Small Molecules

Abstract

Lysosomal storage disorders are rare genetic disorders due to deficient lysosomal activity, which leads to progressive accumulation of nonmetabolized substrates. Patient's clinical outcomes have significantly improved since the advent of enzyme replacement therapy, even though this therapeutic approach presents important limitations, such as immune reactions, low bioavailability of recombinant enzymes, and incapability to reach the central nervous system. New strategies based on gene therapy or small molecules have been proposed and tested as an alternative to enzyme replacement therapy or to complement it. Small molecules are orally administrated, no antigenic compound that can diffuse across cell membranes and distribute in steady-state concentrations, also reaching the central nervous system. Substrate reduction therapy, pharmacological chaperones, and stop-codon read-through enhancers are small molecules currently available for the treatment of lysosomal storage disorders. This article describes the characteristics of this class of compounds and the possible strategies to improve their efficiency in future development.

Molecular Approaches for the Treatment of Pompe Disease

“…The recognition of premature termination codons (PTCs) generated by nonsense mutations by the ribosome triggers nonsense-mediated decay (NMD), an evolutionarily preserved mechanism of cellular surveillance and control [45,46], resulting in mRNA degradation. Seldomly (in less than 1% of cases), a partially complementary tRNA binds the premature stop codon, causing the insertion of a random amino acid to allow translation to continue and producing a potentially stable, albeit abnormal, protein [47]. This mechanism, known as suppression of termination, or stop codon readthrough [46], can be enhanced and exploited by nonsense suppression therapy, a group of approaches aimed at suppressing translation termination by employing various substances [46].…”

“…This mechanism, known as suppression of termination, or stop codon readthrough [46], can be enhanced and exploited by nonsense suppression therapy, a group of approaches aimed at suppressing translation termination by employing various substances [46]. The rate at which read-through occurs depends on the amount of mRNA available and on the type of stop codon arising from the mutation, with UAA being the least amenable, UGA the most amenable, and UAG an intermediate [47].…”