Advancing Gene-Targeted Therapies for Central Nervous System Disorders Proceedings of a Workshop (2019) / Chapter Skim
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4 Translating Gene-Targeted Therapies from Bench to Bedside
4 Translating Gene-Targeted Therapies from Bench to Bedside
Pages 27-36
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From page 27... ...
. • Natural history studies and patient registries are critical enablers of clinical trial recruitment for life-threatening and rare diseases (Panzara, Sampaio, Vaishnaw)
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From page 28... ...
In his opening remarks for the session on translation, moderator Daniel Burch, global medical officer at PPD Biotech, echoed earlier remarks about the excitement and fast-moving nature of the gene-targeted therapy field, and characterized working in this area during the past few years as "drinking from a fire hose." R Jude Samulski showed videos of two boys with Duchenne muscular dystrophy (DMD)
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From page 29... ...
-enabling studies are exploring the distribution of the conjugates and gene knockdown in particular cell types as well as identifying novel ligands that exert knockdown only in specific cell types within the CNS. While cell models can be useful translational tools, animal models are especially important for CNS disorders, said Anastasia Khvorova.
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From page 30... ...
A second key innovation is the use of Bayesian repeated measure modeling to adapt the trial based on interim dystrophin analyses, said Panzara. Simultaneously, they will develop a Bayesian disease progression model, which will incorporate historical control data and interim biopsy data to predict the probability of success and potentially to adjust enrollment in an ongoing fashion to improve the efficiency of the trial.
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From page 31... ...
Vaishnaw added that appropriate endpoints and biomarkers are particularly difficult to identify for rare diseases for which natural history studies are so difficult. Balancing risks and benefits and establishing minimal effect sizes will also differ depending on other disease-specific factors, such as whether a condition is fatal and debilitating or slowly progressive, said Reape.
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From page 32... ...
Because the treatment requires the presence of viable retinal cells, surrogate markers such as retinal thickness and visual field were used to assess retinal viability, although she noted that those tests do not directly assess retinal function. REGULATORY PATHWAYS Gene therapies fall into the regulatory category of advanced therapy medicinal products, which also includes cell therapies and xenotransplantation, said Peter Marks, director of the Center for Biologics Evaluation and Research (CBER)
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From page 33... ...
For the treatment of CNS disorders, the invasiveness of gene therapy approaches is somewhat more acceptable than for systemic disorders, she said, because of the 20-year history of using deep brain stimulation as a treatment approach for Parkinson's disease (PD) ; however, intravenous delivery would represent a major step forward over intrathecal administration.
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From page 34... ...
Transitioning from First to Second Generation Vectors In January 2019, a statement from Peter Marks and Scott Gottlieb, then FDA Commissioner, predicted that by 2020, FDA would be receiving more than 200 IND applications per year and that by 2025, they would be approving 10 to 20 cell and gene therapy products per year.5 Samulski expressed concern that with this "tsunami of therapeutics" coming forward at a time when the technology is in the midst of a shift from first to second generation technologies, drug developers might be unwilling or 5 Statement from FDA Commissioner Scott Gottlieb, M.D., and Peter Marks, M.D., Ph.D., director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective gene therapies. See https://www.fda.gov/news-events/pressannouncements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd- director-center-biologics (accessed June 5, 2019)
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From page 35... ...
Thus, a major challenge for gene therapy drug development is chemistry, manufacturing, and control, he said, noting that vector production for both non-clinical and clinical vectors is difficult and expensive. Moreover, while relatively small doses are needed for subretinal injections to treat ocular indications, other CNS gene therapies may require much larger doses depending on the delivery method and indication.
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From page 36... ...
36 ADVANCING GENE-TARGETED THERAPIES FOR CNS DISORDERS and contaminating nucleic acids, he said, adding that only a few companies have mastered this process to date. He suggested that the translation of scientific advances made in academic laboratories to commercially manufactured products that help patients could be advanced by developing a set of non-proprietary AAV vectors and a "cookbook" of how to engineer vectors that could transfer easily into proprietary systems.
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