Preparing for clinical trials: Natural history and outcome measures in autosomal recessive cingulate muscular dystrophies - LGMD2

Coordinator Dott.ssa Grazia D'Angelo
Neuromuscular Unit IRCCS Eugenio Medea, Bosisio Parini
Prof. Giacomo Comi
Dino Ferrari Centre, Department of Pathophysiology and Transplantation University of Milan, Fondazione CA' GRANDA Ospedale Maggiore Policlinico, Milan.
Prof.ssa Elena Pegoraro
Neuromuscular Unit, Department of Neuroscience, University of Padua

Autosomal recessive cingulate muscular dystrophies are a group of heterogeneous diseases typically characterized by progressive muscle weakness and with prevalent involvement of the scapular and pelvic girdle. Although individually very rare, the set of all currently known forms of LGMD2 form an important differential diagnostic group within neuromuscular diseases.

Despite advances in knowledge of pathogenic mechanisms and differential diagnostics, a therapy capable of halting and/or slowing the course of the disease is still lacking.

The only medical therapy available is symptomatic treatment of complications, with the goal of improving expectations and quality of life.

While in Duchenne dystrophy it has been widely demonstrated that steroid therapy improves muscle strength (e.g. via prolongation of autonomous walking) and quality of life (Manzur AY, 2008; MacDOnald G, 2013), in cingulate dystrophies trials to date have proved unsuccessful, such as one carried out on 25 subjects with LGMD2B,dysferlinopathy (Walter MD, 2013).

A placebo-control study involving intravenous administration of MYO-029 (a myostatin-inhibiting antibody designed to stimulate muscle mass growth) was conducted on 116 subjects including some suffering from LGMD2 A (calpain 3 deficiency) and 2I (FKRP deficiency); however, confirmation of the molecule's safety was not associated with a demonstration of efficacy (Wagner MG, 2008).

Other small pharmacological trials have been conducted or are still in progress with Coenzyme Q 10 and Lisinopril (NCT01126697) in different forms of LGMD2, but at the current state of knowledge we are not able to demonstrate a safe efficacy.

The low clinical efficacy of the molecules tested so far was due not only to the intrinsic characteristics of the molecules themselves and to their mechanisms of action, but also to the absence of safe and repeatable measures for evaluating the efficacy of the treatments themselves.

Preclinical studies in animal models (characterized for various forms of LGMD2) will be able to help us understand the pathophysiological mechanisms and identify specific therapeutic targets. Once the targets have been defined in animal models, a "stainless" transition strategy towards clinical application must be developed.

While preclinical studies (in abnormal and cellular models) are an essential element in the development of therapies, this therapeutic development cannot occur without a good understanding of the phenotype and clinical history of each form of LGMD2, the identification of meaningful outcome measures, standard of care guidelines, up-to-date patient registries and, ideally, biomarkers to guide understanding of disease severity or drug response.

The lack of natural histories of disease related to low numbers of diagnosed patients, the absence of standard of care measures (which obviously have an essential role on the natural history of a disease) and the absence of valid and meaningful outcome measures are the obstacles that have most limited the development of clinical trials in LGMD2.

Many of the Italian third level centers dealing with muscular dystrophies of the cingulate have contributed, in recent years, through a TelethonUILDM project (Telethon-UILDM Grant GUP10006) to the collection of a large case series of subjects affected by muscular dystrophies of the cingulate with identification of specific phenotypic characteristics or initial characterizations of outcome measures (Magri F et al.ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases.BMC Neurol. 2015 Sep 24;15:172; Magri F et al . Revised geneticclassification of Limb Girdle Muscular Dystrophies. Curr Mol Med. 2014 Oct 10; Magri F et al. Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients. Neuromuscul Disord. 2012 Nov;22(11):934-43; D'Angelo MG et al.Respiratory pattern in an adult population of dystrophic patients. J Neurol Sci. 2011 Jul 15;306(1-2):54-61; Guglieri M et al.Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mutat. 2008 Feb;29(2):258-66).

The primary aim of our project is to define, on a sample of subjects affected by LGMD2 (especially LGMD2A, calpainopathies), the natural history of the disease through an observation of several years and through this, to identify outcome measures able to define specific moments of the evolution of the disease and / or disease markers, which can define milestones on which potentially, future experimental therapies can go to act.

The clinical data of patients affected by LGMD2 (mainly LGMD2A and LGMD2B )afferent to the various centers will be collected, adequately anominized, according to a mode that provides for the presence of two groups of data:

1) information with anamnestic data definable as Fixed (demographic data, familiarity, time of onset of the pathology; time of clinical diagnosis, genetic diagnosis, characteristics of the muscle biopsy, if performed)
2) information relative to neuromuscular evaluations, cardiac and pneumological evaluations with connected instrumental examinations, haematochemical examinations, functional motor evaluations according to internationally recognised scales/methods, muscular imaging evaluations and other evaluations (e.g. neuropsychological, ophthalmological, otorhinolaryngological, logopaedic) carried out on the patient over the years, of each outpatient/ inpatient access.

It will be first developed a rough model of database in excell version, first platform of comparison, in order to provide a schematic representation of the data and then on the basis of web application designed specifically for "neuromuscular database" already developed at IRCCS E Medea that provides clinical data entry in absolute security for privacy, maintains traceability of users and accesses, and allows in addition to insertion also extrapolation of data both of the individual patient, both groups of patients for detailed analysis.

At present, complete clinical data including anamnestic data, diagnostic data (muscle biopsy, biochemical analysis, genetic analysis) of about 60 patients have been collected; among these 60 patients, at least one complete evaluation including neuromuscular evaluation through internationally recognized scales, cardiorespiratory evaluation through instrumental tests such as electrocardiogram, 24-hour electrocardiogram, echocardiogram, spirometry and oxygen saturation recording, muscular nuclear magnetic resonance) has been recorded and among these 15 patients have evaluations already recorded several times during their life (between 3 and 12 evaluations).

We hypothesize in the next 3 years to be able to collect on a population of at least 80 patients the data of 3 different steps in time, about 12 months apart.

Starting from these data, we hypothesize to be able to identify both outcome measures able to define specific moments in the evolution of the disease and disease markers, which can define milestones on which future experimental therapies can potentially act.

From a strictly medical point of view, such a detailed collection of the natural history of a disease may also provide new indications for a better care of patients and lay the groundwork for the drafting of updated guidelines of "standard of care" for patients with LGMD2.

The data obtained will be disseminated internationally by means of communications at congresses and publications in indexed medical-scientific journals and compared on platforms of meetings at European level (such as ENMC meetings).

Consultancy for young physician-neurologists dedicated part time to clinical data collection

Expenditure on genetic analysis and muscle magnetic resonance studies related to machinery, reagents

Expenses for maintaining and improving the database

Dissemination of collected data, with hypothesis of 2nd International Calpaina 3 conference, conceivable in fall 2017

Dissemination of data collected through publications in indexed journals

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