Human Islet Amyloid Polypeptide (hIAPP) Protofibril-Specific Antibodies for Detection and Treatment of Type 2 Diabetes.

Autor: Bortoletto AS; Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Neuroscience, Department of Molecular and Cellular Biology, Translational Biology and Molecular Medicine Program, Medical Scientist Training Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Graham WV; Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA., Trout G; Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Neuroscience, Department of Molecular and Cellular Biology, Translational Biology and Molecular Medicine Program, Medical Scientist Training Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Bonito-Oliva A; Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA., Kazmi MA; Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA., Gong J; Celdara Medical, 16 Cavendish Court, Lebanon, NH, 03766, USA., Weyburne E; Celdara Medical, 16 Cavendish Court, Lebanon, NH, 03766, USA., Houser BL; Celdara Medical, 16 Cavendish Court, Lebanon, NH, 03766, USA., Sakmar TP; Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.; Department of Neurobiology, Care Sciences, and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, 17164, Sweden., Parchem RJ; Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Department of Neuroscience, Department of Molecular and Cellular Biology, Translational Biology and Molecular Medicine Program, Medical Scientist Training Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2022 Dec; Vol. 9 (34), pp. e2202342. Date of Electronic Publication: 2022 Oct 18.
DOI: 10.1002/advs.202202342
Abstrakt: Type 2 diabetes mellitus (T2D) is a major public health concern and is characterized by sustained hyperglycemia due to insulin resistance and destruction of insulin-producing β cells. One pathological hallmark of T2D is the toxic accumulation of human islet amyloid polypeptide (hIAPP) aggregates. Monomeric hIAPP is a hormone normally co-secreted with insulin. However, increased levels of hIAPP in prediabetic and diabetic patients can lead to the formation of hIAPP protofibrils, which are toxic to β cells. Current therapies fail to address hIAPP aggregation and current screening modalities do not detect it. Using a stabilizing capping protein, monoclonal antibodies (mAbs) can be developed against a previously nonisolatable form of hIAPP protofibrils, which are protofibril specific and do not engage monomeric hIAPP. Shown here are two candidate mAbs that can detect hIAPP protofibrils in serum and hIAPP deposits in pancreatic islets in a mouse model of rapidly progressing T2D. Treatment of diabetic mice with the mAbs delays disease progression and dramatically increases overall survival. These results demonstrate the potential for using novel hIAPP protofibril-specific mAbs as a diagnostic screening tool for early detection of T2D, as well as therapeutically to preserve β cell function and target one of the underlying pathological mechanisms of T2D.
(© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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