9
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Improving translational studies: lessons from rare neuromuscular diseases

      editorial
      *
      Disease Models & Mechanisms
      The Company of Biologists

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          ABSTRACT

          Animal models play a key role in the development of novel treatments for human disease. This is particularly true for rare diseases – defined as disorders that affect less than 1 in 2000 people in the human population – for which, very often, there are no effective methods of treatment. Pharmaceutical companies are increasingly focussing on the development of therapies for the more than 7000 rare diseases. Because the majority of these are the result of single gene disorders, the exceptional ability to manipulate the mouse genome means that many such studies will take place in the laboratory mouse. But how good are the mouse models and how useful are they in assessing the potential for translational medicine? In this Editorial, I will discuss current difficulties in translational research as well as examples of good laboratory practice and guidelines that are being implemented to improve the translational potential of animal studies in the field of neuromuscular rare diseases. This could represent a potentially useful approach for adoption by other disease fields to achieve a greater success rate in translational studies.

          Abstract

          Drug Discovery Collection: This Editorial reviews problems and some solutions to the translational use of animal models in the rare neuromuscular diseases context. This can serve as a model for other disease fields.

          Related collections

          Most cited references9

          • Record: found
          • Abstract: found
          • Article: not found

          Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

          Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health. We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. Types of studies: randomized controlled trials adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events. One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible. The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31). Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy.

            Although murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin, the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration, fibrosis and severe functional deficit comparable to that of DMD limb muscle, although adult mice show no overt respiratory impairment. Progressive functional changes include reductions in strength (to 13.5% of control by two years of age), elasticity, twitch speed and fibre length. The collagen density rises to at least seven times that of control diaphragm and ten times that of mdx hind-limb muscle. By 1.5 years of age, similar but less severe histological changes emerge in the accessory muscles of respiration. On the basis of these findings, we propose that dystrophin deficiency alters the threshold for work-induced injury. Our data provide a quantitative framework for studying the pathogenesis of dystrophy and extend the application of the mdx mouse as an animal model.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma.

              Duchenne muscular dystrophy (DMD) is the most common, lethal genetic disorder of children. A number of animal models of muscular dystrophy exist, but the most effective model for characterizing the structural and functional properties of dystrophin and therapeutic interventions has been the mdx mouse. Despite the approximately 20 years of investigations of the mdx mouse, the impact of the disease on the life span of mdx mice and the cause of death remain unresolved. Consequently, a life span study of the mdx mouse was designed that included cohorts of male and female mdx and wild-type C57BL/10 mice housed under specific pathogen-free conditions with deaths restricted to natural causes and with examination of the carcasses for pathology. Compared with wild-type mice, both mdx male and female mice had reduced life spans and displayed a progressively dystrophic muscle histopathology. Surprisingly, old mdx mice were prone to develop muscle tumors that resembled the human form of alveolar rhabdomyosarcoma, a cancer associated with poor prognosis. Rhabdomyosarcomas have not been observed previously in nontransgenic mice. The results substantiate the mdx mouse as an important model system for studies of the pathogenesis of and potential remedies for DMD.
                Bookmark

                Author and article information

                Journal
                Dis Model Mech
                DMM
                dmm
                Disease Models & Mechanisms
                The Company of Biologists
                1754-8403
                1754-8411
                1 October 2015
                1 October 2015
                : 8
                : 10 , SUBJECT COLLECTION: MODEL SYSTEMS IN DRUG DISCOVERY
                : 1175-1177
                Affiliations
                Department of Comparative Biomedical Sciences, Royal Veterinary College , London, NW1 0TU, UK
                Author notes

                Dominic Wells is previous Chair (2012-2015) and Core Committee member (2009-2015) of the Treat-NMD Advisory Committee on Therapeutics.

                [* ]Author for correspondence ( dwells@ 123456rvc.ac.uk )
                Article
                DMM022616
                10.1242/dmm.022616
                4610241
                26438690
                1ac1b2ae-aec1-4c4a-bb65-6d72272a5b81
                © 2015. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                Categories
                Editorial

                Molecular medicine
                Molecular medicine

                Comments

                Comment on this article