Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial
As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (...
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| description | As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5.
ClinicalTrials.gov Phase I: NCT02442557; Phase IIa: NCT02442570. |
| doi_str_mv | 10.1371/journal.pone.0143366 |
| format | Article |
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ClinicalTrials.gov Phase I: NCT02442557; Phase IIa: NCT02442570.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0143366</identifier><identifier>PMID: 26599332</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; alpha-Crystallin B Chain - administration & dosage ; alpha-Crystallin B Chain - therapeutic use ; Animal models ; Antigens ; Care and treatment ; Clinical trials ; Complications and side effects ; Crystal structure ; Crystallin ; Crystallinity ; Data processing ; Development and progression ; Double-Blind Method ; Female ; Health aspects ; Heat shock proteins ; Human behavior ; Humans ; Immune system ; Immunogenicity ; Immunological memory ; Immunology ; Inflammation ; Interferon ; Intervention ; Intravenous administration ; Lesions ; Ligands ; Lymphocytes ; Lymphocytes T ; Macrophages ; Magnetic resonance ; Magnetic resonance imaging ; Male ; Memory cells ; Microglia ; Middle Aged ; Multiple sclerosis ; Multiple Sclerosis - drug therapy ; Multiple Sclerosis, Relapsing-Remitting - drug therapy ; Nervous system ; Oxidative stress ; Patient outcomes ; Patients ; Product development ; Regression analysis ; Studies ; Toll-like receptors ; Treatment Outcome ; Tumor necrosis factor-TNF ; γ-Interferon</subject><ispartof>PloS one, 2015-11, Vol.10 (11), p.e0143366-e0143366</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 van Noort et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 van Noort et al 2015 van Noort et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-aa3c5f8c7b6bcabbc93299b9e511490753bdcdf18889891fa26564b49f1f13553</citedby><cites>FETCH-LOGICAL-c692t-aa3c5f8c7b6bcabbc93299b9e511490753bdcdf18889891fa26564b49f1f13553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657879/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657879/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26599332$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van Noort, Johannes M</creatorcontrib><creatorcontrib>Bsibsi, Malika</creatorcontrib><creatorcontrib>Nacken, Peter J</creatorcontrib><creatorcontrib>Verbeek, Richard</creatorcontrib><creatorcontrib>Venneker, Edna H G</creatorcontrib><title>Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5.
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Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5.
ClinicalTrials.gov Phase I: NCT02442557; Phase IIa: NCT02442570.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26599332</pmid><doi>10.1371/journal.pone.0143366</doi><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult alpha-Crystallin B Chain - administration & dosage alpha-Crystallin B Chain - therapeutic use Animal models Antigens Care and treatment Clinical trials Complications and side effects Crystal structure Crystallin Crystallinity Data processing Development and progression Double-Blind Method Female Health aspects Heat shock proteins Human behavior Humans Immune system Immunogenicity Immunological memory Immunology Inflammation Interferon Intervention Intravenous administration Lesions Ligands Lymphocytes Lymphocytes T Macrophages Magnetic resonance Magnetic resonance imaging Male Memory cells Microglia Middle Aged Multiple sclerosis Multiple Sclerosis - drug therapy Multiple Sclerosis, Relapsing-Remitting - drug therapy Nervous system Oxidative stress Patient outcomes Patients Product development Regression analysis Studies Toll-like receptors Treatment Outcome Tumor necrosis factor-TNF γ-Interferon |
| title | Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T11%3A20%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Therapeutic%20Intervention%20in%20Multiple%20Sclerosis%20with%20Alpha%20B-Crystallin:%20A%20Randomized%20Controlled%20Phase%20IIa%20Trial&rft.jtitle=PloS%20one&rft.au=van%20Noort,%20Johannes%20M&rft.date=2015-11-23&rft.volume=10&rft.issue=11&rft.spage=e0143366&rft.epage=e0143366&rft.pages=e0143366-e0143366&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0143366&rft_dat=%3Cgale_plos_%3EA435602073%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1735663683&rft_id=info:pmid/26599332&rft_galeid=A435602073&rft_doaj_id=oai_doaj_org_article_a750ee5785aa466688567139af314930&rfr_iscdi=true |