Methods for improved endovascular thrombectomy using 3,3′-diindolylmethane
Inventors
Zeligs, Michael A. • Jacobs, Irwin C.
Assignees
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Publication Number
US-11529331-B2
Publication Date
2022-12-20
Expiration Date
Abstract
Provided herein are methods of enhancing mechanical thrombectomy during endovascular therapy for acute thrombosis using 3,3′-diindolylmethane.
Core Innovation
The invention relates to DIM (3,3′-diindolylmethane) and DIM analogs as small-molecule NETosis inhibitors for use in acute ischemic stroke (AIS) with large vessel occlusion (LVO) undergoing endovascular therapy (EVT) with mechanical thrombectomy (MT). It addresses an unmet need associated with NET-driven thrombus propagation that is linked to longer recanalization times and more device passes.
The disclosed approach is centered on inhibiting PMN activation and inhibiting NET formation and NET propagation to reduce thrombus burden in the context of EVT with MT. The description supports the mechanistic rationale with extracellular DNA release concepts using Sytox Orange extracellular DNA release assay and micrococcal nuclease (MNase) assay, and with histologic and immunofluorescence evidence in an arterial thrombosis mouse model using fibrin content and immune staining (CD45, Ly6G, CitH3) to show reduced fibrin and reduced leukocytes/neutrophils/NETs after oral and IV DIM dosing.
The invention further describes DIM formulation approaches including oral self-microemulsifying drug delivery system (SMEDDS) and intravenous (IV) premix or intravenous microparticle suspension. Example formulations are referenced as BR-9001 SMEDDS and BR2022 IV premix, and the description discusses adjunct or combination/co-administration strategies with other NET inhibitory or inflammatory agents, including example clinical trial design elements and dosing ranges.
Claims Coverage
The document includes one independent claim and multiple dependent claims that refine the method by specifying adjunct optional tPA use, administration and formulation details, anatomic AIS territory, an MT outcome measure, and administration timing before EVT.
Administering DIM to improve total cumulative neurobehavioral functional outcome during EVT with MT for AIS with LVO
A method of improving total cumulative neurobehavioral functional outcome in a subject with AIS undergoing EVT with MT for LVO by administering a therapeutically effective amount of 3,3′-diindolylmethane (DIM), optionally in combination with recombinant tissue plasminogen activator (tPA).
Oral DIM using a self-microemulsifying drug delivery system formulation
The method further provides that the DIM is orally administered using a self-microemulsifying drug delivery system formulation.
DIM SMEDDS formulation with specified excipients
The method where the DIM formulation includes DIM and specified excipients including caprylocaproyl polyoxyl-8 glycerides, lauroyl polyoxyl 32 glycerides, polyethylene-polypropylene-polyethylene copolymer, oleoyl polyoxyl-6 glycerides, and phosphatidyl choline.
AIS defined by cerebral artery territory and MT context
The method where the AIS involves the anterior, middle, or posterior cerebral arteries and is subject to MT.
Improving clot retrieval success and restoration of cerebral circulation for MT
The method further defined to improve the success rate of clot retrieval and restoration of cerebral circulation for MT in AIS.
Administering DIM before EVT
The method including administering DIM to the subject before EVT.
Overall, claim coverage centers on administering therapeutically effective DIM to improve total cumulative neurobehavioral functional outcome in AIS subjects with LVO undergoing EVT with MT, with optional recombinant tPA, and further refines the approach by specifying oral SMEDDS delivery, cerebral artery territory, an MT success and restoration outcome, and timing of DIM administration before EVT.
Stated Advantages
Improving total cumulative neurobehavioral functional outcome in a subject with AIS undergoing EVT with MT for LVO.
Improving the success rate of clot retrieval and restoration of cerebral circulation for MT in AIS.
Documented Applications
Adjunct or combination use of DIM and DIM analogs as NETosis inhibitors in acute ischemic stroke (AIS) with large vessel occlusion (LVO) undergoing endovascular therapy (EVT) with mechanical thrombectomy (MT), including optional use with recombinant tissue plasminogen activator (tPA).
Oral administration using a self-microemulsifying drug delivery system and IV administration via premix or intravenous microparticle suspension in the AIS and EVT with MT context.
Reducing NET-related thrombus propagation effects in an arterial thrombosis mouse model associated with fibrin content and leukocyte, neutrophil, and NET markers after oral and IV DIM dosing.
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