Methods of Using Compositions Comprising Variants and Fusions of FGF19 Polypeptides for Treatment of Nonalcoholic Fatty Liver Disease

Abstract

The invention relates to variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of FGF19 and / or FGF21, and variants or fusions of FGF19 and / or FGF21 proteins and peptide sequences (and peptidomimetics), having one or more activities, such as bile acid homeostasis modulating activity, and methods for and uses in treatment of bile acid and other disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 15 / 895,812 filed Feb. 13, 2018, which is a division of U.S. Ser. No. 14 / 655,314 filed Jun. 24, 2015, now U.S. Pat. No. 9,925,242, which is a 371 national stage application of international application Serial No. PCT / US2013 / 077782 filed Dec. 26, 2013, which claims the benefit of U.S. Ser. No. 61 / 746,499 filed Dec. 27, 2012, U.S. Ser. No. 61 / 779,604 filed Mar. 13, 2013, and U.S. Ser. No. 61 / 887,129 filed Oct. 4, 2013, each of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The invention relates to variants of fibroblast growth factor 19 (FGF19) proteins and peptide sequences (and peptidomimetics) and fusions of FGF19 and / or fibroblast growth factor 21 (FGF21) proteins and peptide sequences (and peptidomimetics), and variants of fusions of FGF19 and / or FGF21 proteins and peptide sequences (and peptidomimetics) that modulate bile acid homeostasis, and me...

AI Technical Summary

Problems solved by technology

As surfactants or detergents, bile acids are potentially toxic to cells, and the size of the bile acid pool is tightly regulated within the liver and intestine to prevent cytotoxic accumulation.

Bile acid synthesis (along with ileal resection) disrupts the enterohepatic circulation of bile acids, decreases plasma total and LDL cholesterol, and increases levels of HDL cholesterol, apolipoprotein (apo)-AI, and triglycerides.

More particularly, when intestinal expression of the bile acid transporters is reduced, the intestine is less efficient at bile acid reabsorption (Type 1 bile acid malabsorption).

Similarly, if intestinal motility is affected by gastro-intestinal surgery, or bile acids are deconjugated by small intestinal bacterial overgrowth, absorption is less efficient (Type 3 bile acid malabsorption).

Failure to form bile results in progressive cholestatic liver injury and death.

Patients with advanced cholestasis feel ill, tire easily, and are often nauseated.

Phenothiazine-derivative agents, including chlorpromazine, can cause sudden fever and inflammation, although symptoms usually disappear after cessation of the agents.

Itching over the skin may be severe if the condition is advanced.

If not diagnosed or if diagnosed improperly, such inborn errors can result in liver failure or progressive chronic liver disease.

This condition develops a short time after treatment begins, follows a predictable pattern, and usually causes liver damage.

As the disease progresses, persistent toxic build-up of bile acids causes progressive liver damage marked by chronic inflammation and fibrosis.

Symptoms may also include weight loss and fatigue.

Unfortunately, many patients do not tolerate cholestyramine and colestipol, often because of the poor texture and taste of the resin powder.

Despite the efficacy and safety of UDCA administration for cholesterol gallstone dissolution, it is not frequently used today because of the success of laparoscopic cholecystectomy, which provides a rapid cure for symptomatic disease.

In patients with a short-bowel syndrome, a bile acid deficiency occurs in the proximal intestine, leading to impaired micellar solubilization.

This, plus the decreased surface area and rapid transit time, leads to severe fat malabsorption.

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