A peptidomimetic for LIMP-2 based activation of Glucocerebrosidase as a Gaucher/Parkinson’s Disease therapeutic NU 2016-019
INVENTORS Dimitri Krainc* Michael Schwake
SHORT DESCRIPTION LIMP-2-based peptidomimetic compounds to facilitate glucocerebrosidase activation in Gaucher and Parkinson’s Disease
BACKGROUND Mutations in glucocerebrosidase (GCase) cause Gaucher Disease. Additionally, GCase mutations are a major risk factor in Parkinson’s Disease, as well as other related synucleiopathies. GCase activity is reduced in Parkinson’s Disease, and large amounts of functional GCase are needed to effectively treat Gaucher Disease.
ABSTRACT In this novel therapeutic pathway, NU scientists present a structure-based drug design from the reference of LIMP-2 for the activation of GCase. The inventors identified LIMP-2 as a peptide that binds and activates GCase. Furthermore, a single helix (Helix 5) within LIMP-2 is sufficient to achieve this binding and activation. This single helix can form the basis of peptidomimetic compounds essential to therapeutics. The Helix 5 peptide was able to bind both wild-type, fully functional GCase and mutated, disease-associated GCase. When fused to a cell-penetrating peptide, it was able to activate lysosomal GCase and reduce α-synuclein, a critical determinant for Parkinson’s Disease. These results validate Helix 5 as a therapeutic and the LIMP-2-GCase interaction as a potential target. Helix 5 can also bind and activate recombinant GCase, increasing the efficiency and therapeutic benefits for Enzyme Replacement Therapy. Peptidomimetics structured after Limp-2 Helix 5 can be used in the treatment of Gaucher Disease, Parkinson’s Disease, and other synucleinopathies.
APPLICATIONS • Activation of glucocerebrosidase in the central nervous system • Peptidomimetic compounds for glucocerebrosidase activation • Facilitation of Enzyme Replacement Therapy and gene therapy • Treatment of Gaucher and Parkinson’s Disease
ADVANTAGES • Therapeutic implicated in multiple neurological diseases/synucleinopathies • Reduced cost of therapy • More effective treatment for a broader range of Gaucher Disease patients (including neurological symptoms) PUBLICATION Zunke F, Andresen L, Wesseler S, Groth J, Arnold P, Rothaug M, Mazzulli JR, Krainc D, Blanz J, Saftig P, Schwake M. (2016). Characterization of the complex formed by β-glucocerebrosidase and the lysosomal integral membrane protein type-2. Proc Acad Ntl Sci, 113(14), 3791-3796. https://doi.org/10.1073/pnas.1514005113
IP STATUS US patent application has been filed.
INVO CONTACT Bhaskar Chetnani, PhD Assistant Director/Senior Invention Manager (p) 847-467-3095 (e) bhaskar.chetnani@northwestern.edu
B. Shows helix 5 in LIMP-2 is essential for GCase pulldown, creating the base for the peptidomimetic compound F. Shows sustained activation of GCase following treatment with the isolated helix 5.