Functional significance of dystrophin positive fibres in Duchenne muscular dystrophy.

Abstract

The age when boys lose the ability to walk independently is one of the milestones in the progression of Duchenne (usually <1%) or very weak labelling on a much higher proportion (about 25%). The mean age at loss of mobility among the DMD patients with no dystrophin labelling on tissue sections was 7 9 years (range 63-9 5) while the mean age among those with some labelling was 9'9 years (range 8*0-11-9); this is a significant difference. Quantitative estimates of dystrophin abundance were obtained from densitometric analysis of dystrophin bands on blots. In the whole group of 36 patients, a significant positive relationship was found between the abundance of dystrophin and the age at loss of independent mobility. It is concluded that even the very low concentrations of dystrophin found in DMD patients may have some functional significance.

Dystrophin as a therapeutic biomarker: Are we ignoring data from the past?

“…Over twenty years ago, low-level dystrophin expression in DMD patient muscle was reported [12][13][14], and Nicholson and colleagues hypothesized that dystrophin in DMD muscle could result from exon skipping [12]. Gangopadhyay et al [13] found up to 10-12% of normal dystrophin levels in DMD patients with deletions of exons 3-7, but no evidence of framerestoring exon skipping.…”

“…However, the validity of such markers as surrogate indicators of dystrophin presence and functionality, and their utility in evaluating emerging therapies for DMD is unproven. Furthermore, the ability of surrogate biomarkers to discriminate therapy-mediated benefits from those due to variable (low) levels of endogenous dystrophin, frequently detected in DMD muscle [12,36], remains questionable at this time.…”

“…Although at this time, the amount of dystrophin needed to confer clinical benefits remains uncertain, it is evident that low levels of dystrophin expression can mitigate disease progression [12].…”

“…Although the Nicholson study [12] [19] could potentially be used to monitor dystrophin expression and function, but will need to be further evaluated. An additional limitation of dystrophin detection in muscle biopsies is that the sample may not reflect the expression pattern in other muscles, and furthermore, quantification of dystrophin expression on sections can be problematic.…”

“…Because of the well-documented detection of dystrophin in DMD muscle [12][13][14], it is reasonable to expect that the use of dystrophin as a treatment biomarker should require analysis of base-line expression. The sensitivity of current immunofluorescent quantification methods [20,21] should allow reproducible fold-change quantification at even low levels of baseline expression, but whether dystrophin expression is measured by western blotting or by immunohistochemistry techniques, it is logical that fold changes and not fractional increases in dystrophin production above baseline will be needed to ameliorate disease progression in DMD.…”