Idebenone as a Novel Therapeutic Approach for Duchenne Muscular Dystrophy

Abstract

Progressive loss of pulmonary function leads to early morbidity and mortality in Duchenne muscular dystrophy (DMD) due to both expiratory impairment with ineffective airway clearance, and inspiratory impairment leading to nocturnal and daytime hypoventilation and respiratory failure. Glucocorticoid steroids have become a mainstay of DMD therapy with well-documented efficacy on muscle strength and respiratory function. However, the side-effect profile restricts their long-term use, particularly in non-ambulant patients. Idebenone improves secondary mitochondrial dysfunction caused by dystrophin deficiency, intracellular calcium accumulation and increased reactive oxygen species (ROS). Idebenone-mediated improved bioenergetics leads to enhanced adenosine triphosphate (ATP) production and reduced ROS. Based on this rationale, idebenone has been investigated clinically for efficacy on reducing respiratory function decline in exploratory phase II (DELPHI) and confirmatory phase III (DELOS) trials. Idebenone significantly reduced the loss of respiratory function in 8-18-year-old DMD patients who were not using concomitant glucocorticoids. These results indicate that idebenone can modify the natural course of respiratory disease progression in DMD, which is relevant in clinical practice where loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD. KeywordsDuchenne muscular dystrophy, idebenone, respiratory function, peak expiratory flow, glucocorticoid steroid 1,2 increase quality of life and life expectancy, the disease is still associated with early morbidity and mortality. In DMD, progressive weakness of the chest wall muscles precedes weakness of the diaphragm (used predominantly for inspiratory function) and leads to restrictive lung volume changes measured as reduced total lung capacity and forced vital capacity (FVC). [3][4][5][6][7] Initially, this loss of lung volume results from the inability to pull up the respiratory system to total lung capacity and to push it down to residual volume. In later disease stages, additional restrictions occur as a result of progressing muscle fibrosis and changes in lung and chest wall recoil, thoracic wall compliance and spinal deformities (i.e. scoliosis).In the late first decade the earliest signs of respiratory impairment manifest by reduced static airway pressures (maximal expiratory and inspiratory pressures). The gradual loss of respiratory function in DMD measured by spirometry usually begins early in the second decade and progresses to restrictive pulmonary syndrome, impaired respiratory secretion clearance, life-threatening pulmonary infections due to ineffective cough, nocturnal and daytime hypoventilation, obstructive apnoeas and eventually respiratory failure during the late second or third decade of life. 3,[8][9][10]

Longitudinal pulmonary function testing outcome measures in Duchenne muscular dystrophy: Long-term natural history with and without glucocorticoids

“…In the Mc-Donald et al [30] study, boys 10-20 years of age who were not on GC showed a decline in FVC of 8.5%/year. Similarly, in a placebo arm of a clinical trial, FVC%p declined 8.7% in a largely non-ambulant cohort of glucocorticoids non-treated patients with mean age of 15.0 ± 2.5 [9,38] . Hahn and colleagues studied 7-25 year olds and measured a 7.9% decline [39] .…”

“…FVC, and PEFr may be reliably measured in DMD patients older than age 6 [4][5][6] . Measurement of pulmonary function in DMD including spirometry, static airway pressures and their relationship to diaphragmatic and chest wall weakness and fibrosis has been reviewed in detail elsewhere [6][7][8][9] .…”

Long-term data with idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy

“…Idebenone, a synthetic short-chain benzoquinone, improves mitochondrial function, restores ATP production and catalytically reduces reactive oxygen species, thereby addressing the muscle cell damaging consequences of dystrophin deficiency (as reviewed in [12] ). Idebenone showed a cardio-protective effect and improved exercise performance in the dystrophin-deficient mdx mouse model of DMD [13] .…”

Utrophin influences mitochondrial pathology and oxidative stress in dystrophic muscle

“…Consequently, the development of antioxidants for the treatment of DMD has been a substantial line of research with numerous compounds investigated, e.g. coenzyme Q 10 , catalase, green tea extract, Epigallocatechin gallate, BN82270, Idebenone, melatonin and N-acetylcysteine [ 14 , 43 – 49 ]. Mitochondrial Ca 2+ overload is known to promote ROS generation and membrane permeability in healthy muscle [ 13 , 50 ].…”