Table 2.
Pros and Cons of the potential therapeutic approaches for centronuclear myopathies
| Approach | Products | Pros | Cons |
|---|---|---|---|
| Gene, RNA and protein replacement | |||
| MTM1 gene delivery | AAV-MTM1; AAV-MTM1 dead phosphatase | Single injection; longterm expression; partial organ-specific delivery | Not fine-tunable; no treatment interruption; immunity to AAV; immunity to MTM1 |
| Myotubularin delivery | 3E10Fv-myotubularin | Fine-tunable; possible treatment interruption | Re-administration needed; immunity to MTM1 or 3E10Fv |
| DNM2 RNA trans-splicing | AAV-5’ pre-trans-splicing nucleotides | Single injection; longterm expression | Requires DNA delivery (naked, liposome, viral-based); potential toxicity of pre-trans-splicing molecules |
| Allele-specific DNM2 RNA silencing | AAV-shRNA | Single injection; allele-specificity decreasing on-target toxicity | Late treatment appeared less efficient for reversion; immunity to AAV |
| Normalizing the disease pathway | |||
| MTMR2 expression | AAV-MTMR2 | Single injection; longterm expression; partial organ-specific delivery | Not fine-tunable; no treatment interruption; immunity to AAV |
| PI3K inhibition | Wortmannin; LY294002; PI-103 | Fine-tunable; possible treatment interruption | Re-administration needed; poor organ specificity; on-target toxicity (lack of specific PIK3C2B inhibitor) |
| DNM2 reduction or normalization | antisense oligonucleotides | Fine-tunable; possible treatment interruption; sequence substitution | Re-administration needed; poor organ specificity; on-target toxicity |
| AAV-shRNA | Single injection; longterm expression | Not fine-tunable; no treatment interruption; immunity to AAV; on-target toxicity | |
| Treating the general muscle unbalance | |||
| Autophagy activation | mTOR inhibitors (RAD001, AZD8055) | Fine-tunable; possible treatment interruption | Re-administration needed; poor organ specificity; on-target toxicity |
| Myostatin inhibition | ActRIIB-mFC | Fine-tunable; possible treatment interruption; in clinical use | Re-administration needed; poor organ specificity; on-target toxicity; good histological but poor functional improvements in XLMTM model |
| Other potential approaches | |||
| Acetylcholinesterase inhibition | pyridostigmine; edrophonium | Fine-tunable; possible treatment interruption; in clinical use for myopathies (FDA approved) | Symptomatic treatment |
| Cell transplantation | syngeneic WT myoblasts | Ex vivo cell manipulation possible | Re-administration needed; systemic delivery difficult; longterm effect unknown |
Notes: Extent of positive outcomes in animal models do not necessarily translate in human. Pros and Cons and mode of delivery may change depending on results in pre-clinical development and methodological updates.