Table 1.
Highlights of Promising Therapeutic Strategies.
| Strategy | Pros | Cons | Specific Therapy | Pre-Clinical/Clinical Results | Refs |
|---|---|---|---|---|---|
| 1. In vivo gene correction | If stem cells are repaired this may be a true cure. Mutation independent |
May cause off-site mutations.Safe delivery to all muscle cells is not yet perfected. | SRP-9001. rAAV-rh74 delivery of micro-dystrophin, 1 injection. | NCT03375164, 03769116, 04626674. Patients had long-term gene expression and phenotype improvements. Phase 3 is now recruiting. Some patients developed antibodies to the virus. | [5,6] |
| Pf-06939926. rAAV9 delivery of mini-dystrophin, 1 injection, 2 doses. | NCT0336502, NCT04281485, NCT05429372. Patients had gene expression, and an average 3.5-point increase in the NSAA score. A total of 40% of patients experienced vomiting and/or nausea. Phase 3 trial on hold due to a patient’s death. | [7] | |||
| SGT-001, rAAV9 delivery of micro-dystrophin, 1 injection, 2 doses. | NCT03368742. Variable dystrophin expression. Phenotype improvement in 6MWT and NSAA scores. Many severe adverse effects; liver and kidney injuries. | [8] | |||
| Mutation specific | CRISPR/Cas9 | Achieved 60% of normal dystrophin in a canine DMD model | [9] | ||
| 2. In vivo mRNA correction | These have demonstrated clinical benefits. | Safe delivery to all muscle cells is not yet perfected. Some adverse drug reactions. Must be continually re-administered. Mutation specific |
Read through; Ataluren | NCT01826487, NCT01557400. Reduces many of the disease symptoms, such as loss of ambulation and respiratory decline | [10,11,12] |
| Exon 51 skipping; Eteplirsen | NCT02255552. Small, if any, improvements over the control group at 96 weeks post treatment. Delay in pulmonary decline. | [13,14,15] | |||
| Exon 53 skipping; Vitolarsen | Achieved an average of 5.9% of normal dystrophin levels after 20 weeks of treatment | [16] | |||
| Exon 51 skipping; Drisapersen | NCT01254019. Some benefit with post hoc statistics in the 6MWT, clinical trials terminated | [17] | |||
| Exon 53 skipping; Golodirsen | NCT02310906. Decreased muscle function decline. | [18,19] | |||
| Exon 45 skipping; Casimersen | NCT02500381. Confirmed safety. | [20,21] | |||
| 3. Upregulation of supporting molecules | Will treat most DMD patients. Low side-effects. | Utrophin | NCT02858362. Study was halted due to lack of efficacy. | [22] | |
| Integrin-α7; SU9516 | PC., Slows disease progression | [23] | |||
| Integrin-α7; Obestatin | PC. Increased force production and other aspects of the mdx phenotype | [24] | |||
| Sarcospan | PC, decreases mdx muscle pathology including cardiomyopathy | [25,26] | |||
| 4. Enhancing muscle metabolism | FDA-approved for Type 2 diabetes | Increase pAMPK; Metformin | NCT01995032. No DMD reducing results. | [27,28] | |
| Increase PGC1α | NCT01856868. Some benefit for the patients. | [29] | |||
| 5. Novel steroids | Fewer side-effects | May still decrease patient’s immune response | Deflazacort | A retrospective patient study identified benefits of deflazacort over prednisone. | [30] |
| Vamorolone | PC. Vamorolone reduces fibrosis, inflammation and cardiomyopathy in mdx mice with reduced side effects. NCT02760264, 02760277, 03038399. Improvement in muscle function over natural history values and fewer side-effects then with corticosteroids. |
[31,32] | |||
| 6. Repurposing pharmaceuticals | Less expensive. Already passed human safety trials. | Tamoxifen | NCT02835079. Lower decreases in muscle and respiratory functions. | [33] | |
| Simvastatin | PC. Reduced pathology and increased muscle function. | [34,35] | |||
| Zidovudine (AZT) | PC. Reduced pathology and increased muscle function. | [36] | |||
| 7. Cell Transplants | Requires immune suppression. | Myoblasts | NCT02196467. Local high-density cell injections with immune suppression. Dystrophin was detected at the injection site at 4-weeks post-injections. | [37] | |
| Additionally benefitted skeletal muscles. | Cardiospheres | NCT02485938. Coronary injections without immune suppression. At 12-months post treatment only the treated patients had reduced size of myocardial scars. | [38] | ||
| No immune suppression is needed. Intraosseous, systemic delivery | Dystrophin expressing chimeric cells (DEC) |
PC. Skeletal, cardiac and diaphragm muscle improvements up to 180 days post single injection. | [39,40,41,42,43,44,45] |
NCT: NIH clinical trials number, this number indicates clinical trial data on DMD patients will follow; PC: denotes preclinical data on the mdx mouse; 6MWT: 6-min walk test; NSAA: North Star ambulatory assessments.