P.13.12 An objective method for immunofluorescence analysis of dystrophin levels in muscle from DMD patients in clinical studies

Beekman, C.; Testerink, Janwillem; Giannakopoulos, Stavros; Kreuger, D.; Sipkens, Jessica A.; Deutekom, J. van; Campion, G.; Kimpe, S. de; Lourbakos, Afrodite

doi:10.1016/j.nmd.2013.06.606

Cited by 3 publications

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“…before exon 8) have been found to have a more benign disease course, probably because a subset of these patients can produce very low amounts of dystrophin due to spontaneous exon skipping or the use of alternative initiation sites (Flanigan et al, 2009). Indeed, patients involved in an exon 44 skipping trial showed higher dystrophin levels at baseline than patients involved in exon 51 skipping trials (Beekman et al, 2013).…”

Section: Outcome Measuresmentioning

confidence: 99%

Translational and Regulatory Challenges for Exon Skipping Therapies

et al. 2014

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Several translational challenges are currently impeding the therapeutic development of antisensemediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures and different forms of approval was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology (COST) Action "Networking towards clinical application of antisense-mediated exon skipping for rare diseases" (www.exonskipping.eu). The workshop included participants from patient organisations, academia and members of staff from the European Medicine Agency and MEB. This statement paper contains the key outcomes of this meeting.

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Section: Outcome Measuresmentioning

confidence: 99%

Translational and Regulatory Challenges for Exon Skipping Therapies

et al. 2014

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“…In the past it was always assumed that muscle fibers from DMD patients did not produce dystrophin, aside from the occasional revertant fibers. However, with more sophisticated microscopes, cameras and detectors it has now become apparent that almost all fibers from DMD patients express trace amounts of dystrophin [28,36] and [29](unpublished observation C Beekman and A Lourbakos, Prosensa Therapeutics, Leiden, the Netherlands (2013)). The levels of these trace amounts vary between fibers and between patients and generally patients will also have revertant fibers where dystrophin is expressed at high levels.…”

Section: Standardization Of Dystrophin Quantification In Clinical Trialsmentioning

confidence: 99%

“…Notably, after treatment of patients in the phase 2 dose regimen study with drisapersen, a shift towards higher dystrophin intensities could be observed in the majority of post-treatment samples compared to pre-treatment fibers [37]. Furthermore, a 30% increase in intensities was observed for post-treatment samples vs pre-treatment samples from patients involved in the phase 2a trial with PRO044 for exon 44 skipping [36](unpublished observations, C Beekman and A Lourbakos, Prosensa Therapeutics, Leiden, the Netherlands (2013)). The method also revealed higher intensities for spectrin in DMD and BMD samples than healthy samples (unpublished observations, C Beekman and A Lourbakos, Prosensa Therapeutics, Leiden, the Netherlands (2013)).…”

mentioning

confidence: 94%

“…They also observed variation in dystrophin levels between fibers from different muscles from one individual (lowest in tibialis anterior and highest in gastrocnemius, 30% difference)(unpublished observations, C Beekman and A Lourbakos, Prosensa Therapeutics, Leiden, the Netherlands (2013)). Furthermore, (very) low levels of dystrophin ("trace amounts") can be detected for most DMD patients, while intermediate levels were found for BMD patients [36]. Like for healthy muscle, dystrophin intensities varied between fibers for BMD and DMD patients (up to three-fold) (unpublished observations, C Beekman and A Lourbakos, Prosensa Therapeutics, Leiden, the Netherlands (2013)).…”

mentioning

confidence: 96%

“…A third method is currently in use by Prosensa Therapeutics ("Lourbakos method") and was presented at the World Muscle Society meeting 2013 [36] and has been submitted for publication (unpublished observations, C Beekman and A Lourbakos, Prosensa Therapeutics, Leiden, the Netherlands (2013)). Biopsy quality was assessed by hematoxylin and eosin staining, which was also used to evaluate freezing artefacts and muscle quality (relative amount of fibrotic and adipose tissue).…”

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confidence: 99%

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Dystrophin Analysis in Clinical Trials

Aartsma‐Rus

2014

Journal of Neuromuscular Diseases

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Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease with unmet medical need. The disease is caused by mutations that disrupt the open reading frame of the dystrophin protein that is required to maintain muscle fiber stability during contraction. Lacking dystrophin patients' muscle fibers are continuously damaged eventually leading to replacement of muscle tissue by fibrotic and adipose tissues and loss of muscle function. Many therapeutic approaches aiming at dystrophin restoration are in development, and some have been or are being tested in clinical trials. For these approaches, showing dystrophin restoration or increased dystrophin expression could serve as a pharmacodynamic biomarker to confirm mechanism of action. This review provides an overview of methods currently in use to assess dystrophin in clinical trial muscle biopsies and discusses challenges of dystrophin quantification and using dystrophin as a biomarker in clinical trials.

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Families’ experiences with medical research for pediatric rare diseases : a qualitative ethnographic study of parents and children participating in clinical trials for Duchenne muscular dystrophy (DMD)

Condin¹

2014

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P.13.12 An objective method for immunofluorescence analysis of dystrophin levels in muscle from DMD patients in clinical studies

Cited by 3 publications

References 0 publications

Translational and Regulatory Challenges for Exon Skipping Therapies

Translational and Regulatory Challenges for Exon Skipping Therapies

Dystrophin Analysis in Clinical Trials

Families’ experiences with medical research for pediatric rare diseases : a qualitative ethnographic study of parents and children participating in clinical trials for Duchenne muscular dystrophy (DMD)

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