Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises

Abstract

Different approaches have been utilized or proposed for the treatment of lysosomal storage disorders (LSDs) including enzyme replacement and hematopoietic stem cell transplant therapies, both aiming to compensate for the enzymatic loss of the underlying mutated lysosomal enzymes. However, these approaches have their own limitations and therefore the vast majority of LSDs are either still untreatable or their treatments are inadequate. Missense mutations affecting enzyme stability, folding and cellular trafficking are common in LSDs resulting often in low protein half-life, premature degradation, aggregation and retention of the mutant proteins in the endoplasmic reticulum. Small molecular weight compounds such as pharmaceutical chaperones (PCs) and proteostasis regulators have been in recent years to be promising approaches for overcoming some of these protein processing defects. These compounds are thought to enhance lysosomal enzyme activity by specific binding to the mutated enzyme or by manipulating components of the proteostasis pathways promoting protein stability, folding and trafficking and thus enhancing and restoring some of the enzymatic activity of the mutated protein in lysosomes. Multiple compounds have already been approved for clinical use to treat multiple LSDs like migalastat in the treatment of Fabry disease and others are currently under research or in clinical trials such as Ambroxol hydrochloride and Pyrimethamine. In this review, we are presenting a general overview of LSDs, their molecular and cellular bases, and focusing on recent advances on targeting and manipulation proteostasis, including the use of PCs and proteostasis regulators, as therapeutic targets for some LSDs. In addition, we present the successes, limitations and future perspectives in this field.

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

“…Similarly, N-butyl-deoxynojirimycin (NB-DNJ) showed a more efficient correction of enzyme activity of GAA in combination with recombinant GAA in Pompe fibroblasts. Overall, NB-DNJ improved the trafficking of mutant GAA to lysosomes, enhanced the enzyme maturation, and increased the enzyme stability in Pompe disease fibroblasts and in a Pompe mouse model [67,68]. These results led to the design of a clinical trial to evaluate the effect of a combined ERT and PC treatment strategy, showing a significant increase in blood GAA activity, suggesting an improved stability of recombinant GAA in blood in the presence of the PC [69].…”

“…N-acetylcysteine (NAC), a compound that was proposed as an allosteric chaperone for GAA, showed promising results in vitro [66]. This PC enhanced the enzymatic activity of a recombinant GAA, improving the efficacy of ERT in Pompe disease [66,67]. Additionally, NAC enhanced the activity of mutated GAA in Pompe fibroblasts and in COS7 cells overexpressing mutated GAA [66].…”

“…In galactosialidosis, caused by a combined deficiency of β-galactosidase and N-acetyl-αneuraminidase due to a primary defect of protective protein/cathepsin A, it was observed that NOEV can enhance β-galactosidase activity in skin fibroblasts from patients with the early infantile and the juvenile/adult form [67,70]. Similarly, pyrimethamine (PYR) was identified as a competitive inhibitor of β-hexosaminidase, thus representing an alternative for the treatment of Tay-Sachs and Sandhoff diseases, since it produced an increase in the enzyme activity in 44% of the evaluated mutations [71].…”

“…The use of PYR reached phase II clinical trials for treatment of patients affected with late-onset GM2 gangliosidosis. A total of eight patients were evaluated during 16 weeks at doses of up to 50 mg/day, reaching a 4-fold enhancement of HexA activity in leukocytes [67,72]. On aspartylglucosaminuria, an LSD caused by mutations in the gene coding for aspartylglucosaminidase (AGA), glycine and aspartic acid have been tested as PC.…”

Lysosomes as a therapeutic target

“…Other examples of this strategy include afegostat in Gaucher disease (which failed in a phase II clinical trial in 2009 due to lack of efficacy), pyrimethamine in Sandhoff disease and Tay-Sachs disease, and ambroxol in Gaucher disease with neurological symptoms (TABLe 4). Agents that are at earlier developmental stages include N octylβ valienamine, a competitive inhibitor of βglucosidase, for Gaucher disease; N acetylcysteine for Pompe disease; α lobeline, 3,4,7trihydroxyisoflavone and azasugar in Krabbe disease; and N octyl4epi β valienamine and 5N,6S(N′butyliminomethylidene) 6thio1deoxygalactonojirimycin indicated in GM1 gangliosidosis 289 . The chemical structures of these pharmacological chaperones have been described recently 290,291 .…”