التفاصيل البيبلوغرافية
| العنوان: |
Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis. |
| المؤلفون: |
Colazo JM, Hoogenboezem EN, Keech MC, Francini N, Shah V, Yu F, Lo JH, Sorets AG, McCune JT, Cho H, DeJulius CR, Michell DL, Maerz T, Vickers KC, Gibson-Corley KN, Hasty KA, Crofford L, Cook RS, Duvall CL |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 28. Date of Electronic Publication: 2023 Dec 28. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin 'hitchhiking' for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA.
Editorial Summary: Lipophilic siRNA conjugates optimized for albumin binding and "hitchhiking" can be leveraged to achieve preferential delivery to and gene silencing activity within arthritic joints. Chemical stabilization of the lipophilic siRNA enables intravenous siRNA delivery without lipid or polymer encapsulation. Using siRNA sequences targeting MMP13, a key driver of arthritis-related inflammation, albumin hitchhiking siRNA diminished MMP13, inflammation, and manifestations of osteoarthritis and rheumatoid arthritis at molecular, histological, and clinical levels, consistently outperforming clinical standards of care and small molecule MMP antagonists. |
| تواريخ الأحداث: |
Date Created: 20230619 Latest Revision: 20240103 |
| رمز التحديث: |
20240103 |
| مُعرف محوري في PubMed: |
PMC10274717 |
| DOI: |
10.1101/2023.05.31.542971 |
| PMID: |
37333210 |
| قاعدة البيانات: |
MEDLINE |
