This study evaluates the therapeutic potential of the lipid-conjugated antimiR-23b, X82108, designed to promote MBNL1/2 upregulation through inhibition of miR-23b, and highlights X82108 as a promising systemic therapy for DM1.
Abstract
Summary Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder caused by CTG repeat expansions in the DMPK gene, leading to the formation of toxic RNA foci that sequester essential splicing regulators MBNL1/2. Beyond muscle impairment, DM1 affects also the brain, leading to significant cognitive deficits, behavioral abnormalities, and intellectual disabilities. This study evaluates the therapeutic potential of the lipid-conjugated antimiR-23b, X82108, designed to promote MBNL1/2 upregulation through inhibition of miR-23b. Systemic administration of X82108 in mice and non-human primates efficiently crosses the blood-brain barrier, increasing MBNL1 in the brain. In DMSXL transgenic mice, treatment increases Mbnl1/2, reduces toxic DMPK, and restores normal splicing patterns across all brain regions. These molecular improvements correlate with improved behavioral outcomes, including reduced impulsivity and normalized exploratory activity. Collectively, the findings highlight X82108 as a promising systemic therapy for DM1, targeting not only muscular features as we have previously shown but also DM1-related CNS alterations.
Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.
Cecilia Sanchez-Santos, Alberto Jiménez-Amor, Loreto Martínez-González et al.· Journal of Medicinal Chemist...· 0 citations
It is demonstrated that TMZ mitigates dystrophic pathology by targeting the ATP6AP2 signaling axis and dampening macrophage-mediated inflammatory responses, highlighting its potential as a novel immunopharmacological therapeutic strategy for DMD.
Lin Zhou, Yu Zhang, Xinxin Tan et al.· International Immunopharmaco...· 0 citations
Parkinson’s disease is the second most common progressive neurodegenerative disorder, marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor and non-motor impairments. Its etiology involves environmental toxins (pesticides, heavy metals, air pollutants), genetic mutations (LRRK2, SNCA, PARK2, PINK1, PARK7), oxidative stress, and mitochondrial dysfunction. Recent therapeutic strategies focus on neuroprotective agents that target oxidative stress and protein aggregation. Senescence Marker Protein30 (SMP30), also known as regucalcin, is an aging-related protein critical for antioxidative defense, calcium homeostasis, and neuronal survival. This study explores the potential of BL-918, along with gluconolactone and five control drugs (levodopa, carbidopa, ropinirole, pramipexole, amantadine), to enhance mouse SMP30 (Protein Data Bank Identifier [PDB ID]: 4GN7) structural modulation using
in silico
approaches. Molecular docking (AutoDock Vina) revealed BL-918 had the highest binding affinity (–10.2 kcal/mol). Molecular dynamics (GROMACS) demonstrated structural stability of the SMP30-BL-918 complex over 100 ns, supported by root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), and solvent accessible surface area (SASA) analyses. Hydrogen bonding was initially strong but transient. SwissADME and ProTox 3.0 characterized BL-918 as a viable therapeutic lead, outlining key pharmacokinetic targets for future optimization. Protein Contact Atlas and STRING analysis identified key non-covalent and protein-protein interactions. Due to BL-918’s low inhibition constant (
K
i
= 3.33 × 10
–
8
M), which indicates a high binding affinity, and its ADMET profile, it is suggested that BL-918 could potentially modulate SMP30 at the functional protein level. These strong initial docking interactions, despite exhibiting a decline in hydrogen bonds during molecular dynamics simulations, may lead to downstream regulatory effects that could be associated with increased expression of the SMP-30 protein, pending experimental validation.
Hardi M. Makwana, S. S. Swain, B. Paital et al.· Journal of Applied Pharmaceu...· 0 citations
Introduction Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is an autosomal dominant polyglutamine neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3). Mutant ataxin-3 accumulation, oxidative stress, mitochondrial dysfunction, and impaired protein quality control contribute to its pathogenesis; however, no disease-modifying therapy is currently available. Omaveloxolone (RTA-408), an activator of nuclear factor erythroid 2–related factor 2 (Nrf2), is approved for Friedreich’s ataxia, but its therapeutic potential in SCA3 remains unclear. Methods We evaluated the effects of RTA-408 in MJD78 cells and Drosophila SCA3 models. Cell viability, apoptosis, mutant ataxin-3 levels, Nrf2-associated antioxidant proteins, p62/autophagy-related markers, and mitochondrial phenotypes were assessed in MJD78 cells. Survival, climbing ability, and external eye degeneration were evaluated in SCA3tr-Q78 flies. Results In MJD78 cells, 0.3 and 0.5 μM RTA-408 more consistently improved cell viability, reduced apoptosis, and decreased detectable mutant ataxin-3 accumulation than 0.1 μM RTA-408. RTA-408 increased the nuclear-to-cytoplasmic Nrf2 ratio and upregulated NQO1, HO-1, and SOD2 without significantly altering intracellular or mitochondrial reactive oxygen species levels. RTA-408 also increased p62 expression, whereas ATG7, Beclin 1, LAMP2, and the LC3-II/LC3-I ratio showed limited or nonsignificant changes, indicating p62 upregulation without definitive evidence of canonical autophagic flux activation. In addition, 0.3 μM RTA-408 partially shifted mitochondrial morphology from globe-like to elongated forms and increased mitochondrial DNA copy number. In SCA3tr-Q78 flies, RTA-408 partially improved survival, locomotor performance, eye size, and pigmentation, with more evident benefits at earlier stages. Conclusion These findings support the protective potential of RTA-408 in SCA3-related models. Its effects were associated with activation of Nrf2-related antioxidant responses, p62 upregulation, and selected improvements in mitochondrial phenotypes. Further studies are needed to clarify the underlying mechanisms and determine the translational potential of RTA-408 for SCA3.
Shin-Hung Pan, Juichih Chang, Wan-Hsuan Lin et al.· Frontiers in Pharmacology· 0 citations
Charcot-Marie-Tooth disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain, and loss of sensation in limbs. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated into spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in altered distribution of mitochondria in axons. Unbiased quantitative proteomic profiling of the endogenous MFN2 interactome revealed dose-dependent remodelling by the R94Q variant across 412 proteins, highlighting candidate mechanisms in disease pathology. Importantly, we showed that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.
Lydia H. Jestice, Larissa Butler, Rebecca A. Lea et al.· JCI Insight· 0 citations
Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models.
Kelsey Keith, Min Peng, Cristina Remes et al.· bioRxiv· 0 citations