The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism

Evaluating the diagnostic and prognostic value of cardiac biomarkers for heart disease and major adverse cardiac events in patients with muscular dystrophy

Abstract Background Heart disease is recognized as the leading cause of morbidity and mortality in patients with muscular dystrophy (MD). Validating and testing for heart disease in this vulnerable cohort of patients will allow for early cardiac interventions, monitoring, and improved outcomes. Purpose To evaluate the diagnostic and prognostic value of baseline B-type natriuretic peptide (BNP) and high-sensitive troponin I (hsTnI) for cardiomyopathy and major adverse cardiac events (MACE), respectively, in patients with MD. Methods A prospective cohort study was conducted at our clinic following 117 patients [median age, 42 years (interquartile range [IQR], 26–50); 49 (41.88%) women] diagnosed with a dystrophinopathy, limb-girdle MD, type 1 myotonic dystrophy, or facioscapulohumeral MD. Patients received multifaceted care as part of the multidisciplinary pathway allowing for a complete assessment of patient clinical status. Cardiac assessment included physical exam and electrocardiogram as well as subsequent echocardiogram and cardiac magnetic resonance imaging. Receiver operating curves and corresponding Youden's Indices were utilized to assess the diagnostic abilities of the biomarkers and for subsequent derivation of hazard ratios (adjusted by patient demographics and diagnosis of cardiomyopathy and respiratory disease) for incidence of MACE (defined as the composite of arrhythmia, device implantation, cardiac-related hospitalization, incident heart failure, and cardiac-related mortality). Results At baseline, 35 (29.91%) patients were diagnosed with a cardiomyopathy. B-type natriuretic peptide was an effective diagnostic marker of cardiomyopathy with an area under the curve (AUC) of 0.64 (95% confidence interval (CI), 0.52–0.76; P=0.017), as was hsTnI (AUC, 0.69 [95% CI, 0.58–0.80]; P=0.001). In combination, BNP and hsTnI showed additive diagnostic ability for cardiomyopathy [AUC: 0.72 (95% CI, 0.61–0.83); P&amp;lt;0.001]. Over a median follow-up period of 2.09 years (IQR, 1.17–2.81) there were 36 confirmed MACE. Patients were stratified based on cutoff values of BNP and hsTnI established a priori defined as 30.50 pg/mL and 7.61 ng/L, respectively. Patients with BNP levels above the cutoff value had a 4.76-fold (95% CI, 2.13–10.65; P&amp;lt;0.001) greater risk of MACE than patients with BNP levels below. Patients with hsTnI levels above the cutoff value had a 3.98-fold (95% CI, 1.96–8.12; P&amp;lt;0.001) greater risk of MACE than patients with hsTnI levels below. Importantly, patients with biomarker levels above both cutoff values had a 5.28-fold (95% CI, 2.42–11.51; P&amp;lt;0.001) greater risk of MACE than patients with biomarker levels below both cutoffs. Conclusion Our study demonstrates that by including measures of BNP and hsTnI as part of a comprehensive cardiac assessment, the diagnosis of cardiomyopathy and prognostication of MACE can be improved in patients with MD. Risk Stratification of MACE Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): University Hospital Foundation, University of Alberta </jats:sec

Gene transfer to skeletal muscle using hydrodynamic limb vein injection: current applications, hurdles and possible optimizations

International audienc