and gene therapy products.
|
From page 39... ...
Human Gene Therapy 24(4)
|
From page 40... ...
2000. Biotechnology on the RAC-FDA/NIH regulation of human gene therapy.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.