{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T02:49:43Z","timestamp":1773456583559,"version":"3.50.1"},"reference-count":145,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T00:00:00Z","timestamp":1705881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["5R24EY028764"],"award-info":[{"award-number":["5R24EY028764"]}]},{"name":"NIH","award":["R01EY033805"],"award-info":[{"award-number":["R01EY033805"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Approximately 6% of adults worldwide suffer from peripheral artery disease (PAD), primarily caused by atherosclerosis of lower limb arteries. Despite optimal medical care and revascularization, many PAD patients remain symptomatic and progress to critical limb ischemia (CLI) and risk major amputation. Delivery of pro-angiogenic factors as proteins or DNA, stem, or progenitor cells confers vascular regeneration and functional recovery in animal models of CLI, but the effects are not well replicated in patients and no pro-angiogenic biopharmacological procedures are approved in the US, EU, or China. The reasons are unclear, but animal models that do not represent clinical PAD\/CLI are implicated. Consequently, it is unclear whether the obstacles to clinical success lie in the toxic biochemical milieu of human CLI, or in procedures that were optimized on inappropriate models. The question is significant because the former case requires abandonment of current strategies, while the latter encourages continued optimization. These issues are discussed in the context of relevant preclinical and clinical data, and it is concluded that preclinical mouse models that include age and atherosclerosis as the only comorbidities that are consistently present and active in clinical trial patients are necessary to predict clinical success. Of the reviewed materials, no biopharmacological procedure that failed in clinical trials had been tested in animal models that included advanced age and atherosclerosis relevant to PAD\/CLI.<\/jats:p>","DOI":"10.3390\/genes15010135","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T03:50:22Z","timestamp":1705895422000},"page":"135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Translational Relevance of Advanced Age and Atherosclerosis in Preclinical Trials of Biotherapies for Peripheral Artery Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6431-3642","authenticated-orcid":false,"given":"Keith","family":"Webster","sequence":"first","affiliation":[{"name":"Vascular Biology Institute, University of Miami, Miami, FL 33146, USA"},{"name":"Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1161\/CIRCRESAHA.121.318266","article-title":"New Directions in Therapeutic Angiogenesis and Arteriogenesis in Peripheral Arterial Disease","volume":"128","author":"Annex","year":"2021","journal-title":"Circ. 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