Emerging drugs for Duchenne muscular dystrophy

Abstract

Introduction: Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile.

Areas covered: Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings.

Expert opinion: Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis and decreasing oxidative stress. Additional targets include inhibiting NF-κB to reduce inflammation or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect.

Figure 1

Oxidative and NF-kB pathways are highly interactive in DMD muscle collaborating to produce muscle fiber necrosis. Macrophages generate inflammatory cytokines and reactive oxidative species (ROS) are the direct consequence of dystrophin deficiency and membrane instability. The illustration shows a macrophage with activated NF-κB leading to secretion of pro-inflammatory molecules, TNF-α, IL-1 & IL-6. A dystrophic muscle fiber shows reactive oxygen species generated by multiple insults to the muscle fiber: 1) Ca²⁺ influx through muscle membrane related to membrane fragility leads to Ca²⁺ overload in the mitochondria and energy deficiency; 2) increased NADPH oxidase activity known to accompany dystrophin deficiency adds to ROS generation which in turn stimulates stretch-activated channels (SAC) resulting in Ca²⁺ entry into muscle fiber further contributing to mitochondrial dysfunction; 3) ROS exacerbates the dystrophic pathology by peroxidation of the lipid bilayer of the muscle membrane. ROS provokes the NF-κB signaling pathway leading to production of TNF-α and other cytokines. Moreover, TNF-α produced by activated macrophages enhances NF-κB activation in the muscle.

Figure 2

The left side of the figure depicts activation of NF-κB occuring only in the presence of a fully assembled IKK complex composed of 3 catalytic subunits: IKKα and IKKβ that bind to the regulatory subunit IKKγ, also known as NEMO. Following a stimulus for activation of NF-κB by inflammatory cytokines like TNF-α the intact IKK complex promotes phosphorylation and degradation of IkB proteins, which in turn unmasks a nuclear localization signal permitting NF-κB translocation to the nucleus and subsequent transcription of cytokine and chemokine genes that enhance the inflammatory process. The consequences of adding NEMO binding domain (NBD) peptide (red) are depicted. NBD is an 11 amino acid peptide that binds to the c-terminal region of both IKKα & IKKβ inhibiting the formation of active IKK complex. Consequently, downstream signaling events are blocked.

Figure 3

The role of different isoforms of nNOS, namely nNOSµ and nNOSβ in skeletal muscle, is illustrated. Two binding sites of nNOSµ can be seen: at the dystrophin rod domain and at α-syntrophin (a member of dystrophin-glycoprotein complex). NO derived from nNOSµ enhances blood flow to muscle during activity by preventing vasoconstriction of nearby blood vessels during muscle contraction; the increased blood flow is a source of oxygen supply to the muscle during exercise. In contrast, nNOSβ signaling at the Golgi complex regulates force generation during and after exercise generating cGMP dependent protein kinase G (PKG). (Adapted with permission of the American Society for Clinical Investigation from Percival et al. 2010 [117]). Abbreviations: nNOS- nitric oxide synthase; BV-blood vessel; aDG-alpha-dystroglycan; b-DG- beta-dystroglycan; NO- nitric oxide; Syn –syntrophin; GTP- guanosine triphosphate; sGC- soluble guanylyl cyclase; cGMP- cyclic guanosine monophosphate