Enzyme enhancement therapeutics for lysosomal storage diseases: Current status and perspective.

Small-molecule- enzyme enhancement therapeutics (EETs) have emerged as attractive agents for the treatment of lysosomal storage diseases (LSDs), a broad group of genetic diseases caused by mutations in genes encoding lysosomal enzymes, or proteins required for lysosomal function. The underlying enzyme deficiencies characterizing LSDs cause a block in the stepwise degradation of complex macromolecules (e.g. glycosaminoglycans, glycolipids and others), such that undegraded or partially degraded substrates progressively accumulate in lysosomal and non-lysosomal compartments, a process leading to multisystem pathology via primary and secondary mechanisms. Missense mutations underlie many of the LSDs; the resultant mutant variant enzyme hydrolase is often impaired in its folding and maturation making it subject to rapid disposal by endoplasmic reticulum (ER)-associated degradation (ERAD). Enzyme deficiency in the lysosome is the result, even though the mutant enzyme may retain significant catalytic functioning. Small molecule modulators - pharmacological chaperones (PCs), or proteostasis regulators (PRs) are being identified through library screens and computational tools, as they may offer a less costly approach than enzyme replacement therapy (ERT) for LSDs, and potentially treat neuronal forms of the diseases. PCs, capable of directly stabilizing the mutant protein, and PRs, which act on other cellular elements to enhance protein maturation, both allow a proportion of the synthesized variant protein to reach the lysosome and function. Proof-of-principle for PCs and PRs as therapeutic agents has been demonstrated for several LSDs, yet definitive data of their efficacy in disease models and/or in downstream clinical studies in many cases has yet to be achieved. Basic research to understand the cellular consequences of protein misfolding such as perturbed organellar crosstalk, redox status, and calcium balance is needed. Likewise, an elucidation of the early in cellulo pathogenic events underlying LSDs is vital and may lead to the discovery of new small molecule modulators and/or to other therapeutic approaches for driving proteostasis toward protein rescue.