Therapeutic approach to lung disease

Inventors

Sun, Xin • XU, Jinhao • Young, Lisa

Assignees

Childrens Hospital of Philadelphia CHOP • Vanderbilt University • University of California San Diego UCSD

Abstract

The present disclosure provides a novel animal model of NEHI, and method of preventing and/or treating a pulmonary disease, particularly the lung-based complications in NEHI, such as pulmonary edema, by targeting the PNEC product, such as the CGRP signaling. Also disclosed is the pharmaceutical composition for preventing and/or treating a pulmonary edema and/or other pulmonary disease, particularly, NEHI, comprising one or more CGRP signaling antagonist and/or inhibitor of the present disclosure.

Core Innovation

The disclosure describes a first NEHI mouse model engineered with an NKX2-1 point mutation (Nkx2-1 R191L). In this model, NEHI-like phenotypes are reported, including pulmonary neuroendocrine cell (PNEC) hyperplasia, growth retardation/failure to thrive, reduced oxygen saturation, and pulmonary edema.

The disclosure identifies excess PNEC-derived calcitonin gene-related peptide (CGRP) as a mediator of the NEHI-associated pulmonary edema and related physiological deficits. CGRP levels are reported as elevated in bronchoalveolar lavage, and exogenous intranasal CGRP is reported to induce increased lung wet-to-dry ratio.

Genetic inactivation of Calca (CGRP) in the NEHI background is reported to rescue edema and gas-exchange defects. Endothelial-specific inactivation of the CGRP receptor co-receptor Calcrl (Calcrl cKO) is reported to reduce edema and improve oxygen saturation, supporting CGRP signaling as a target.

The disclosure further provides pharmacological evidence that an intranasal CGRP receptor antagonist, BIBN-4096, reverses NEHI-associated pulmonary edema and physiological deficits. The document also describes pharmaceutical compositions and administration concepts using CGRP signaling antagonists, including small-molecule CGRP antagonists for inhalation delivery.

Claims Coverage

The partial content includes two independent claims: a method for treating pulmonary edema and a pharmaceutical composition for treating pulmonary edema. The inventive focus across the independent claims is the use of therapeutically effective CGRP signaling antagonists, selected from specified compound lists.

Across the independent claims, the disclosed coverage centers on pulmonary edema treatment by administering therapeutically effective amounts of specified CGRP signaling antagonists, either as a method of treatment or as a pharmaceutical composition.

Stated Advantages

Documented Applications