| Abstrakt: |
Sarcoglycanopathies (LGMDR3-6) are the most severe forms of autosomal recessive limb-girdle muscular dystrophies. Sarcoglycanopathies, due to mutations in sarcoglycan (SG) genes, are characterized by progressive weakness of the shoulder and pelvic muscles. Most of these genetic defects, accounting for about the 65%, are missense mutations. They lead to a non-properly folded, even though potentially functional protein that is removed from the cellular context through the quality control (QC) system. Treatments with a small molecule called C17, belonging to the CFTR modulator family, resulted in the effective rescue of the mutant R98Halpha-SG in vivo in a mouse model characterized by "humanized hind-limbs" expressing the mutated-SG. In particular, this compound produced a general amelioration of the pathological phenotype, and, most importantly, the recovery of the muscle force. These very promosing results moved us toward an in-depth investigation of the pharmacological properties of this compound, performing preliminary ADME (adsorption, distribution, metabolism and elimination) studies. We assessed the concentration-time (C-T) kinetic relationship, the biodistribution, the formation of drug metabolites in vitro and in vivo, and the elimination from the body. The in vitro drug biotransformation studies resulted in no formation of C17 derivatives using both human and mouse hepatic fractions (microsomes and S9 fraction). On the other hand, the analysis of urine and faeces of C17-treated mice evealed the presence of 2 metabolites in urine and 5 metabolites in faeces. These results could suggest that C17 is not metabolized at the level of liver, but rather through the activity of intestinal drug metabolizing enzymes. The analysis of gut content of C17-treated mice is ongoing. The concentration-time kinetic relationship revealed that C17 reaches the maximum concentration in the plasma after 2 hours from the administration and it is well distributed in all the mouse body compartments. Through the C17 steadystate study, we observed that C17 achieves the pharmacological plateau after 3 days. It was interesting to observe that at the level of the brain, heart and particularly skeletal muscle, our target-tissue, the pattern is compatible with the way of administration and the concentration-time kinetic of the plasma. After 48 hours from the injection, the C17 corrector is still detectable in skeletal muscles, and this information allowed us to perform a new chronic treatment with a lengthened regimen of administration that resulted, as in Scano et al. (2022), in an effective recovery of the tibialis anterior force as the rescue of the sarcoglycans mutant and the sarcoglycan complex at the sarcolemma. [ABSTRACT FROM AUTHOR] |
