Polynucleotide agents targeting factor xii (hageman factor) (F12) and methods of use thereof

Abstract

The invention relates to polynucleotide agents targeting Factor XII (F12) gene, and methods of using such polynucleotide agents to inhibit expression of Factor XII and to treat subjects having a Factor XII-associated disease, e.g., heredity angioedema (HAE), prekallikrein deficiency, malignant essential hypertension, hypertension, end stage renal disease, or Fletcher Factor Deficiency.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 16 / 068,444, filed on Jan. 17, 2019, which is a 35 U.S.C. § 371 national stage filing of International Application No. PCT / US2017 / 012420, filed on Jan. 6, 2017, which in turn claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 276,279, filed on Jan. 8, 2016. The entire contents of each of the foregoing applications are hereby incorporated herein by reference.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 29, 2020, is named 121301_05303_SL.txt and is 133,714 bytes in size.BACKGROUND OF THE INVENTION[0003]Hereditary Angioedema (HAE) is a rare autosomal dominant disorder that causes recurrent edema and swelling of the extremities, face, larynx, upper respiratory tract, abdomen, trunk, and genitals...

AI Technical Summary

Benefits of technology

The present invention provides polynucleotide agents and compositions that target nucleic acids encoding a Factor XII (F12) gene and interfere with its function. These agents can be used to treat disorders associated with elevated expression of F12, such as hereditary angioedema, Flectcher Factor Deficiency, Essential hypertension, and Contact Activation Pathway-Associated Diseases. The invention also provides methods and combination therapies for using these agents. The polynucleotide agents are designed to be complementary to the nucleotide sequence of the target region of the F12 gene.

Problems solved by technology

Edema swelling is often disfiguring and disabling, results in frequent hospitalization, and patients may require psychiatric care to treat disease-associated anxiety.

Abdominal attacks can cause severe pain, nausea and vomiting, and may lead to inappropriate surgeries.

Furthermore, over half of HAE patients also experience life-threatening laryngeal edema during their lifetime that may require emergency tracheostomy to prevent asphyxiation.

HAE affects an estimated 6,000 to 10,000 individuals of varying ethnic groups in the United States and causes significant economic harm to patients, accounting for 15,000 to 30,000 hospital visits and 20 to 100 sick days per year.

Consequently, mutations causing C1INH deficiency or F12 gain-of-function result in excess production of bradykinin and onset of HAE angioedema.

Androgens are unsuitable for short-term treatment of acute attacks because they take several days to become effective, and they can have significant side effects and may affect growth and development adversely.

As a result, androgens are used only for long-term prophylaxis and are typically not administered to pregnant women or children.

Furthermore, current therapeutics used to treat acute attacks must be administered intravenously numerous times per week or may cause side-effects that require drug administration and subsequent patient monitoring in a hospital, thereby limiting their regular prophylactic use to manage the disease long-term.

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