'Theranostischer' Ansatz unter Verwendung eines 'Trojanischen Pferdes' bei Atherosklerose.
Zusammenfassung der Projektergebnisse
The accumulation of apoptotic cells in the necrotic core plays a pivotal role in atherosclerotic plaques. The pathological upregulation of a “don’t eat me” molecule known as CD47 leads to defective programmed cell removal. Pro-phagocytic therapies, such as anti-CD47 antibodies, have been used to stimulate the phagocytic clearance of apoptotic cells. However, the clearance of red blood cells which results in anaemia might limit the translational potential of the antibody-based strategy. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of signal-regulatory protein alpha’s (SIRPα) downstream effector molecule Src homology 2 domain-containing phosphatase-1 (SHP-1). This „Trojan horse“-system, which targets the anti-phagocytic CD47-SIRPα signalling axis, reactivated efferocytosis locally and prevented atherosclerosis without inducing a significant on-target or off-target toxicity in apolipoprotein E-deficient mice. Additionally, single-cell RNA sequencing revealed an anti-inflammatory signature in those modulated, nanoparticle-exposed macrophages. Taken together, our approach of using macrophage-specific nanoparticles represents a significant advance for this class of drugs.
Projektbezogene Publikationen (Auswahl)
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Nanoparticle Therapy for Vascular Diseases. Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):635-646
Flores AM, Ye J, Jarr KU, Hosseini-Nassab N, Smith BR, and Leeper NJ
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Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade. Proc Natl Acad Sci USA. 2020 Jul 7;117(27):15818-15826
Wang Y, Nanda V, Direnzo D, Ye J, Xiao S, Kojima Y, Howe KL, Jarr KU, Flores AM, Tsantilas P, Tsao N, Rao A, Newman AAC, Eberhard AV, Priest JR, Ruusalepp A, Pasterkamp G, Maegdefessel L, Miller CL, Lind L, Koplev S, Björkegren JLM, Owens GK, Ingelsson E, Weissman IL, Leeper NJ
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Leeper NJ. 18F-Fluorodeoxyglucose- Positron Emission Tomography Imaging Detects Response to Therapeutic Intervention and Plaque Vulnerability in a Murine Model of Advanced Atherosclerotic Disease-Brief Report. Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2821-2828
Jarr KU, Ye J, Kojima Y, Nanda V, Flores AM, Tsantilas P, Wang Y, Hosseini- Nassab N, Eberhard AV, Lotfi M, Käller M, Smith BR, Maegdefessel L
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Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis. Nat. Nanotechnol. 2020 Feb;15(2):154-161
Flores AM, Hosseini-Nassab N, Jarr KU, Ye J, Zhu X, Wirka R, Leen Koh A, Tsantilas P, Wang Y, Nanda V, Kojima Y, Zeng Y, Lotfi M, Sinclair R, Weissman IL, Ingelsson E, Smith BR, and Leeper NJ
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Chitinase 3 like 1 (CHI3L1) is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability. Cardiovasc Res. 2021 Jan 20;cvab014
Tsantilas P, Lao S, Wu Z, Eberhard A, Winski G, Vaerst M, Nanda V, Wang Y, Kojima Y, Ye J, Flores A, Jarr KU, Pelisek J, Eckstein HH, Matic L, Hedin U, Tsao PS, Paloschi V, Maegdefessel L, Leeper NJ
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Effect of CD47 Blockade on Vascular Inflammation. N Engl J Med. 2021 Jan 28;384(4):382- 383
Jarr KU, Nakamoto R, Doan BH, Kojima Y, Weissman IL, Advani RH, Iagaru A, Leeper NJ
