Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders  Giancarlo Parenti, Generoso Andria, Kenneth J Valenzano  Molecular Therapy  Volume 23, Issue 7, Pages 1138-1148 (July 2015) DOI: 10.1038/mt.2015.62 Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 The cellular pathways that control folding of lysosomal enzymes. During synthesis, proteins (in this case, lysosomal enzymes or proteins) are cotranslationally assisted by molecular chaperones and folding factors (e.g., heat-shock proteins) that interact with partially folded, aggregation-prone structural motifs of the nascent protein. Upon recognition and binding to the nascent polypeptide, molecular chaperones can stabilize protein conformation, inhibit premature misfolding, and prevent aggregation. Enzymes that are correctly folded and stable pass the quality control (QC) of the endoplasmic reticulum (ER), exit the ER efficiently, and traffic to lysosomes. Mutant, misfolded enzymes may undergo ER retention or be recognized by the ER QC, retro-translocated to the cytosol, and degraded by ER-associated degradation systems (ERAD). Molecular Therapy 2015 23, 1138-1148DOI: (10.1038/mt.2015.62) Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions

Figure 2 Mechanism of action of pharmacological chaperones. Pharmacological chaperones (hexagons) are small-molecule ligands that selectively bind and stabilize otherwise unstable enzymes and enhance or partially restore their folding and stability. Enzymes that are rescued by pharmacological chaperones can be normally trafficked, thus increasing residual activity in lysosomes. Molecular Therapy 2015 23, 1138-1148DOI: (10.1038/mt.2015.62) Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions

Figure 3 Correlations between residual activity and LSD phenotype. For most LSDs, correlations have been observed between residual enzyme activity and disease severity. It has been speculated that substrate storage occurs if residual activity falls below a certain threshold. For several LSDs, it has been assumed that a threshold activity of approximately 10% is sufficient to prevent storage, while 3–5% residual activity is associated with attenuated phenotypes. LSD, lysosomal storage disorder. Molecular Therapy 2015 23, 1138-1148DOI: (10.1038/mt.2015.62) Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions