MRC Centre for Translational Research in Neuromuscular Disease
UCL Institutes of Neurology and Child Health
Post: Clinical Research Associates x 2 posts
Grade: UCL CL7
Reports to: Professor Francesco Muntoni, Professor of Paediatric Neurology, UCL Institute of Child Health and MRC Centre Co-Director
Accountable to: Professor Mike Hanna, MRC Centre Director
Overview of the Posts:
The MRC Centre for Neuromuscular Diseases is a partnership between the UCL Institutes of Neurology and Child Health, and Newcastle University, and is a recognised centre of excellence for clinical research training and education in neuromuscular diseases. For more information on the MRC Centre and its partners please visit http://www.cnmd.ac.uk/. Both posts will be primarily based at the UCL Institute of Child Health.
The MRC Centre for Neuromuscular Diseases was funded by an MRC Centre grant award in 2008, which was renewed in 2013. It is the largest clinical and research centre in the UK for patients with muscle wasting diseases such as muscular dystrophy, inclusion body myositis and peripheral neuropathy. The MRC Centre is closely linked with the National Hospital Adult Centre for Neuromuscular Diseases, and the paediatric Dubowitz Neuromuscular Centre at Great Ormond Street Hospital. The joint paediatric and adult neuromuscular activities are recognised as a Muscular Dystrophy Campaign centre of clinical and research excellence. There is also major support from the Department of Health through National Specialist Commissioning for three of its specialist services in congenital muscular dystrophy and myopathies, muscle channel diseases, McArdle disease and mitochondrial diseases. This direct funding now amounts to over £2 million per annum.
These posts provide an exciting opportunity and are suitable for adult and paediatric neurology, paediatrician or genetic trainees interested in neuromuscular disease. Applicants should hold GMC registration and MRCP or equivalent, and be intending to pursue a career in academic adult / paediatric neurology or genetics. Excellent organisational and IT skills, the ability to act independently, and a very high level of patient care are also required. The posts will provide excellent training opportunities to broaden clinical and research skills (including next generation sequencing and the use of antisense therapies, cellular and animal models, detailed phenotyping of patients) and acquire experience of clinical trials. The applicants are expected to pursue a higher degree and generate publications. There are two posts available, and both posts will have both a laboratory component as well as a clinical component. The exact breakdown of these components can be discussed with the individual applicants as there is flexibility.
Examples of potential projects on offer include:
1. Developing anti sense oligonucleotide (AO) therapies for a range of inherited neuromuscular diseases.
Experimental use of AOs in neuromuscular conditions is progressing very rapidly. Most of the experience is on Duchenne muscular dystrophy (DMD): in the years between 2007 and 2013 eight clinical trials using AOs to induce exon skipping in DMD have been performed and two more studies initiated. Many of these have been done by Professor Muntoni’s group at ICH targeting exon 51 [Kinali et al, Lancet Neurol. 2009 Oct;8(10):918-28.; Cirak et al, Lancet. 2011 Aug 13;378(9791):595-605.])[ Cirak et al, 2011; Mendell 2013]. Francesco Muntoni currently leads an EU funded consortium developing antisense therapies for DMD boys who can benefit exon 53 skipping (http://www.skip-nmd.eu/).
AOs are also being used in other inherited neuromuscular diseases. Recently ISIS Pharmaceutics completed a phase I study of another AO administered intrathecally in spinal muscular atrophy (SMA) due to SMN1 mutations; a phase II study with multiple repeated doses in the same condition is currently underway (http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1902404&highlight=); and a phase III study will commence in 3Q2014.
There are also a large number of other inherited neuromuscular diseases that AO therapies may be suitable for AO therapies including some of the inherited neuropathies.
The project is aimed at the further development, design and preclinical testing of AO therapies to other neuromuscular diseases.
2. Duchenne muscular dystrophy secondary to DMD mutations leading to loss of the reading frame; deep clinical / genomic phenotyping to improve stratification for experimental trials.
The clinical course of Duchenne muscular dystrophy (DMD) is however variable, with some children losing the ability to walk at six years of age, and others at twelve. Improved understanding of the determinants of the observed variability will be helpful to better understand disease pathogenesis, improve delivery of personalised medical care and stratify DMD patients recruited in future clinical trials.
In this study we will take advantage of the established Paediatric North Star Network (http://www.ucl.ac.uk/ich/research-ich/dubowitz/clinical-networks) and link it to adult neuromuscular centres involved in the care of adults with DMD. We will collect validated clinical outcome measures (North Star functional scale; 10mwalk test; Gower’s manoeuvre, 6minWalkTest; Forced Vital Capacity; cardiac ejection fraction) and information on medication (corticosteroid medication; cardiac protective medications). This information will be correlated to information on DNA for genomic SNP profiling of a number of previously identified genes considered to affect disease severity. We will correlate these SNPs with a. yearly functional decline; b. age at loss of ambulation; c. age at respiratory failure; d. severity of cardiomyopathy.
