Chemical chaperone therapy: clinical effect in murine G_M1‐gangliosidosis

Abstract

Certain low-molecular-weight substrate analogs act both as in vitro competitive inhibitors of lysosomal hydrolases and as intracellular enhancers (chemical chaperones) by stabilization of mutant proteins. In this study, we performed oral administration of a chaperone compound N-octyl-4-epi-beta-valienamine to G(M1)-gangliosidosis model mice expressing R201C mutant human beta-galactosidase. A newly developed neurological scoring system was used for clinical assessment. N-Octyl-4-epi-beta-valienamine was delivered rapidly to the brain, increased beta-galactosidase activity, decreased ganglioside G(M1), and prevented neurological deterioration within a few months. No adverse effect was observed during this experiment. N-Octyl-4-epi-beta-valienamine will be useful for chemical chaperone therapy of human G(M1)-gangliosidosis.

Pharmacological chaperone therapy for Gaucher disease: a patent review

“…This counterintuitive concept (namely, using inhibitors to elicit enzyme activity) set the basis for a brand new therapeutic approach to LSDs: the pharmaceutical chaperone therapy (PCT). Proof of principle of the feasibility of this therapeutic approach has been given for some of the most relevant LSDs, including G M1 gangliosidosis [50], Fabry disease (FD) [51], Pompe disease (PD) [52] and, of course, GD [53].…”

“…It has been demonstrated that some pharmacological chaperone candidates cross over the BBB, therefore being potentially useful for the treatment of patients with neuronophatic affections. For instance, NB-DNJ, used in SRT modality for GD and a potential chaperone for the acid -glucosidase involved in Pompe disease, evenly distribute in a variety of tissues in model animals [54] and NOEV (N-octyl-4-epi--valienamine), a chaperone for the-galactosidase involved in G M1 glangliosidosis, is rapidly localized in most areas of the brain [50] (Table 4). …”

Central nervous system therapy for lysosomal storage disorders

“…Chaperones are in the early stages of clinical development, but have shown promising results in cell culture and animal models for a number of lysosomal disorders, including Gaucher disease, Fabry disease, Pompe disease, MPS I, GM 1 -gangliosidosis, and Tay-Sachs disease. 38,56,57,84,86,97,102,121,139,146 Bone Marrow, Hematopoietic Stem Cell, and Umbilical Cord Blood Transplantation Allogenic BMT, HSCT, and, more recently, umbilical cord blood transplantation have been mainstays of therapeutic intervention for many LSDs that have significant brain involvement, although therapeutic efficacy has been variable. After transplantation, donor cells with normal lysosomal enzyme function populate the bone marrow.…”

Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy

“…Even their original K/O mice, despite GM1 ganglioside accumulation in the brain, show no overt clinical phenotype until 4-5 months of age [22]. They have reported administering N-octyl-4-epi-β-valienamine (NOEV) orally for up to 16 weeks to these transgenic mice [23]. After 8 weeks of NOEV treatment, total GM1 ganglioside levels in the brain were reduced by ~3 fold and remained at that level despite another 8 week treatment.…”