Substrate reduction therapy for inborn errors of metabolism

Abstract

Inborn errors of metabolism (IEM) represent a growing group of monogenic disorders each associated with inherited defects in a metabolic enzyme or regulatory protein, leading to biochemical abnormalities arising from a metabolic block. Despite the well-established genetic linkage, pathophysiology and clinical manifestations for many IEMs, there remains a lack of transformative therapy. The available treatment and management options for a few IEMs are often ineffective or expensive, incurring a significant burden to individual, family, and society. The lack of IEM therapies, in large part, relates to the conceptual challenge that IEMs are loss-of-function defects arising from the defective enzyme, rendering pharmacologic rescue difficult. An emerging approach that holds promise and is the subject of a flurry of pre-/clinical applications, is substrate reduction therapy (SRT). SRT addresses a common IEM phenotype associated with toxic accumulation of substrate from the defective enzyme, by inhibiting the formation of the substrate instead of directly repairing the defective enzyme. This minireview will summarize recent highlights towards the development of emerging SRT, with focussed attention towards repurposing of currently approved drugs, approaches to validate novel targets and screen for hit molecules, as well as emerging advances in gene silencing as a therapeutic modality.

Keywords: drug discovery and design; gene silencing; inborn errors of metabolism; small molecules; substrate reduction.

Figure 1.. SRT examples applied to linear pathways of metabolite interconversion.

(A) Schematic diagram illustrating the general concept of SRT, where E₂ is the defective enzyme, and E₁ is the inhibitory target for SRT. (B) Pathway of tyrosine degradation. (C) Pathway of glycogen biosynthesis and targeted degradation in lysosome. (D) Pathway of glyoxylate metabolism in hepatocytes. (E) Pathway of galactose metabolism. For (B–E), blue letters denote enzymes targeted by SRT, red letters denote the defective enzymes.

Figure 2.. SRT examples applied to biosynthesis and degradation pathway of a storage material.

(A) Schematic diagram illustrating the general concept of SRT, where E_a1, E_a2, and E_a3 are anabolic enzymes for biosynthesis (yellow arrows) of storage material, while E_c1, E_c2, and E_c3 are catabolic enzymes for degradation (green arrows). In this scheme, the defective enzyme is E_c2, while the target enzyme for SRT is E_a2. (B) Pathway of sphingolipid biosynthesis (yellow arrows) and degradation (green arrows). (C) Pathway of glycosaminoglycan biosynthesis (yellow arrows) and degradation (green arrows). For (B,C), blue letters denote enzymes proposed as SRT targets, to address the metabolic defects shown in red letters.