Developing standard procedures for murine and canine efficacy studies of DMD therapeutics: report of two expert workshops on “Pre-clinical testing for Duchenne dystrophy”: Washington DC, October 27th–28th 2007 and Zurich, June 30th–July 1st 2008

Research Center for Genetic Medicine, Children's National Medical Center, Washington DC, USA.
Neuromuscular Disorders (Impact Factor: 2.64). 07/2009; 19(7):502-6. DOI: 10.1016/j.nmd.2009.05.003
Source: PubMed


2.3. Cardiac function readouts and MRI in mdx, GRMD phenotype, preclinical and clinical FDA requirementsChris Spurney outlined the method of cardiac imaging (high frequency echocardiography) that is currently used at CNMC pre-clinical mouse facility. He noted the statistical power of cardiac measurements and the usefulness to non-invasively evaluate cardiac function during therapeutic interventions. He also briefly outlined some of the strategies (e.g., isoproterenol administration) to improve the mdx model to study cardiac function. Andrew Hoey briefly described kyphosis index and effect on thoracic area in normal and mdx mice. He described various cardiac measurements ranging from in vivo (Echo, Millar Catheter, and ECG), in vitro (isolated heart, left atria and electrophysiology) and ex vivo on isolated cardiomyocytes (patch clamp, cell shortening and calcium measurements) and histology (fibrosis) to evaluate cardiac function in the mdx mouse model. Volker Straub described various cardiac evaluation methods (clinical symptoms, MRI, echocardiography and catheterization and histology) and reviewed published literature on this subject. He mentioned that there are several open questions (e.g., when to study cardiac function, which parameter should one assess and which range of cardiac volumes should one use for the assessment) that need to be discussed. He indicated that MRI evaluation has several strengths that include studying distribution of pathology, pathophysiology, monitoring of therapies, assessment of heart and diaphragm, and morphometry. However he noted that there is no bench mark data for mdx mice and no consensus on how to generate and analyze the data. He also briefly described the TREAT-NMD network and principal areas of its activity in Europe and around the world.In the second session of the morning, Laxminarayan Hegde outlined the broad range of preclinical pharmacology evaluation methods and specifically discussed the drug discovery process, the factors influencing druggability of test agents, the role of surrogate endpoints and biomarkers, the predictive power of animal models and physiological endpoints relevant for preclinical drug evaluation using mdx mice. Joe Kornegay described the Golden Retriever Muscular Dystrophy (GRMD) dog model; how this model mirrors human DMD and how the larger size of dogs is advantageous for studying pathogenesis and proof of concept therapeutic studies. He outlined several functional, biochemical, cardiac and respiratory measures that are used to evaluate the GRMD model. Lois M. Freed discussed non clinical FDA requirements, different types of investigational new drug applications such as standard investigational new drug (IND), exploratory IND (Pharmacokinetics, Pharmacodynamics, micro-dosing and mechanism of action) and botanical products/dietary supplements. She highlighted that pediatric indications may need juvenile animal studies (rodent, non-rodent), in which the age of animals at initiation should be appropriate for the study. Furthermore, developmental parameters (e.g., neurobehavioral, reproductive, skeletal) should be considered in evaluating drugs in young animals. Diana Escolar described various steps and planning of human clinical trials for DMD. She noted that proof-of-principle studies are not equivalent to therapeutic preclinical efficacy trials and clinicians input are important from the beginning of the drug development plan. She also outlined several regulatory check points, faster first in man clinical trials, human micro-dosing studies and their utility, exploratory INDs, derivation of starting clinical dose steps and planning early first in human trials. John Porter underlined the need of a rigorous experimental design and of solid efficacy data when studies on animal models are meant for translation to patients. Funding agencies require higher stringency than journal publications because of substantial resources invested. In this view, a consensus on endpoints and success criteria for the tested therapy would be undoubtedly useful.

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Available from: Raffaella Willmann, May 08, 2014
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    • ". The EU funding which allowed the establishment of the TREAT-NMD network has facilitated the development of various tools and resources which aim to advance translational research in NMD. At the preclinical level, standardized operating procedures for animal models and for the conduct of preclinical trials aim to reduce the risks of misinterpretation of animal studies and optimize the molecules heading for clinic [10] [11] "

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    • "Good translation from preclinical to clinical efforts and conducting multinational clinical trials require standardisation of preclinical and clinical tests and infrastructure. TREAT-NMD aimed to address this and TREAT- NMD activities have contributed to the publication of standard operating procedures (SOPs) for the assessment of animal models [2] [3] [4], the establishment of patient registries [5], the formation of a care and trial site registry [6] and the collection of biomaterial for biomarker discovery. Through its website and the close collaboration with patient organisations around the world and the Centre for Disease Control, TREAT-NMD has been instrumental in developing, publishing and disseminating best-practice guidelines for clinical care and management of individuals with DMD [7] [8] [9]. "

    Full-text · Article · Sep 2014 · Neuromuscular Disorders
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    • "Standardized protocols for the assessment of most of the recommended parameters have already been produced by specialized working groups of experts and are reported in brackets (pdfs available on [10]). "
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    ABSTRACT: Duchenne Muscular Dystrophy is an X-linked disorder that affects boys and leads to muscle wasting and death due to cardiac involvement and respiratory complications. The cause is the absence of dystrophin, a large structural protein indispensable for muscle cell function and viability. The mdx mouse has become the standard animal model for pre-clinical evaluation of potential therapeutic treatments. Recent years have seen a rapid increase in the number of experimental compounds being evaluated in the mdx mouse. There is, however, much variability in the design of these pre-clinical experimental studies. This has made it difficult to interpret and compare published data from different laboratories and to evaluate the potential of a treatment for application to patients. The authors therefore propose the introduction of a standard study design for the mdx mouse model. Several aspects, including animal care, sampling times and choice of tissues, as well as recommended endpoints and methodologies are addressed and, for each aspect, a standard procedure is proposed. Testing of all new molecules/drugs using a widely accepted and agreed upon standard experimental protocol would greatly improve the power of pre-clinical experimentations and help identifying promising therapies for the translation into clinical trials for boys with Duchenne Muscular Dystrophy.
    Full-text · Article · Jul 2011 · Neuromuscular Disorders
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