“Therapeutic Targets in the CMDs” Conference, July 9-11, 2009
Dr. Sebahattin Cirak
During his pediatric training at the University Hospital Essen (Germany) under the supervision of Dr. Thomas Voit, Dr. Cirak discovered two new CMD genes: a novel form of CMD caused by mutations in Nesprin-1 and a new genetic locus at chromosome 7. He also discovered a gene, KLHL9 that leads to distal myopathy. His expertise is in genome wide mapping using microsatellite markers and SNPs including linkage analysis. During his pediatric training, Dr. Cirak gained extensive experience in the diagnosis and care of neuromuscular disorders and in muscle pathology.
Currently Dr. Cirak works at the Dubowitz Neuromuscular Centre in London where the team is currently working to find the missing genes for the unclassified CMDs using positional cloning at chromosome 7p21 and chromosome 1q42 loci. Dr. Cirak is assisting with the development of a CMD Chip for fast and effective CMD diagnosis and CMD gene discovery. Together with the team, he is working to characterize CMD natural history progression. He is also responsible for the execution of two important Duchenne muscular dystrophy trials: PTC124 and systemic exonskipping, under the supervision of Prof. Francesco Muntoni.
Dr. Cirak’s aim is to bridge clinic to translational research, as a qualified pediatrician and chemist, targeting the development of treatment strategies for CMD.
Dr. Jacintha Rooney
Dr. Rooney is currently working in Dr. Dean Burkin’s lab at the University of Nevada. Her initial research began with the understanding that the absence of α7 integrin leads to congenital myopathy in mice and humans. To elucidate the role of the α7β1 integrin in maintaining skeletal muscle integrity, she generated mice deficient for both dystrophin and α7 integrin (mdx/α7-/-). These animal models display severe signs of muscular dystrophy caused in part by a reduced capacity for muscle repair. Cardiotoxin injection in α7β1-/- mouse muscle was found to induce a severe and prolonged muscle injury with impaired activation of satellite cells. Laminin-111 treatment was found to significantly improve the regenerative capacity in the α7-/- muscle.
In further studies, she identified laminin-111 as a novel protein-based treatment for DMD. A single systemic dose of laminin-111 was found to successfully stabilize mdx skeletal muscle and to reduce muscle degeneration, suggesting that laminin-111 could be a very potent therapy for DMD. This work demonstrated for the first time that delivery of laminin-111 protein successfully prevents muscle disease in dystrophic mice and suggests that laminin-111 may be a highly potent, novel protein therapeutic for all MD patients and suggests that systemic delivery of extracellular matrix molecules represents a novel paradigm for the treatment of many genetic diseases.
Currently, she is greatly excited to be investigating the effectiveness of laminin-111 in the dyw mouse model of laminin-deficient CMD.
Jamie Marshall (4th year PhD student)
Since she was little, Jamie Marshall has dreamt of working on something that would make a direct impact on society and help improve the lives of others. After receiving her basic training in genetics, molecular biology, and stem cell biology of the fruit fly as an undergraduate student, she decided to switch fields. Jamie is currently a 4th year PhD student in Dr. Rachelle Crosbie’s lab at UCLA.
Her current research focuses on the development of methods to modulate protein glycosylation as a means to alleviate dystrophy. Working with Dr. Linda Baum’s group, Dr. Crosbie’s lab has used high throughput screening to identify compounds that increase glycosylation. Jamie is currently characterizing the effects of sarcospan on protein glycosylation and the UGC.
Dr. Alessia Angelin
Dr. Angelin began her work on mitochondrial physiology and apoptosis as an undergraduate student in 2002 in the Professor Paolo Bernardi’s lab. She defended her PhD thesis on the role of mitochondria in the pathogenesis of Ullrich Congenital Muscular Dystrophy (UCMD) in 2007.
Her current focus in on pathogenic mechanisms that involve the mitochondrial permeability transition pore in human collagen VI related muscular dystrophies and the identification of possible molecular targets for pharmacologic therapy.
Dr. Angelin has studied the pathogenic mechanism of UCMD using physiological assays (mostly microscopy) and biochemical techniques. She has analyzed biopsies and myoblasts obtained from UCMD patients with different genetic defects of the COL6 genes and variable clinical presentations, and identified increased apoptosis, mitochondrial morphological alterations and functional dysfunctions in muscle tissue. These defects could be normalized using cyclosporin A (CsA), a cyclophilin inhibitor that desensitizes the PTP, or Debio025, a CsA analogue that is devoid of immunosuppressive activity. She contributed to a pilot clinical trial with CsA in UCMD patients and demonstrated the efficacy of the treatment by the normalization of mitochondrial dysfunction, decrease of apoptotic rates and increased muscle regeneration. Bethlem Myopathy (BM) is a milder but more common form of disease caused by COLVI deficiency and it represents a continuous clinical spectrum with UCMD. Dr. Angelin is working to establish whether mitochondria are also involved in the pathogenesis of BM.
Dr. Sandrine Arbogast
Dr. Arbogast currently works in Dr. Ana Ferreiro’s lab at the Institute of Myology in Paris. After obtaining her PhD, she worked in Dr. Reid’s lab studying the biologic importance of redox-active signalling molecules (reactive oxygen speciies and nitric oxide derivatives) as regulators of skeletal muscle function. She is particularly interested in CMD associated with mutations in the SEPN1gene. Her recent findings demonstrate that selenoprotein N plays a key role in redox homeostasis and that oxidative/nitrostative stress is a primary pathogenic mechanism in SEPN 1. These findings pave the way for a SEPN 1 pharmacologic treatment.
