We are accepting candidatures for PhD students enthusiastic about finding cures for neuromuscular diseases or willing to explore and learn gene therapy technologies using models of neuromuscular diseases. PhD candidates should hold at least an upper second-class honours degree (or equivalent) in a relevant area. Candidates with experience in molecular biology or with an interest in human diseases are particularly encouraged to apply.
The Gene Medicine Laboratory for Rare Diseases is focused on finding new treatments for muscle pathologies. We use gene therapy technologies to target molecular defects in pre-clinical models of rare neuromuscular diseases such as Duchenne muscular dystrophy (DMD), Oculopharyngeal muscular dystrophy (OPMD) and Facioscapulohumeral muscular dystrophy (FSHD).
DMD is a rare neuromuscular condition affecting ~1:2500 newborn boys. It is due to mutations on a gene called dystrophin and children affected by this muscle wasting disease are confined in a wheelchair in their teens, need ventilation shortly after and generally die due to respiratory or cardiac failure in their mid-thirties. We have been working on using antisense strategies and gene therapy applications to treat this disease and brough to the market one of the few medicines currently approved by the Food and drug administration (Vyondys53). We also generated a viral vector derived gene therapy agent that is currently in clinical trial in France and UK (GNT0004).
OPMD is a rare neuromuscular disease affecting ~1:100000 adults. It is due to mutations to Poly-A binding protein nuclear 1 gene coding for a PABPN1, a protein involved in many crucial biological pathways. Adults are generally diagnosed in their mid-fifties and experience muscle weakness, drooping of the upper eyelids muscles (ptosis) and difficulty in swallowing (dysphagia). Late in life, proximal limbs are also affected leading to substantial reduction in mobility. We have recently developed a gene therapy application that can be used for the local treatment of pharyngeal muscles and that is now in clinical trial in US and Canada. We are currently optimizing better therapies that can be used for systemic administration so that the proximal limbs weakness can also be treated.
FSHD is a relatively common hereditary autosomal dominant disease with an estimated prevalence of 5 to 13 per 100,000. FSHD affects muscles in the face, shoulder girdle and upper arms, and often extends to the trunk and lower limbs as the disease progresses causing about 20% of patients becoming wheelchair bound. Although life expectancy is normal, over 90% of FSHD patients experience chronic fatigue. Aberrant expression of the double homeobox 4 (DUX4) gene has been suggested as a predominant cause of FSHD pathogenesis as this gene expresses a protein able to affect several biological pathways. Targeting DUX4 has great potential in providing a cure for the disease and we and others have developed several approaches to suppress DUX4 expression or its downstream activity.
We work with national and international academics and with Industry partners to develop therapeutic agents that have potential for clinical translation based on:
Antisense oligonucleotides (AO) to induce exon skipping or to increase gene expression
siRNA/shRNA therapeutics to silence gene expression;
Gene replacement approaches based on viral (Adeno-associated virus and Lentivirus) and non-viral vectors;
Gene editing applications to correct genetic defects or to modify transcriptional processes;
Pharmacological agents that can improve the dystrophic pathology and that can have additive or synergistic effects when combined with gene therapy applications.
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