{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:23:38Z","timestamp":1774344218236,"version":"3.50.1"},"reference-count":83,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fighting Blindness (FFB) Translational Research Acceleration Program (TRAP) Award"},{"name":"National Eye Institute P30 Core","award":["P30EY01373"],"award-info":[{"award-number":["P30EY01373"]}]},{"name":"National Cancer Institute P30 Core","award":["P30CA043703"],"award-info":[{"award-number":["P30CA043703"]}]},{"DOI":"10.13039\/100001039","name":"Cleveland Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001039","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Adeno-associated viruses (AAVs) are a promising gene therapy technology, but major technical challenges remain. One problem is that commonly used AAVs have a low efficiency in penetrating the blood\u2013brain barrier (BBB) and the blood\u2013retina barrier (BRB). Consequently, gene delivery to the nervous system has limitations. Another problem is that AAVs induce immune reactions that cause serious side effects. To avoid immune reactions, the AAV dose must be reduced to lower levels that may result in insufficient gene delivery. Researchers have been modifying viral capsid protein sequences and searching for effective peptide sequences to solve these problems. As a result, Cell-Penetrating Penta-Peptides (CPP5s) have been shown to be effective in improving the BBB\/BRB penetration of AAVs and suppressing immune reactions against AAVs. CPP5s were originally developed from peptide sequences of the Bax (a pro-apoptotic protein) binding domain of Ku70 (a DNA repair protein) and from negative control cell-penetrating peptides without Bax-binding activity. This article will discuss the background science of CPP5s and future directions of CPP5s for AAV-mediated gene delivery to the nervous system as well as other organs.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030395","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"395","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Improvement of Adeno-Associated Virus (AAV)-Based Technologies by Cell-Penetrating Penta-Peptides (CPP5s)"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0822-0240","authenticated-orcid":false,"given":"Charles W.","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia","family":"Diener","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigemi","family":"Matsuyama","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Case Comprehensive Cancer Center, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.bbrc.2004.07.054","article-title":"Bax-Inhibiting Peptide Derived from Mouse and Rat Ku70","volume":"321","author":"Yoshida","year":"2004","journal-title":"Biochem. 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