Treatment of sepsis and related inflammatory conditions by local neuromodulation of the autonomic nervous system

Inventors

Bright, Corinne • VENKATESWARA-RAO, Kondapavulur T. • STEIN, Emily

Abstract

Methods of use, formulations, and devices for delivering therapeutic drugs locally to the region of the spleen are described herein. A method for treating sepsis and other inflammatory disease conditions can include inserting a drug delivery system inside the body, advancing the device to the spleen through the splenic artery, splenic vein or other blood vessel adjacent to the splenic nerves, or within a ligament associated with the spleen, such as the splenorenal or gastrosplenic ligaments.

Core Innovation

The document describes local chemo-neuromodulation by targeting autonomic innervation of the spleen and other lymphoid organs to treat sepsis and inflammatory conditions. It frames a neuro-immune mechanism in which sympathetic splenic nerve norepinephrine/acetylcholine signaling and the cholinergic anti-inflammatory pathway modulate pro- and anti-inflammatory cytokines, including TNF-b1, IL-1b2, IL-6, HMGB1, IL-10, and TGF-b2.

The approach includes delivering a therapeutic agent locally to nerve target sites outside of the vasculature while positioning a catheter in a blood vessel directly proximate to the nerve target site. In one described route, delivery to the spleen or related structures is performed from the splenic artery or via the splenic vein, including perivascular or ligament-based routes associated with the splenorenal and gastrosplenic ligaments.

The document specifies injectable in situ forming hydrogel slurry formulations configured to limit spread of the hydrogel beyond the nerve target site, including localization and sustained-release strategies using hydrogels, implants, microspheres, and nanoparticles. It further describes catheter/needle systems with imaging guidance, and endovascular catheter architectures that include anchoring and vessel-wall penetration using a microneedle or micro-aperture for perivascular delivery, together with monitoring or verification using nerve stimulation/electrophysiology or electrode sensors.

Claims Coverage

The partial claim set provided contains one independent claim (clm-00001). Across the dependent claims, the inventive coverage focuses on three core inventive groupings: (i) catheter positioning and access from a pulmonary artery to a nerve target site outside the blood vessel, (ii) neuromodulatory drug delivery as an injectable in situ forming hydrogel slurry configured to limit hydrogel spread, and (iii) specified refinements to the nerve target site and delivery mechanics via catheter penetration and alternate delivery forms.

The claim coverage centers on percutaneous catheter positioning in a blood vessel directly proximate to a nerve target site accessible from a pulmonary artery, with extracascular delivery of amitriptyline or other neuromodulatory drug as an injectable in situ forming hydrogel slurry configured to limit hydrogel spread. Dependent claims further narrow the nerve target to specific cranial nerves, ganglia, or plexuses, and add refined delivery options including implant delivery and catheter penetration of the blood vessel wall.

Stated Advantages

Documented Applications