Insect physiology: The emerging story of ecdysis

AbstractThe 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

The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development.

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 15were 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\u27s chances of successfully bringing new rare disease drugs to registration and ultimately to market

The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

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 marke

A call for transparent reporting to optimize the predictive value of preclinical research

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

Identification and characterization of a novel target for eclosion hormone in the tobacco hornworm, Manduca sexta

The insect neuropeptide eclosion hormone (EH) interacts in a positive feedback loop with two other hormones to trigger ecdysis behavior in the hawkmoth, Manduca sexta. There is also evidence that EH may act at other targets to coordinate physiological changes that must occur with ecdysis. Recently, the use of an antibody that recognizes the second messenger cyclic guanosine monophosphate (cGMP) in fixed tissue has allowed us to identify a novel target for EH in the proximal region of the abdominal transverse nerves of Manduca. Here we show that a significant increase in cGMP can be measured in vivo in the transverse nerves at a time when EH is normally released in the animal. Furthermore, in vitro experiments revealed that the ability of the transverse nerve to respond to EH is abruptly lost after the pupal ecdysis. Finally, it was found that up to 40% of the cGMP produced by the STNR in response to EH is exported out of the cells in probenecid-sensitive manner, and there is a significant increase in the hemolymph concentration of cGMP at the time of pupal ecdysis. Microscopic examination of transverse nerve sections revealed that the cGMP-positive filaments are the processes of intrinsic cells, and the area in which they reside was named the subtransverse nerve region (STNR). Ultrastructurally, the cells of the STNR fall into two groups: large-granule containing cells and ribosome rich cells. EH-stimulated cGMP immunoreactivity appears to be restricted to the ribosome rich cells. The discrete STNRs of the abdominal transverse nerves can be identified as early as the first instar and probably originates embryologically. After the time of wandering in the last instar, the cells of the STNR begin to divide and spread in a flat sheet between the transverse and dorsal nerves of each ganglion, and are positive for myosin by pupal stage 8. These STNR-derived cells appear to form the ventral diaphragm muscles of the adult. This is the first evidence in any insect that a reservoir of myoblasts exists in close proximity to the transverse nerves and the first evidence that myoblasts are a target for EH

Challenges in drug development for muscle disease: a stakeholders' meeting

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

Gene therapy as a potential therapeutic option for Duchenne muscular dystrophy: A qualitative preference study of patients and parents.

ObjectivesDuchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that causes progressive weakness and early death. Gene therapy is an area of new therapeutic development. This qualitative study explored factors influencing parents' and adult patients' preferences about gene therapy.MethodsWe report qualitative data from 17 parents of children with DMD and 6 adult patients. Participants responded to a hypothetical gene therapy vignette with features including non-curative stabilizing benefits to muscle, cardiac and pulmonary function; a treatment-related risk of death; and one-time dosing with time-limited benefit of 8-10 years. We used NVivo 11 to code responses and conduct thematic analyses.ResultsAll participants placed high value on benefits to skeletal muscle, cardiac, and pulmonary functioning, with the relative importance of cardiac and pulmonary function increasing with disease progression. More than half tolerated a hypothetical 1% risk of death when balanced against Duchenne progression and limited treatment options. Risk tolerance increased at later stages. Participants perceived a 'right time' to initiate gene therapy. Most preferred to wait until a highly-valued function was about to be lost.ConclusionParticipants demonstrated a complex weighing of potential benefits against harms and the inevitable decline of untreated Duchenne. Disease progression increased risk tolerance as participants perceived fewer treatment options and placed greater value on maintaining remaining function. In the context of a one-time treatment like gene therapy, our finding that preferences about timing of initiation are influenced by disease state suggest the importance of assessing 'lifetime' preferences across the full spectrum of disease progression

Patient Engagement Practices in Clinical Research among Patient Groups, Industry, and Academia in the United States: A Survey

<div><p>Objective</p><p>Patient-centered clinical trial design and execution is becoming increasingly important. No best practice guidelines exist despite a key stakeholder declaration to create more effective engagement models. This study aims to gain a better understanding of attitudes and practices for engaging patient groups so that actionable recommendations may be developed.</p><p>Methods</p><p>Individuals from industry, academic institutions, and patient groups were identified through Clinical Trials Transformation Initiative and Drug Information Association rosters and mailing lists. Objectives, practices, and perceived barriers related to engaging patient groups in the planning, conduct, and interpretation of clinical trials were reported in an online survey. Descriptive and inferential statistical analysis of survey data followed a literature review to inform survey questions.</p><p>Results</p><p>Survey respondents (n = 179) valued the importance of involving patient groups in research; however, patient group respondents valued their contributions to research protocol development, funding acquisition, and interpretation of study results more highly than those contributions were valued by industry and academic respondents (all p < .001). Patient group respondents placed higher value in open communications, clear expectations, and detailed contract execution than did non–patient group respondents (all p < .05). Industry and academic respondents more often cited internal bureaucratic processes and reluctance to share information as engagement barriers than did patient group respondents (all p < .01). Patient groups reported that a lack of transparency and understanding of the benefits of collaboration on the part of industry and academia were greater barriers than did non–patient group respondents (all p< .01).</p><p>Conclusions</p><p>Despite reported similarities among approaches to engagement by the three stakeholder groups, key differences exist in perceived barriers and benefits to partnering with patient groups among the sectors studied. This recognition could inform the development of best practices for patient-centered clinical trial design and execution. Additional research is needed to define and optimize key success factors.</p></div

Supplementary Material - TIRS716715_Supplement_S1 - Assessing the Financial Value of Patient Engagement: A Quantitative Approach from CTTI’s Patient Groups and Clinical Trials Project

<p>Supplementary Material - TIRS716715_Supplement_S1 - Assessing the Financial Value of Patient Engagement: A Quantitative Approach from CTTI’s Patient Groups and Clinical Trials Project by Bennett Levitan, Kenneth Getz, Eric L. Eisenstein, Michelle Goldberg, Matthew Harker, Sharon Hesterlee, Bray Patrick-Lake, Jamie N. Roberts, and Joseph DiMasi in Therapeutic Innovation & Regulatory Science</p