Duchenne muscular dystrophy (DMD) is a severe progressive muscle wasting disorder. DMD is caused by reading frame disrupting mutations in the DMD gene resulting is an absence of the dystrophin... Show moreDuchenne muscular dystrophy (DMD) is a severe progressive muscle wasting disorder. DMD is caused by reading frame disrupting mutations in the DMD gene resulting is an absence of the dystrophin protein. Dystrophin is an important muscle protein as it provide stability upon muscle fiber contraction. Currently there is no therapy for the majority of the DMD patients. As part of the standard of care patient receive symptomatic treatment e.g. corticosteroids, respiratory and cardiac support. Various therapeutic approached are currently under development. Most advanced therapeutic approach is aimed to restore dystrophin production by using antisense oligonucleotides (AON): exon skipping. This thesis focusses on delivery of AON to skeletal and cardiac muscle for DMD. With the help of phage display technology combined with next generation sequencing analyses, muscle homing peptides have been identified. In this thesis is described how for the first time these homing peptides upon conjugation to a 2OMePS AON resulted in increased delivery and exon skipping in a mouse model for DMD. In Conclusion, muscle homing peptides have the potential to facilitate delivery of AONs and perhaps other compounds to skeletal and cardiac muscle. Show less
Hooijmans, M.T.; Niks, E.H.; Burakiewicz, J.; Anastasopoulos, C.; Berg, S.I. van den; Zwet, E. van; ... ; Kan, H.E. 2017
In this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in... Show moreIn this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in muscle of DMD patients with a semi-quantitative method. Dixon MRI showed to be more sensitive to subtle changes. Implementation of a multipeak model to account for multiple lipid spectrum peaks in this method allowed even more sensitive measurements. We evaluated non-contractile and contractile cross-sectional areas in leg muscles of DMD patients. Combined with strength measurements we could measure muscle quality and showed muscle hypertrophy and fatty infiltration to be two distinct processes. We explored the relation between dystrophin levels and fat in BMD patients and found no such relation, but did find a relation between strength and age in a subgroup, demonstrating the location of the mutation to be a major determinant of disease severity. Using T2 MRI as inflammatory marker in DMD/BMD patients and healthy controls we showed an increased T2 in DMD patients. Finally we investigated the muscle energy metabolism in BMD patients with MRS and showed increased PDE/ATP ratios prior to onset of fatty infiltration, consequently 31P MRS could be another potential outcome parameter. Show less
