Francesco Muntoni

Professional background

I am a paediatric neurologist with an interest in clinical and molecular aspects of neuromuscular disorders in children. I have worked in London since 1993, initially at the Hammersmith Hospital/Imperial College London where I was the Director of the Dubowitz Neuromuscular Centre (DNC) from 1996. In 2007, I moved together with the entire academic team and the clinical services associated with the DNC to the Institute of Child Health (ICH) and Great Ormond Street Hospital (GOSH). The DNC is the largest academic paediatric Neuromuscular Centre in UK and in 2001 was designated by the Nationally Commissioning Group as the reference centre for the clinical, pathological and genetic aspects related to congenital muscular dystrophies and congenital myopathies.

Regarding my contribution to research, in collaboration with other groups in Europe and USA, we have established very effective networks which allowed the identification of a number of disease loci and genes involved in neuromuscular disorders (14 different disorders in collaboration with external collaborators). My own group identified 2 novel disease genes (FKRP and LARGE).

Manipulation of splicing as a therapeutic strategy for neuromuscular disorders

I am interested in the regulation of splicing, and in collaboration with Prof Ian Eperon, we are working on exon inclusion in spinal muscular atrophy using tailed oligonucleotides (TOES).

Since 2005, I have been working as the Principal Investigator of the MDEX Consortium on two clinical trials focused on assessing the safety and efficacy of antisense oligonucleotides (molecular patches) for inducing exon skipping in Duchenne muscular dystrophy boys. At the end of 2008 we have completed the first part of this study, the intramuscular part, and showed that this approach is effective and well tolerated in boys affected by Duchenne muscular dystrophy who would benefit from the skipping of exon 51 (see Q&A section). In 2008, we have obtained regulatory authorisation to perform a systemic study using the same molecular patch in a group of younger boys with Duchenne muscular dystrophy. Recruitment for this study which will be performed in London and in Newcastle has started in early 2009. The study of the splicing in the muscle biopsies of treated children will be performed in the DNC.

Relevant references

Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford E, McCulley C, Poppwell L, Graham I, Dickson G, Wood M, Wells DJ, Wilton S, Holt T, Kole R, Straub V, Bushby K, Sewry CA, Morgan JE, Muntoni F. Local Restoration of Dystrophin Expression in Duchenne Muscular Dystrophy: A Single Blind, Placebo-controlled Dose Escalation Study Using Morpholino Antisense Oligomer AVI-4658. Lancet Neurol. 2009 8(10):918-28 

Arechavala V, Graham I, Adams A, Popplewell L, Aartsma-Rus A, Kinali M, Morgan J, van Deutekom J, Wilton S, Dickosn G, Muntoni F. Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Human GeneTherapy, 2007; 18(9):798-810 

Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach-Faller N, Rudnik-Schoneborn S, Blaschek A, Wolf NI, Harting I, North K, Smith J, Muntoni F, Brockington M, Quijano-Roy S, Renault F, Herrmann R, Hendershot LM, Schroder JM, Lochmuller H, Topaloglu H, Voit T, Weis J, Ebinger F, Zerres K. Mutations in SIL1 cause Marinesco-Sjogren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet. 2005 37(12):1312-4 

Budde BS, Namavar Y, Barth PG, Poll-The BT, Nürnberg G, Becker C, van Ruissen F, Weterman MA, Fluiter K, T Te Beek E, Aronica E, van der Knaap MS, Höhne W, Toliat MR, Crow YJ, Steinlin M, Voit T, Roelens F, Brussel W, Brockmann K, Kyllerman M, Boltshauser E, Hammersen G, Willemsen M, Basel-Vanagaite L, Krägeloh-Mann I, de Vries LS, Sztriha L, Muntoni F, Ferrie CD, Battini R, Hennekam RC, Grillo E, Beemer FA, Stoets LM, Wollnik B, Nürnberg P, Baas F.; tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nature Genetics, 2008 Sep;40(9):1113-8

Skordis LA, Dunckley MG, Yue B, Eperon IC, Muntoni F. Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4114-9.

Neri M, Torelli S, Brown S, Ugo I, Sabatelli U, Merlini L, Spitali P, Rimessi P, Gualandi F, Sewry CA, Ferlini A, Muntoni F. Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscular Disorders, 2007; Dec;17(11-12):913-8.

Muntoni F, Wells D. Genetic treatments in muscular dystrophies. Current Opinion in Neurology, 2007; 20(5):590-4.

Muntoni F, Bushby K, vanOmmen GJ. 149th ENMC International Workshop and 1st TREAT-NMD Workshop on: "Planning phase I/II clinical trials using systemically delevered antisense oligonucleotides in Duchenne muscular dystrophy". Neuromuscula Disord. 2008; Mar;18(3):268-75.

Links

http://www.ich.ucl.ac.uk/ich/academicunits/dubowitzneuro muscular centre/Homepage

http://www.cnmd.ac.uk/

http://clinicaltrials.gov/ct/show/NCT00159250

Ongoing Relevant Research Support

2005-2008 Department of Health: MDEX Consortium. A 4 years phase l/ll intramuscular clinical trial of antisense oligonucleotides in DMD: Muntoni, PI

2005-2009 Welcome Trust: Correcting splicing: development of therapies based on targeted oligonucleotide enhancers of splicing: Muntoni & Eperon, PIs

2007-2011 Medical Research Council & AVI BioPharma: Mdex Consortium . A phase l/ll clinical trial in DMD using systemically delivered antisense oligonucleotides. Muntoni, PI

2008-2011 Muscular Dystrophy Campaign: Centre Grant to the combined Dubowitz and Institute of Neurology Neuromuscular Centre: Muntoni, PI Hanna & Reilly, co-PIs

2007-2012 EU FP6: TREAT-NMD Network of Excellence in Neuromuscular Disorders: Muntoni, collaborator, Bushby, PI

2008-2010 Gavriel Meier Trust: Antisense oligonucleotides to restore the reading frame in Duchenne patients with out-of-frame duplications: part of MDEX Consortium (Wells & Wilton)

2008-2013 Medical Research Council: Centre grant for London & Newcastle for Neuromuscular disease: Hanna, PI, Muntoni, co-PI and London Centre co-director

Contact details:
Professor Francesco Muntoni, FRCPCH, FMedSci
Professor of Paediatric Neurology
Head of the Dubowitz Neuromuscular Centre
1st Floor, UCL Institute of Child Health
30 Guilford Street
London WC1N 1EH
Tel: 020 7905 2111
Fax: 020 7905 2832
Email: This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

updated: 09.02.09