The outcome of this study will help the planning of clinical management (for example cardiac surveillance) and will affect design of clinical trials and interpretation of ongoing studies. These include clinical trials on antisense oligonucleotide therapies; and randomised cardiac protection and steroid therapy in DMD.
3. Functional and molecular consequences of dystrophin deficiency in Duchenne and Becker muscular dystrophy patients
Dystrophin deficiency is responsible for Duchenne (DMD) and Becker (BMD) muscular dystrophies, two allelic conditions. Dystrophin is absent or present in trace amounts in DMD, while BMD patients produce reduced levels of a shortened protein, due to intragenic in-frame deletions. Dystrophin deficiency makes muscle more susceptible to exercise induced damage and triggers a complex series of events that include inflammatory changes, regeneration and eventually substitution of muscle by connective tissue. Animal model (mdx mouse) studies have identified the time course of the dynamic activation of the different pathological pathways, but limited information on the contribution of these processes at different timepoints is available in D/BMD. Recent studies suggest that circulating miRNA are dysregulated in mdx mice and in D/BMD, provide insight on specific cellular events and offer a promising opportunity to look into the different stages of the dystrophic disease progression and correlate it with the primary biochemical defect. To obtain further insight on D/BMD pathophysiology we will correlate the time course of miRNA expression in a large series of D/BMD patients stratified on the basis of their amount of dystrophin protein expression. Effect of muscle exercise on muscle damage will also be studied in a subset of patients.
4. 4.
Identification and functional characterisation of novel disease genes responsible for neuromuscular disorders
Paediatric neuromuscular disorders are a heterogeneous group of conditions, due to mutations of > 100 genes. Currently approximately 30% of paediatric neuromuscular patients have mutations in unknown genes.
With this study we intend to use clinical, pathological and muscle imaging features to identify homogeneous group of patients in whom to perform whole exome sequencing (WES).
This project is part of a wider collaborative project on WES in neuromuscular disorders, which led in 2012 and 2013 to the identification of seven novel genes for neuromuscular disorders, all now published. We currently have additional possible novel genes that require further characterisation as they might represent novel disease genes. Furthermore, we would like to characterise further the function of recently identified genes responsible for novel neuromuscular diseases.
Responsibilities
1. Clinical
1.1. To undertake, subject to honorary clinical contract, outpatient neuromuscular clinics in Great Ormond Street Hospital or at the National Hospital for Neurology and Neurosurgery. A DBS check will be required for the award of an honorary clinical contract.
2. Teaching and R&D
2.1 To provide ad-hoc teaching for doctors, nurses, medical students, other healthcare
professionals and external organisations in both formal and informal settings.
2.2 To maintain study folders in line with guidance from R&D Department.
2.3 To acquire the knowledge and skills essential for effective research governance.
3. Management
3.1 To ensure the highest standard of record keeping, maintaining accurate and appropriate patient records, including the strict confidentiality of all records.
3.2 To attend Departmental and other meetings, as appropriate.
4. Professional
4.1 To act at all times in accordance with the highest professional standards, and to ensure that these are maintained in the delivery of all aspects of patient care.
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.2 To ensure that he/she is covered, at all times, by appropriate medical indemnity.
5. General
5.1 As duties and responsibilities change, the job description will be reviewed and amended in consultation with the post holder.
5.2 The post holder will carry out any other duties as are within the scope, spirit and purpose of the job as requested by the line manager.
5.3 The post holder will actively follow UCL policies, including Equal Opportunities policies.
5.4 The post holder will maintain an awareness and observation of Fire and Health & Safety Regulations.
Person Specification
Essential Criteria
· Registered Medical Practitioner
· Completed general medical training
· MRCP or equivalent
· Resourceful and able to act on own initiative
· Excellent organisational skills
· Exceptional inter-personal skills with an ability to work co-operatively in a multidisciplinary setting
· A very high level of consideration and care for patients and research subjects
· Interested in research and a commitment to quality in the research process
· Interest in neuromuscular diseases
Desirable Criteria
· Experience in paediatric or adult Neurology / genetics at SHO or equivalent level
· Experience of clinical / translational research
· Experience of neuromuscular diseases
· Excellent presentation and teaching skills
· Understanding of research methodology
· Experience of computing (database, word processing, statistics, email)
Appointment
The posts are available from October 2014, and are funded for three years in the first instance. There will be flexibility with the start date. It will be offered subject to satisfactory references, satisfactory completion of a probationary period of nine months, and health clearance by the Occupational Health Department.
Starting salary on the UCL CL7 scale £34,163 per annum including London Allowance. The appointment is superannuable under the Universities’ Superannuation Scheme (USS) or, subject to eligibility, the National Health Service Pension Scheme (NHSPS).
Annual Leave: 41 days per annum (27 days’ annual leave + 6 UCL ‘closure days’ + 8 public holidays)
Hours of Work: 36.5 per week
Applications
You should apply for this post through UCL’s online recruitment - www.ucl.ac.uk/hr/jobs - where you can download a full job description and person specification.
For queries relating to the application process, please contact Samantha Robinson, Personnel Officer, UCL Institute of Neurology, Queen Square, London WC1N 3BG (email: )