Table 1.
DMD therapies under development. Several strategies have been employed to further develop the different types of therapies (specific strategy), which are in different stages of research, either clinical or pre-clinical (research stage and selected models). A brief summary of the results of these strategies is mentioned (results of therapy) with selected references. IV: Intravenous; IM: intramuscular; IP: intraperitoneal.
| Therapy | Specific Strategy | Research Stage and Selected Models | Results of Therapy | Selected References |
|---|---|---|---|---|
| Utrophin up-regulation | Utrophin transgene | Preclinical—mdx/utrn−/− | Transgenic utrophin expression which improved pathology in skeletal muscle, but not heart. | [107,108,109] |
| Zinc fingers | Preclinical—cultured cells, mdx muscle | Successful activation of utrophin improved muscle function and reduced pathology in TA. No heart data. | [110,111,112] | |
| Biglycan | Preclinical—mdx | Localizes utrophin to sarcolemma. Treatment reduced pathology in quadriceps and diaphragm and improved physiology in EDL. No heart data. | [113] | |
| SMT C1100 | Preclinical—mdx; Clinical trials—Phase Ia and Ib |
Preclinically: increased RNA and protein of utrophin in skeletal and cardiac muscle. Reduced pathology and improved muscle function in skeletal muscle. Phase Ia: mild side-effects at higher dose. Phase Ib: no data. | [114,115] | |
| Read-through therapy | Gentamicin | Preclinical—mdx; Clinical trials—Phase I | Preclinically: Low levels of dystrophin expression, including in heart, protection against muscle damage in EDL. Clinical trials: inconclusive. | [116,117] |
| Negamycin | Preclinical—mdx | Antibiotic drug to reduce side effects seen in gentamycin. Subcutaneous injections negamycin safer than gentamycin, but induced low dystrophin expression in skeletal muscle and heart. | [118] | |
| PTC124 | Preclinical—HEK293 cells and mdx; Clinical trials—Phase I, 2a/b |
Preclinically: 20%–25% increase in dystrophin in TA, diaphragm and heart. Improved physiological function of EDL. Clinical trials: Generally well tolerated. Overall no significant improvement, but certain subgroups responded well to treatment. | [119,120,121,122] | |
| RTC13/RTC14 | Preclinical—mdx | RTC13 demonstrated better efficacy (restored dystrophin in skeletal muscle and heart) than gentamicin, PTC124 and RTC14. Improved muscle function and decreased serum CK. | [123] | |
| Viral gene therapy | Lentivirus | Preclinical—myotubes, primary myoblasts and mdx | Transfection with mini- or microdystrophin: 20%–25% dystrophin expression in TA muscles (for 2 year period). Less central nucleation, but no protection from muscle injury. Able to transfect TA myogenic progenitor cells. | [124,125,126] |
| ‘Gutted’ adenovirus | Preclinical—mdx | IM with full dystrophin cDNA displayed dystrophin expression, improved muscle force and protected against muscle damage. | [127] | |
| rAAV2/AAV8 | Preclinical—mdx | Chimeric vector containing codon-optimized micro-dystrophin. IV injection resulted in almost 100% transfection, effective dystrophin expression in skeletal muscle and heart and improved muscle function. No immunological response was observed. | [128] | |
| rAAV6 | Preclinical—mdx/utrn−/− and mdx | Microdystrophin rAAV6 administered in 1 month old mdx/utrn−/− increased life span, improved pathology and dystrophin (1 year post-injection). Dystrophin restored in heart and heart mass normal, but function not recovered. 20 mo mdx (4 months after injection) showed dystrophin expression in skeletal muscle and heart and improved pathology. | [129,130] | |
| AAV9 | Preclinical—GRMD and mdx | IV mini-dystrophin administration to GRMD revealed varied dystrophin expression, also in heart. Micro-dystrophin administration in young mdx induced dystrophin expression and slowed progression of cardiac phenotype. 10 mo mice expressed dystrophin and cardiac function improved. | [131,132,133] | |
