{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:31:47Z","timestamp":1790829107450,"version":"4.1.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"30","license":[{"start":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T00:00:00Z","timestamp":1658102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,7,26]]},"abstract":"<jats:p>\n                    The C-natriuretic peptide (CNP) analog vosoritide has recently been approved for treatment of achondroplasia in children. However, the regimen requires daily subcutaneous injections in pediatric patients over multiple years. The present work sought to develop a long-acting CNP that would provide efficacy equal to or greater than that of vosoritide but require less frequent injections. We used a technology for half-life extension, whereby a drug is attached to tetra-polyethylene glycol hydrogels (tetra-PEG) by \u03b2-eliminative linkers that cleave at predetermined rates. These hydrogels\u2014fabricated as uniform \u223c60-\u03bcm microspheres\u2014are injected subcutaneously, where they serve as a stationary depot to slowly release the drug into the systemic circulation. We prepared a highly active, stable CNP analog\u2014[Gln\n                    <jats:sup>6,14<\/jats:sup>\n                    ]CNP-38\u2014composed of the 38 C-terminal amino acids of human CNP-53 containing Asn to Gln substitutions to preclude degradative deamidation. Two microsphere [Gln\n                    <jats:sup>6,14<\/jats:sup>\n                    ]CNP-38 conjugates were prepared, with release rates designed to allow once-weekly and once-monthly administration. After subcutaneous injection of the conjugates in mice, [Gln\n                    <jats:sup>6,14<\/jats:sup>\n                    ]CNP-38 was slowly released into the systemic circulation and showed biphasic elimination pharmacokinetics with terminal half-lives of \u223c200 and \u223c600 h. Both preparations increased growth of mice comparable to or exceeding that produced by daily vosoritide. Simulations of the pharmacokinetics in humans indicated that plasma [Gln\n                    <jats:sup>6,14<\/jats:sup>\n                    ]CNP-38 levels should be maintained within a therapeutic window over weekly, biweekly, and likely, monthly dosing intervals. Compared with vosoritide, which requires \u223c30 injections per month, microsphere [Gln\n                    <jats:sup>6,14<\/jats:sup>\n                    ]CNP-38 conjugates\u2014especially the biweekly and monthly dosing\u2014could provide an alternative that would be well accepted by physicians, patients, and patient caregivers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2201067119","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T15:00:31Z","timestamp":1658156431000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["A long-acting C-natriuretic peptide for achondroplasia"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7274-7961","authenticated-orcid":false,"given":"Eric L.","family":"Schneider","sequence":"first","affiliation":[{"name":"ProLynx, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7360-2350","authenticated-orcid":false,"given":"Christopher W.","family":"Carreras","sequence":"additional","affiliation":[{"name":"ProLynx, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Reid","sequence":"additional","affiliation":[{"name":"ProLynx, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Ashley","sequence":"additional","affiliation":[{"name":"ProLynx, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel V.","family":"Santi","sequence":"additional","affiliation":[{"name":"ProLynx, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,7,18]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0972-6"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2020.115579"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61787"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-1222-2"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2020.170363"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2011.08082.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.218560"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31541-5"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.258251"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0212680"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1117147109"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.7b00218"},{"key":"e_1_3_3_13_2","doi-asserted-by":"crossref","first-page":"e12091","DOI":"10.1002\/eng2.12091","article-title":"Autoclave sterilization of tetra-polyethylene glycol hydrogel biomaterials with \u03b2-eliminative crosslinks","volume":"2","author":"Henise J.","year":"2020","unstructured":"J. Henise, B. Yao, G. W. Ashley, D. V. Santi, Autoclave sterilization of tetra-polyethylene glycol hydrogel biomaterials with \u03b2-eliminative crosslinks. Eng. Rep. 2, e12091 (2020).","journal-title":"Eng. Rep."},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215498110"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/bc5005476"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","first-page":"e12213","DOI":"10.1002\/eng2.12213","article-title":"High-throughput, aseptic production of injectable Tetra-PEG hydrogel microspheres for delivery of releasable covalently bound drugs","volume":"2","author":"Henise J.","year":"2020","unstructured":"J. Henise , High-throughput, aseptic production of injectable Tetra-PEG hydrogel microspheres for delivery of releasable covalently bound drugs. Eng. Rep. 2, e12213 (2020).","journal-title":"Eng. Rep."},{"key":"e_1_3_3_17_2","doi-asserted-by":"crossref","first-page":"e12412","DOI":"10.1002\/eng2.12412","article-title":"Facile preparation of tetra-polyethylene glycol hydrogel microspheres for drug delivery by cross-flow membrane emulsification","volume":"3","author":"Henise J.","year":"2021","unstructured":"J. Henise, B. Yao, G. W. Ashley, D. V. Santi, Facile preparation of tetra-polyethylene glycol hydrogel microspheres for drug delivery by cross-flow membrane emulsification. Eng. Rep. 3, e12412 (2021).","journal-title":"Eng. Rep."},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/9483127"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.20740"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0360992"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.7b00686"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-3011.2004.00151.x"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.9b03127"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2002-220702"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.5b00690"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-1676"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0204172"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.4103\/0976-0105.177703"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31873"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15369"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1177\/0192623312474726"},{"key":"e_1_3_3_32_2","unstructured":"CHMP Safety Working Party CHMP Safety Working Party\u2019s response to the PDCO regarding the use of PEGylated drug products in the paediatric population (2012). https:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2012\/2011\/WC500135123.pdf. Accessed 29 June 2022."},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2005.12.041"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1545"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2201067119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T13:26:16Z","timestamp":1700832376000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2201067119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,18]]},"references-count":34,"journal-issue":{"issue":"30","published-print":{"date-parts":[[2022,7,26]]}},"alternative-id":["10.1073\/pnas.2201067119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2201067119","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,18]]},"assertion":[{"value":"2022-01-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2201067119"}}