Sharon Hesterlee - Academia.edu (original) (raw)
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Papers by Sharon Hesterlee
Orphanet Journal of Rare Diseases, 2015
Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and... more Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD.We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme.To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics.Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to market.
New England Journal of Medicine, 2007
Muscle & Nerve, 2007
Current treatment benefits for patients with muscle disease are limited, but progress in legislat... more Current treatment benefits for patients with muscle disease are limited, but progress in legislative and scientific initiatives have set the stage for the development of new therapies. The MD-CARE Act (Public Law 107-84), which allocates federal resources to muscular dystrophy, was approved by Congress and signed into law by the President of the United States in 2001. This has shifted the emphasis toward translational research. To facilitate a push toward therapy for muscle disorders, the Muscular Dystrophy Association (MDA) sponsored a meeting with representatives from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and other government agencies and academia. Each contributed in different ways. The FDA helped define the necessary data to support investigational new drug (IND) applications including the design of proof-of-principle studies, outcome measures for clinical trials, and the pathway for developing surrogate measures for fast-tracking promising new drugs. The NIH, other government agencies, and the MDA described potential funding sources for translational research. Industry delineated a complementary role with academia, and academic investigators elucidated the current strengths and weaknesses of available clinical endpoints. The meeting provided a format for communication for diverse disciplines that usually have no common meeting ground, helping to lay the foundation for bringing products to market in a timely fashion.
The Journal of Comparative Neurology, 2000
The isolated abdominal central nervous system of Manduca sexta undergoes an increase in cyclic GM... more The isolated abdominal central nervous system of Manduca sexta undergoes an increase in cyclic GMP (cGMP) when exposed to the insect peptide eclosion hormone (EH) before pupal ecdysis. Previously, cGMP immunocytochemistry revealed that the EH-stimulated increase in cGMP was contained in numerous filamentous processes within the transverse nerve associated with each abdominal ganglion. These processes seemed to be the axons of neurosecretory cells projecting to this neurohemal organ. In the present paper, we now show that the EH-stimulated cGMP is not present in neurosecretory terminals. There is no colocalization of the EH-stimulated cGMP with immunoreactivity of two peptides, known to be present in axons in the transverse nerves. Furthermore, there is no colocalization of EH-stimulated cGMP with the synaptic vesicle protein, synaptotagmin. The neurosecretory axons are localized to a narrow band at the anterior margin of the transverse nerve, whereas the cellular elements showing an EH-stimulated cGMP increase are primarily present in the posterior region. There are two cell types in this region: a granular and a nongranular type. The cGMP immunoreactivity seems to be contained within the nongranular type. During adult development, the cells of the posterior compartment spread in a thin layer between the transverse and dorsal nerves, become positive for myosin immunoreactivity between pupal stages 5 and 8, and seem to form the adult ventral diaphragm muscles. We conclude that the EH-sensitive filaments in the transverse nerves of Manduca are most likely to be intrinsic cells that subsequently develop into the ventral diaphragm muscles of the adult.
Current Biology, 1996
The discovery of a new insect peptide hormone that triggers ecdysis - shedding of an old cuticle ... more The discovery of a new insect peptide hormone that triggers ecdysis - shedding of an old cuticle - has revealed hidden layers of intricacy about an insect behavior previously thought to be mediated by a single neuropeptide.
Nature, 2012
The US National Institute of Neurological Disorders and Stroke convened major stakeholders in Jun... more The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.
Orphanet Journal of Rare Diseases, 2015
Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and... more Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD.We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme.To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics.Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to market.
New England Journal of Medicine, 2007
Muscle & Nerve, 2007
Current treatment benefits for patients with muscle disease are limited, but progress in legislat... more Current treatment benefits for patients with muscle disease are limited, but progress in legislative and scientific initiatives have set the stage for the development of new therapies. The MD-CARE Act (Public Law 107-84), which allocates federal resources to muscular dystrophy, was approved by Congress and signed into law by the President of the United States in 2001. This has shifted the emphasis toward translational research. To facilitate a push toward therapy for muscle disorders, the Muscular Dystrophy Association (MDA) sponsored a meeting with representatives from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and other government agencies and academia. Each contributed in different ways. The FDA helped define the necessary data to support investigational new drug (IND) applications including the design of proof-of-principle studies, outcome measures for clinical trials, and the pathway for developing surrogate measures for fast-tracking promising new drugs. The NIH, other government agencies, and the MDA described potential funding sources for translational research. Industry delineated a complementary role with academia, and academic investigators elucidated the current strengths and weaknesses of available clinical endpoints. The meeting provided a format for communication for diverse disciplines that usually have no common meeting ground, helping to lay the foundation for bringing products to market in a timely fashion.
The Journal of Comparative Neurology, 2000
The isolated abdominal central nervous system of Manduca sexta undergoes an increase in cyclic GM... more The isolated abdominal central nervous system of Manduca sexta undergoes an increase in cyclic GMP (cGMP) when exposed to the insect peptide eclosion hormone (EH) before pupal ecdysis. Previously, cGMP immunocytochemistry revealed that the EH-stimulated increase in cGMP was contained in numerous filamentous processes within the transverse nerve associated with each abdominal ganglion. These processes seemed to be the axons of neurosecretory cells projecting to this neurohemal organ. In the present paper, we now show that the EH-stimulated cGMP is not present in neurosecretory terminals. There is no colocalization of the EH-stimulated cGMP with immunoreactivity of two peptides, known to be present in axons in the transverse nerves. Furthermore, there is no colocalization of EH-stimulated cGMP with the synaptic vesicle protein, synaptotagmin. The neurosecretory axons are localized to a narrow band at the anterior margin of the transverse nerve, whereas the cellular elements showing an EH-stimulated cGMP increase are primarily present in the posterior region. There are two cell types in this region: a granular and a nongranular type. The cGMP immunoreactivity seems to be contained within the nongranular type. During adult development, the cells of the posterior compartment spread in a thin layer between the transverse and dorsal nerves, become positive for myosin immunoreactivity between pupal stages 5 and 8, and seem to form the adult ventral diaphragm muscles. We conclude that the EH-sensitive filaments in the transverse nerves of Manduca are most likely to be intrinsic cells that subsequently develop into the ventral diaphragm muscles of the adult.
Current Biology, 1996
The discovery of a new insect peptide hormone that triggers ecdysis - shedding of an old cuticle ... more The discovery of a new insect peptide hormone that triggers ecdysis - shedding of an old cuticle - has revealed hidden layers of intricacy about an insect behavior previously thought to be mediated by a single neuropeptide.
Nature, 2012
The US National Institute of Neurological Disorders and Stroke convened major stakeholders in Jun... more The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.