Table 3.
Therapeutic strategies tested in DM1 mouse models.
| Compound | Target | Administration | Mechanism | Mouse model | Benefits reported in DM1 mice | References |
|---|---|---|---|---|---|---|
| ANTISENSE OLIGONUCLEOTIDES | ||||||
| PS | CUG sequence | Intramuscular injection (local) | Steric hindrance and foci dispersion | DMSXLa HSALR | Dispersion of RNA foci Reduction of CUG RNA Splicing correction | (149) |
| Morpholino | CUG sequence | Intramuscular injection and electroporation (local) | Steric hindrance and foci dispersion | HSALR DMSXLa | Reduction of CUG RNA Splicing correction Mitigation of myotonia | (150) |
| MOE-gapmer | Flanking region | Subcutaneous injection (systemic) | RNase H-mediated degradation | HSALR | Reduction of CUG RNA Splicing correction Improved histology Sustained mitigation of myotonia |
(12) |
| MOE-gapmer | CUG sequence | Intramuscular injection and electroporation (local) | RNase H-mediated degradation | Induced EpA960 | Dispersion of RNA foci Splicing correction |
(151) |
| MOE-gapmer and morpholino | CUG sequence | Intramuscular injection and electroporation (local) | Combined RNase H and foci release | Induced EpA960 | Enhanced reduction of CUG RNA | (151) |
| siRNA | CUG sequence | Intramuscular injection and electroporation (local) | RNAi-mediated RNA degradation | HSALR | Reduction of CUG RNA Dispersion of RNA foci Splicing correction Mitigation of myotonia |
(152) |
| cEt gapmer | DMPK 3′UTR | Subcutaneous injection (systemic) | RNase H-mediated degradation | DMSXL | Reduction of CUG RNA Body weight gain Improved muscle strength Improved histology | (153, 154) |
| siRNA | hACTA1 3′UTR | Intravenous injection of rAAV vectors (systemic) | RNAi-mediated RNA degradation | HSALR | Reduction of CUG RNA Splicing correction Improved histology Mitigation of myotonia |
(155) |
| NUCLEIC ACID BINDING CHEMICALS | ||||||
| Pentamidine, heptamidine and diamidine analogs | CUG transcription | Intraperitoneal injection (systemic) | Inhibition of CUG transcription Foci dispersion and CUG RNA degradation |
HSALR | Reduction of CUG RNA Splicing correction Mitigation of myotonia |
(156–158) |
| Hoescht derivatives | CUG-MBNL complex | Intraperitoneal injection (systemic) | Disruption of RNA foci | HSALR | Splicing correction | (159) |
| Kanamycin derivatives | CUG-MBNL complex | Intraperitoneal injection (systemic) | Disruption of RNA foci | HSALR | Splicing correction | (160) |
| Synthetic peptide | CUG-MBNL complex | Intramuscular injection (local) | Disruption of RNA foci | HSALR | Improved histology Splicing correction |
(161) |
| Actinomycin D | CUG transcription | Intraperitoneal injection (systemic) | Inhibition of CUG transcription | HSALR | Reduction of CUG RNA Splicing correction |
(162) |
| PHARMACOLOGICAL APPROACHES | ||||||
| Ceftriaxone | GLT1, glial glutamate transporter | Intraperitoneal injection (systemic) | Upregulation of GLT1 | DMSXL | Correction of Purkinje cell firing Improved motor coordination |
(50) |
| Bio, Lithium, TDZD-8 | GSK3ß | Intraperitoneal injection (systemic) | GSK3ß inhibition | HSALR | Improved histology Improved muscle strength Mitigation of myotonia |
(13) |
| Ro-31-8220 | PKC | Intraperitoneal injection (systemic) | PKC inhibition | EpA960 | CELF1 downregulation Splicing correction Amelioration of cardiac function |
(88) |
| AICAR | AMPA signaling | Intraperitoneal injection (systemic) | AMPK activation | HSALR | Dispersion of RNA foci Splicing correction Mitigation of myotonia |
(106) |
| Rapamycin and AZD8055 | mTOR signaling | Intraperitoneal injection (systemic) | mTORC1 inhibition | HSALR | Improved muscle function and strength | (106) |
| Anti-TWEAK antibody | TWEAK/Fn14 signaling | Intraperitoneal injection (systemic) | TWEAK | DM5 | Improved muscle histology Improved muscle strength Greater survival |
(110) |
rAAV, recombinant adeno-associated viral; ASO, antisense oligonucleotide; BIO, 6-bromoindirubin-39-oxime; cEt, 2′,4′-constrained ethyl-modified; LNA, locked nucleic acids; MOE, 2′-O-methoxyethyl; PS, 2′-O-methyl phosphorothioate. aThe DMSXL mice used in these studies were hemizygous and carried ~500–800 CTG.