| Cell-based therapy | Myoblasts | Preclinical—mdx Clinical trials |
Ability to differentiate into myotubes. Preclinically: partial dystrophin expression in mdx mice. No heart data. Clinical trial: no beneficial effects |
[134,135] |
| Fibroblasts | Preclinical—mdx | Ability to differentiate into myotubes. Effective transfection with dystrophin expression in immunocompromised mice. No heart data. |
[136] | |
| Bone marrow-derived stem cells | Preclinical—mdx and GRMD | Migrate to damaged muscle areas, differentiate into myogenic cells and aid regeneration. Substantial dystrophin restoration in skeletal muscle of mdx, but no restoration in GRMD dogs. No heart data. | [137,138] | |
| Cd133+ stem cells | Preclinical—scid/mdx; Clinical trial Phase I |
Ability to differentiate into myocytes. Preclinically: effective dystrophin restoration in scid/mdx. No heart data. Clinical trial demonstrated safety. |
[139,140] | |
| Mesangio-blasts | Preclinical—GRMD | Improved functional mobility and partial dystrophin restoration in skeletal muscle. No heart data. | [141] | |
| iPS cells | Preclinical—immuno-compromised mdx | Differentiating iPS cells into muscle precursor cells followed by injection into TA induced dystrophin expression. Cells integrated with muscle cells and settled in satellite cell population. Improved TA function. No heart data. | [142,143,144] | |
| Antisense oligonucleo-tides | 2′O MePS | Preclinical—mdx; Clinical trial Phase III |
Preclinical: IM revealed low dystrophin restoration, even with multiple high doses. Clinical: 6 mg/kg was maximal tolerated dose in patients. Phase III trial did not meet 6MWD endpoint. | [145,146,147,148] |
| PMO | Preclinical—mdx; Clinical trial Phase IIb |
Preclinical: repeat IV administrations of high dose restored dystrophin in multiple skeletal muscles of the mdx mouse, <2% in heart. Clinically: well tolerated and dystrophin present after 48 weeks. At 84 weeks stabilization in the 6MWD; 120 weeks stabilized pulmonary function. | [149,150,151,152,153] (Sarepta press release, February 2014) | |
| Tricyclo-DNA | Preclinical- mdx | Multiple IV administrations and very high doses (200 mg/kg per week) resulted in dystrophin in skeletal muscle and heart, with low levels in the brain and improvements in cardiac and pulmonary function. | [154] | |
| Octa-guanidium conjugated PMO | Preclinical- mdx and GRMD | Capable of restoring dystrophin in skeletal muscle and hearts of mdx mice. This has further been demonstrated in dystrophic dogs. High doses led to adverse events in GRMD. | [155,156] | |
| CPP-AOs- Arginine rich | Preclinical—mdx and mdx/utrn−/− | (RXR)4 multiple IP produced ~100% dystrophin in diaphragm and low levels in skeletal muscles. Single IV restored dystrophin in skeletal muscle and diaphragm, ~50% in the heart. Improved mortality rate and corrected kyphosis in mdx/utrn−/−. (RXRRBR)2: Less toxic, repeat and high dose IV illustrated impressive exon skipping notably in heart (72%). Improvements in cardiac function, with preserved diastolic function after 6 months | [157,158,159,160,161,162,163,164] | |
| CPP-AOs- Pips | Preclinical—mdx | Pip2a and Pip2b: strong exon skipping following IM. Following IV, Pip5e induced high dystrophin restoration body wide including heart. Pip6-PMO series: Pip6a, Pip6b and Pip6f exhibited best dystrophin expression in heart. Long-term IV administration prevented deterioration in heart function in the event of exercise. | [165,166,167] | |
| CPP-AOs- Phage Peptides | Preclinical—mdx | MSP enhanced in vivo skeletal and cardiac muscle binding capacity. B-MSP-PMO showed 2–5 fold improvement in skeletal muscle compared to B-PMO (no dystrophin in heart). T-9 (SKTFNTHPQSTP) specificity in mdx quad and improved specificity over MSP. 12-mer phage resulted in ~25% dystrophin expression in skeletal muscle (75 mg/kg). A 7-mer phage conjugated to 2′OMePS resulted in exon skipping in multiple tissues including heart and diaphragm. |
[168,169,170,171,172]. |