S. Al-Zaidy

Gene Therapy for Muscular Dystrophy: Moving the Field Forward

Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive treatments remain the standard of care for Duchenne muscular dystrophy, loss of ambulation, respiratory failure, and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight the therapeutic progress with emphasis on evolving preclinical data and our own experience in completed clinical trials and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field.

Neurological complications of PCR-proven M. pneumoniae infections in children: prodromal illness duration may reflect pathogenetic mechanism

BACKGROUNDnThe spectrum of neurologic disease attributable to Mycoplasma pneumoniae in children is incompletely understood in part because of limitations of microbiologic diagnostic methods. Our objective was to characterize the neurologic complications of M. pneumoniae in children using stringent diagnostic criteria.nnnMETHODSnAll children admitted to the Hospital for Sick Children over a 16-year period with acute neurologic manifestations and polymerase chain reaction (PCR)-confirmed M. pneumoniae infection were eligible for inclusion. Cases were categorized as definite, probable, or possible according to strength of evidence implicating M. pneumoniae. Children with underlying noninfectious neurologic conditions or an alternative infectious cause were excluded.nnnRESULTSnA total of 365 children had M. pneumoniae detected in the cerebrospinal fluid (CSF) or respiratory tract by PCR, 42 (11.5%) of whom had neurologic disease attributable to M. pneumoniae. The most common clinical syndromes were encephalitis (52%), acute disseminated encephalomyelitis (12%), transverse myelitis (12%), and cerebellar ataxia (10%). Two distinct disease patterns were observed, one with a prolonged prodrome (≥7 days), respiratory manifestations, an immunoglobulin M (IgM) response in peripheral blood, and detection of M. pneumoniae in the respiratory tract, but not the CSF, and one with a brief (<7 days) or no prodrome, less frequent respiratory manifestations and IgM response, and detection of M. pneumoniae in the CSF, but not the respiratory tract.nnnCONCLUSIONSnOur findings support the hypothesis of two separate pathogenetic mechanisms for M. pneumoniae-associated neurologic disease, one related to direct infection of the central nervous system and one indirect, likely immunologically mediated.

Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy

Abstract Follistatin is a ubiquitous secretory propeptide that functions as a potent inhibitor of the myostatin pathway, resulting in an increase in skeletal muscle mass. Its ability to interact with the pituitary activin-inhibin axis and suppress the secretion of follicle-stimulating hormone (FSH) called for caution in its clinical applicability. This limitation was circumvented by the use of one of the alternatively spliced follistatin variants, FS344, undergoing post-translational modification to FS315. This follistatin isoform is serum-based, and has a 10-fold lower affinity to activin compared to FS288. Preclinical studies of intramuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. We herein review the evidence supporting the utility of follistatin as a genetic enhancer to improve cellular performance. In addition, we shed light on the results of the first clinical gene transfer trial using the FS344 isoform of follistatin in subjects with Becker muscular dystrophy as well as the future directions for clinical gene therapy trials using follistatin.

Clinical Follow-Up for Duchenne Muscular Dystrophy Newborn Screening: A Proposal.

New developments in the rapid diagnosis and treatment of boys with Duchenne muscular dystrophy (DMD) have led to growing enthusiasm for instituting DMD newborn screening (NBS) in the United States. Our group has been interested in developing clinical guidance to be implemented consistently in specialty care clinics charged with the care of presymptomatically identified newborns referred after DMD‐NBS. We reviewed the existing literature covering patient‐centered clinical follow‐up after NBS, educational material from public health and advocacy sites, and federal recommendations on effective NBS follow‐up. We discussed the review as a group and added our own experience to develop materials suitable for initial parent and primary care provider education. These materials and a series of templates for subspecialist encounters could be used to provide consistent care across centers and serve as the basis for ongoing quality improvement. Muscle Nerve 54: 186–191, 2016

Milder phenotype of congenital muscular dystrophy in a novel POMT1 mutation

Introduction: Congenital muscular dystrophies (CMD) with hypoglycosylated α‐dystroglycan due to POMT1 mutations are associated with clinical phenotypes that vary in severity.Methods: We describe a patient with congenital hypotonia, generalized weakness, elevated creatine kinase (CK), and normal brain imaging. Results: Histochemical analysis of the index cases muscle showed deficiency of glycosylated α‐dystroglycan and secondary merosin deficiency. Genetic testing revealed a novel mutation in exon 20 of the POMT1 gene. Conclusions: Our patients milder form of CMD adds to the emerging evidence of an expanding phenotype caused by POMT1 mutations. The histopathological findings of the muscle biopsy in this case support the need for careful clinical, genetic, and histochemical diagnostic interpretation. Muscle Nerve 45: 752–755, 2012

G.O.25

Becker muscular dystrophy (BMD), a dystrophinopathy with milder skeletal muscle manifestations compared to Duchenne muscular dystrophy, characteristically demonstrates weakness of knee extensors (KE), accompanied by muscle atrophy and fibrosis. The weakness predisposes to gait impairment and loss of ambulation. Myostatin, a member of the TGF-β superfamily of signal peptides, is expressed in skeletal muscle, acting through the activin type IIB (ACTRIIB) receptor. Follistatin, a myostatin antagonist, inhibits this pathway resulting in muscle hypertrophy, and improved muscle strength. FS315 and FS288 are two isoforms of follistatin generated by alternative splicing. FS315 has no cell-surface affinity providing a safety margin avoiding pituitary–gonadal axis complications. FS344 is the precursor cDNA to FS315. When FS344 is delivered to mdx mice in adeno-associated virus (AAV1. CMV. FS344), muscle mass and strength increase. Similar findings are seen in non-human primates without safety concerns. Six BMD patients, 18xa0years and older with proven in-frame DMD gene mutations were enrolled in a clinical trial. The first 3 subjects received 12 intramuscular (IM) injections of AAV1. CMV. FS344 at a total dose of 6e11 vg/kg in the quadriceps muscles bilaterally. A second cohort received the same number of IM injections at higher total dose (1.2e12 vg/kg). Studies extending beyond one year in Cohort 1 and for six months in Cohort 2 showed no adverse events. The distance walked (meters) on the 6-min walk test (6MWT) was the primary functional outcome measure. At one year the distance walked by two subjects in Cohort 1 increased by 125xa0m and 58xa0m; subject 3 improved modestly by 9xa0m. In Cohort 2, one patient reaching the 6-month time point increased by 108 meters. For the entire group of BMD patients only a single patient declined in distance. Preliminary analysis of muscle biopsies favor increased muscle regeneration contributing to improved function.