Abstract
Recently, it has been shown that blocking the binding of valosin-containing protein (VCP) to mutant huntingtin (mtHtt) can prevent neuronal mitochondrial autophagy in Huntington’s disease (HD) models. Herein, we describe the development and efficacy of a protein-like polymer (PLP) for inhibiting this interaction in cellular and in vivo models of HD. PLPs exhibit bioactivity in HD mouse striatal cells by successfully inhibiting mitochondrial destruction. PLP is notably resilient to in vitro enzyme, serum, and liver microsome stability assays, which render analogous control oligopeptides ineffective. PLP demonstrates a 2000-fold increase in circulation half-life compared to peptides, exhibiting an elimination half-life of 152 hours. In vivo efficacy studies in HD transgenic mice (R6/2) confirm the superior bioactivity of PLP compared to free peptide through behavioral and neuropathological analyses. PLP functions by preventing pathologic VCP/mtHtt binding in HD animal models; exhibits enhanced efficacy over the parent, free peptide; and implicates the PLP as a platform with potential for translational central nervous system therapeutics.
| Original language | English (US) |
|---|---|
| Article number | eado8307 |
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 44 |
| DOIs | |
| State | Published - Nov 1 2024 |
Funding
We would like to thank the members of the Gianneschi laboratory for all the insightful discussions and support. This work made use of (i) the IMSERC MS facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), the State of Illinois, the International Institute for Nanotechnology (IIN), and Northwestern University; (ii) the IMSERC NMR facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), NSF CHE-1048773, and Northwestern University; (iii) the Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCI Cancer Center Support Grant #P30 CA060553; (iv) the Biological Imaging Facility at Northwestern University (RRID:SCR_017767), supported by the Chemistry for Life Processes Institute, the NU Office for Research, the Department of Molecular Biosciences. Microscopy was performed at the Northwestern University Center for Advanced Microscopy supported by CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center; and (v) the Quantitative Bio-element Imaging Center, supported by NASA Ames Research Center NNA06CB93G. This work was supported by the Developmental Therapeutics Core at Northwestern University and the Robert H. Lurie Comprehensive Cancer Center support grant (NCI CA060553). Funding: This work was supported by the International Institute of Nanotechnology Convergence Science Medicine Institute grant (N.C.G.), National Institutes of Health award 1F31AG076334 (M.F.), National Institutes of Health award 1F30AG076317 (K.P.C.), International Institute of Nanotechnology Ryan Fellowship (M.F. and K.P.C.), National Institutes of Health grant R01AG065240 (X.Q.), National Institutes of Health grant R01NS115903 (X.Q.), National Institutes of Health grant R01AG076051 (X.Q.), and National Institutes of Health grant RF1AG074346 (X.Q.). Acknowledgments: We would like to thank the members of the Gianneschi laboratory for all the insightful discussions and support. this work made use of (i) the iMSeRC MS facility at Northwestern University, which has received support from the Soft and hybrid Nanotechnology experimental (ShyNe) Resource (NSF eCCS-2025633), the State of illinois, the international institute for Nanotechnology (iiN), and Northwestern University; (ii) the iMSeRC NMR facility at Northwestern University, which has received support from the Soft and hybrid Nanotechnology experimental (ShyNe) Resource (NSF eCCS-2025633), NSF Che-1048773, and Northwestern University; (iii) the Keck Biophysics Facility, a shared resource of the Robert h. lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCi Cancer Center Support Grant #P30 CA060553; (iv) the Biological imaging Facility at Northwestern University (RRid:SCR_017767), supported by the Chemistry for life Processes institute, the NU Office for Research, the department of Molecular Biosciences. Microscopy was performed at the Northwestern University Center for Advanced Microscopy supported by CCSG P30 CA060553 awarded to the Robert h lurie Comprehensive Cancer Center; and (v) the Quantitative Bio-element imaging Center, supported by NASA Ames Research Center NNA06CB93G. this work was supported by the developmental therapeutics Core at Northwestern University and the Robert h. lurie Comprehensive Cancer Center support grant (NCi CA060553). Funding: this work was supported by the international institute of Nanotechnology Convergence Science Medicine institute grant (N.C.G.), National institutes of health award 1F31AG076334 (M.F.), National institutes of health award 1F30AG076317 (K.P.C.), international institute of Nanotechnology Ryan Fellowship (M.F. and K.P.C.), National institutes of health grant R01AG065240 (X.Q.), National institutes of health grant R01NS115903 (X.Q.), National institutes of health grant R01AG076051 (X.Q.), and National institutes of health grant RF1AG074346 (X.Q.). Author contributions: Conceptualization: N.C.G., X.Q., W.C., M.F., M.P.t., and O.B. investigation: X.Q., W.C., M.F., M.P.t., Y.S., Z.l., d.h., K.B., and O.B. visualization: M.F., W.C., Y.S., and K.P.C. Methodology: X.Q., W.C., M.F., M.J.A., K.P.C., and O.B. Formal analysis: W.C., M.F., Y.S., M.J.A., K.P.C., and Z.l. validation: X.Q., M.F., W.C., and Y.S. data curation: W.C. Project administration: N.C.G., M.F., M.P.t., and W.C. Funding acquisition: N.C.G. and X.Q. Resources: M.F., M.P.t., W.C., and Z.l. Writing\u2014original draft: W.C., M.F., and Y.S. Writing\u2014review and editing: N.C.G., M.F., W.C., M.J.A., Y.S., K.P.C., K.B., and O.B. Supervision: N.C.G., W.C., and O.B. Competing interests: N.C.G. is a cofounder of Grove Biopharma to whom intellectual property related to this work is exclusively licensed. N.C.G, W.C., X.Q., and M.F. are all coinventors on a patent filed by Northwestern University on 2023-08-18 (App. Num. US18/452,059, pending) related, in part, to the work described herein. the other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
ASJC Scopus subject areas
- General
