New treatment opportunities in genetic neuromuscular disorders

Administrator: Haluk Topaloglu , Hacettepe University, Turkey

Professor Yoram Nevo
Chair, Institute of Neurology, Schneider Children's Medical Center of Israel
nevoyoram@gmail.com
Establishing and maintaining an active site for clinical trials
We live in exiting era where new genetic therapies change the course of the disease in previously untreatable neurological disorders. Multicenter clinical trials provide mandatory pathway to study the safety and efficacy of these therapies. In this presentation I will describe the requirements and the process of establishing and maintaining an active site for clinical trials. Participating in clinical trials is a demanding but rewarding process for both patients and families as well as for the staff. It enables the children to receive early on new therapies but occasionally raises ethical issues such as decision between alternative therapies or possible treatment with placebo. High expectations may be associated with severe disappointment. For clinical trials dedicated personnel including primary and sub investigators, coordinators, evaluators as the core staff is required. In addition, multidisciplinary team should be available including nurses, social workers, consultants in hematology, nephrology, gastroenterology and others. The facility in the hospital should be adapted and equipped for different studies and tests. IRB (Helssinki committee) evaluation for children is often meticulous and may require national in addition to local approval. The time duration until actual recruitment and between studies may be prolonged and funding for the activity should be reassured. 

Professor Haluk Topaloglu
Yeditepe University, İstanbul
htopalog@hacettepe.edu.tr
Antisense oligonucleotides in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy 
The two most advances are for DMD and SMA. Ataluren has now been approved by several countries. This is a mutation specific therapy (“stop codon read through”), affecting approximately 15% of the DMD population, and is an oral molecule. It is considered as a ‘disease modifying molecule’. Other therapeutic approaches currently tested in clinical trials include: mutation-specific strategies aiming to correct the underlying genetic cause of the disease (e.g. exon skipping). Eteplirsen is an antisense-oligonucleotide to skip exon 51 of the DMD gene. It is available on the market, however with reservations related to efficacy. Other anti-sense oligonucleotide drugs in the pipeline are Casimersen for exon 45, Golodirsen for exon 53, and Suvodirsen for exon 51 skipping, respectively. Among these Viltolarsen has been in the forefront with a backbone publication.. For SMA, the main aim is to be able to obtain more SMN protein transcripts from the SMN2 gene. Currently, we have two options. The first one is nusinersen, a molecule that prevents alternative splicing out of exon 7 of the SMN2 gene at the mRNA level so that more transcript is yielded. So, this is an exon inclusion. This molecule has been in practice since the end of 2016, and is recognized globally. So far more than 11,000 patients from all types of SMA has recevied or actively ongoing as a regimen. In SMA I, babies younger than 6 months old are expected to benefit better. 

Associate Professor Nicolas Chrestian
Centre Mère-Enfant-Soleil CHU de Québec
nicolas.chrestian.1@ulaval.ca
Gene therapies in neuromuscular disorders: pros and cons
Over the last decade, the neuromuscular therapeutic landscape evolved dramatically. Onasemnogene abeparvovec was the first Adenovirus associated virus (AAV) strategy proved efficient and safe for spinal muscular atrophy (SMA). The AAV9 therapy changed the natural history of the disease but also the management of patient with neuromuscular disorders.
Other AAV based-therapies are in the pipeline and could be applied for neuromuscular disorders particularly a large group of muscular dystrophies. Great hopes are emerging with the minidystrophin approach for Duchenne muscular dystrophie (DMD). Combining these therapies with a structured newborn screening we could see in a near future a generation of children living without significant disabilities or burden related to a neuromuscular disorder. Still, gene therapies are carrying increased responsibilities and potential serious adverse reactions, some can be potentially lethal. Among these potential side effects, there is an increasing concern about immune response. Recent therapeutic trials were on hold concerning Myotubular myopathy, DMD and even SMA due to severe adverse reactions. These situations raised the question of how to handle these new therapies, how protocols need to be structured, how to manage serious side effects and potential immune reaction. 

Assocşate Professor Jiri Vajsar
Division of Neurology, Department of Pediatrics The Hospital for Sick Children
jiri.vajsar@sickkids.ca

Emerging treatments in other genetic neuromuscular disorders
New therapies and treatment trials are ongoing in patients with FSHD, X-linked myotubular myopathy and glycogen storage disorders. In X-linked myotubular myopathy, there is an ongoing trial with AT132, an AAV8 vector containing a functional copy of the MTM1 gene. It has provided patients with significantly improved outcomes based on the ability of AAV8 to target skeletal muscle and increase myotubularin expression in targeted tissues following a single intravenous administration. New investigational treatment in FSHD is with losmapimod, an orally active, selective, small molecule inhibitor that reduces aberrant DUX4 protein activity and is a potential disease modifying treatment in FSHD. Phase 2b randomized, double-blind, placebo controlled multicenter study of losmapimod has been completed and an open label extension study is ongoing. In Pompe disease, Enzyme replacement therapy (ERT) is an approved treatment for all patients. It involves the intravenous administration of recombinant human acid alpha-glucosidase (rhGAA). However, these patients are not fully cured and residual symptoms remain. Improvements to the industrial rhGAA currently used for ERT are being explored.