Pharmacological advances for treatment in Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of dystrophin, essential for muscle fibre integrity. Despite extensive pre-clinical studies, development of an effective treatment has proved challenging. More recently, significant progress has been made with the first drug approval using a genetic approach and the application of pharmacological agents which slow the progression of the disease. Drug development for DMD has mainly used two strategies: (1) the restoration of dystrophin expression or the expression of the compensatory utrophin protein as an efficient surrogate, and (2) the mitigation of secondary downstream pathological mechanisms. This review details current most promising pharmacological approaches and clinical trials aiming to tackle the pathogenesis of this multifaceted disorder.

Dystrophin Dp116: A yet to Be Investigated Product of the Duchenne Muscular Dystrophy Gene

“…Utrophin is an autosomal homologue of dystrophin, suggesting that utrophin expression may compensate for dystrophin deficiency in the treatment of DMD [28]. In contrast to dystrophin, only one short isoform of utrophin has been well characterized to date.…”

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

“…Treatments aimed to ameliorate secondary mechanisms associated with dystropathology are principally directed to reduce inflammation and oxidative stress, these being predominant mechanisms in dystrophic muscle milieu. To date, the standard of care for DMD utilizes anti-inflammatory glucocorticoids including prednisone and deflazacort, which have been recently approved [3,110]. With a general effect on inflammatory response, steroids have been proven to prolong the ambulatory ability of DMD patients with a modest improvement of muscle strength and cardiopulmonary function [3].…”

“…To date, the standard of care for DMD utilizes anti-inflammatory glucocorticoids including prednisone and deflazacort, which have been recently approved [3,110]. With a general effect on inflammatory response, steroids have been proven to prolong the ambulatory ability of DMD patients with a modest improvement of muscle strength and cardiopulmonary function [3]. Although short-term clinical trials reported beneficial effects of corticosteroids, a chronic administration revealed a heterogeneous tolerance and response to treatment together with important side effects [111].…”

“…The progressive muscle degeneration leads to loss of ambulation at 8-12 years with premature death due to cardio-respiratory failure [2]. The genetic causes of the disease are "out of frame" deletions (68%), duplications (11%), and small mutations (20%) in the dystrophin gene, the largest known gene with the highest spontaneous mutation rates in humans [3,4]. These alterations of the translational reading frame result in a dysfunctional or absent dystrophin protein with critical consequences for muscle tissue integrity.…”

Clinical Utility Gene Card for: Becker muscular dystrophy

“…calcium dysregulation) downstream of the deficiency of normal dystrophin in DMD may also prove to be helpful for BMD [44]. Prognosis (please describe)…”