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      Proposed Therapies for Pantothenate-Kinase-Associated Neurodegeneration

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      Publication date (Electronic):
      Journal: Journal of Experimental Neuroscience
      Publisher: SAGE Publications
      Keywords: pantothenate, PKAN, neurodegeneration, coenzyme A, CNS therapy

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          Abstract

          Multiple approaches to therapy have been proposed for the rare inherited neurodegenerative disease associated with mutations in the PANK2 gene, called pantothenate-kinase-associated neurodegeneration (PKAN). Penetration of the blood-brain barrier for treatment of a central nervous system (CNS) disorder is a major challenge in drug discovery. Evaluation of the biochemistry and medicinal chemistry of the proposed therapies reveals potential liabilities among several compounds under consideration for clinical development.

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          Structure-brain exposure relationships.

          A Hitchcock, D Pennington (2006)
          Article 0 comments Cited 129 times – based on 0 reviews     Review now
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            Coenzyme A corrects pathological defects in human neurons of PANK2‐associated neurodegeneration

            Daniel I Orellana, Paolo Santambrogio, Alicia Rubio … (2016)
            Abstract Pantothenate kinase‐associated neurodegeneration (PKAN) is an early onset and severely disabling neurodegenerative disease for which no therapy is available. PKAN is caused by mutations in PANK2, which encodes for the mitochondrial enzyme pantothenate kinase 2. Its function is to catalyze the first limiting step of Coenzyme A (CoA) biosynthesis. We generated induced pluripotent stem cells from PKAN patients and showed that their derived neurons exhibited premature death, increased ROS production, mitochondrial dysfunctions—including impairment of mitochondrial iron‐dependent biosynthesis—and major membrane excitability defects. CoA supplementation prevented neuronal death and ROS formation by restoring mitochondrial and neuronal functionality. Our findings provide direct evidence that PANK2 malfunctioning is responsible for abnormal phenotypes in human neuronal cells and indicate CoA treatment as a possible therapeutic intervention.
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              Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.

              Suzanne Jackowski, Brett Wenner, Kristopher G. Virga … (2007)
              Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice developed severe hypoglycemia. Insulin was reduced, glucagon and corticosterone were elevated, and fasting accelerated hypoglycemia. Metabolic profiling revealed a large increase in acylcarnitines, illustrating the role of carnitine in buffering acyl groups to maintain the nonesterified CoASH level. HoPan triggered significant changes in hepatic gene expression that substantially increased the thioesterases, which liberate CoASH from acyl-CoA, and increased pyruvate dehydrogenase kinase 1, which prevents the conversion of CoASH to acetyl-CoA. These results identify the metabolic rearrangements that maintain the CoASH pool which is critical to mitochondrial functions, including gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid and urea cycles.
              Article 0 comments Cited 35 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Exp Neurosci
                Journal ID (iso-abbrev): J Exp Neurosci
                Journal ID (publisher-id): EXN
                Journal ID (hwp): spexn
                Title: Journal of Experimental Neuroscience
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Electronic): 1179-0695
                Publication date (Electronic): 23 May 2019
                Publication date Collection: 2019
                Volume: 13
                Electronic Location Identifier: 1179069519851118
                Affiliations
                [1-1179069519851118]Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, TN, USA
                Author notes
                [*]Suzanne Jackowski, Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, TN 38105, USA. Email: Suzanne.Jackowski@ 123456STJUDE.ORG
                Author information
                https://orcid.org/0000-0002-6855-1429
                Article
                Publisher ID: 10.1177_1179069519851118 Publisher-manuscript ID: EXN-19-0018
                DOI: 10.1177/1179069519851118
                PMC ID: 6537486
                SO-VID: 8095b9d9-42cd-40ea-97c3-db8af759b6a3
                Copyright © © The Author(s) 2019
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 19 April 2019
                Date accepted : 24 April 2019
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                Funding
                Funded by: american lebanese syrian associated charities, FundRef https://doi.org/10.13039/100012524;
                Funded by: BridgeBio/CoA Therapeutics, Inc., ;
                Award ID: Sponsored Research Agreement
                Categories
                Subject: Commentary
                Custom metadata
                cover-date January-December 2019

                Keywords: pantothenate,pkan,neurodegeneration,coenzyme a,cns therapy
                Data availability:
                Keywords: pantothenate, pkan, neurodegeneration, coenzyme a, cns therapy

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