Method of treating one or more symptoms of pulmonary fibrosis by administering inhibitors of nicotinamide phosphoribotransferase
Inventors
Garcia, Joe G. N. • Hecker, Louise
Assignees
US Department of Veterans Affairs • University of Arizona
Publication Number
US-10993936-B2
Publication Date
2021-05-04
Expiration Date
2038-04-16
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Abstract
Inhibition of the expression and/or function of nicotinamide phosphoribosyltransferase (NAMPT) can reduce, prevent or reverse the pathophysiological vascular changes associated with the onset and progression of Pulmonary Fibrosis. Compositions and methods to inhibit the expression and function of NAMPT for treating and preventing Pulmonary Fibrosis in a subject in need are provided. The compositions and methods are useful for the modulation of pathophysiological processes that contribute to the development and progression of Pulmonary Fibrosis by reducing lung inflammation, aberrant myofibroblast accumulation and deposition of collagen in fibrotic foci.
Core Innovation
The invention provides compositions and methods that inhibit the expression and/or function of nicotinamide phosphoribosyltransferase (NAMPT) to reduce, prevent, or reverse the pathophysiological vascular changes associated with pulmonary fibrosis (PF). These methods include administering one or more NAMPT inhibitors or inhibitors of NAMPT receptors such as TLR4 to modulate processes contributing to the development and progression of PF, including reducing lung inflammation, aberrant myofibroblast accumulation, and collagen deposition in fibrotic foci.
Pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), represents a fatal, progressive disorder characterized by excessive scar tissue formation and irreversible lung damage leading to respiratory failure. Current treatment options moderately slow disease progression without definitively improving quality of life or reversing fibrosis. There is a critical need for improved therapies that address the cellular and molecular mechanisms underlying PF, particularly in aging populations where fibrosis is non-resolving and myofibroblasts are senescent and apoptosis-resistant.
The invention addresses this need by targeting NAMPT and its receptor interactions to hinder the pathological accumulation and persistence of myofibroblasts, which are central to the fibrotic process. By using inhibitors such as antibodies, antibody fragments, small molecules, and functional nucleic acids directed against NAMPT or TLR4, the compositions and methods provide effective reduction of fibrosis-related cellular activities, potentially reversing or preventing disease progression in patients at risk or diagnosed with PF.
Claims Coverage
The patent includes 23 claims focusing on methods of treating pulmonary fibrosis by administering inhibitors targeting NAMPT or its receptor. The following are the main inventive features extracted from the independent claims.
Method for treating pulmonary fibrosis symptoms by NAMPT inhibition
Administering to a patient an effective amount of one or more inhibitors of NAMPT, one or more inhibitors of a NAMPT receptor, or combinations thereof to increase the susceptibility of myofibroblasts to apoptosis, thereby treating one or more symptoms of pulmonary fibrosis.
Specific administration of NAMPT inhibitors in defined dosages
Administering one or more inhibitors of NAMPT in an amount between 0.1 and 15 mg/kg body weight of a human to reduce myofibroblast accumulation and PF symptoms.
Use of antibody fragments targeting NAMPT
Using F(Ab) and divalent F(Ab)2' antibody fragments that specifically bind to NAMPT to inhibit its function.
Antibodies reducing NAMPT and receptor interaction
Administering antibodies or antibody fragments that reduce interaction between NAMPT and its receptor, particularly toll-like receptor 4 (TLR4), to inhibit the NAMPT pathway.
Dosage regimens for NAMPT antibodies
Administering antibodies or fragments by infusion in amounts between about 10 mg and 400 mg, preferably between 50 mg and 200 mg, with infusion durations around one hour, repeated weekly, monthly, or less frequently.
Administration of functional nucleic acids to inhibit NAMPT
Administering functional nucleic acids such as antisense molecules, siRNA, miRNA, aptamers, ribozymes, triplex forming molecules, RNAi, or external guide sequences to inhibit NAMPT expression or function.
Administration of small molecule NAMPT inhibitors
Using small molecule inhibitors including FK-866, MS-1-82, Rari049, and Al-pii135, at dosages between about 1.0 mg/kg and 3.0 mg/kg body weight, with specific mention of Rari049 at about 2.5 mg/kg body weight.
Treatment of idiopathic and familial pulmonary fibrosis by NAMPT inhibition
Applying the methods to patients diagnosed with idiopathic pulmonary fibrosis or familial pulmonary fibrosis.
The independent claims collectively cover the therapeutic use of various NAMPT inhibitors—antibodies, functional nucleic acids, small molecules—and define effective dosages and administration regimens for treating pulmonary fibrosis by enhancing myofibroblast apoptosis and reducing fibrotic pathology.
Stated Advantages
Reduction or prevention of lung inflammation and tissue remodeling associated with pulmonary fibrosis.
Ability to decrease abnormal myofibroblast accumulation and excessive extracellular matrix deposition.
Potential to reverse or slow progression of pulmonary fibrosis beyond currently available therapies which only moderately delay decline.
Monthly dosing regimens that improve patient compliance and reduce injection site reactions compared to more frequent dosing.
Documented Applications
Treatment of pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and familial pulmonary fibrosis, by reducing symptoms such as dyspnea, fatigue, and right heart failure.
Administration of inhibitors to subjects at risk of developing pulmonary fibrosis to prevent onset or progression of the disease.
Use in acute and chronic settings of pulmonary fibrosis, including administration in intensive care settings as rescue or salvage therapy.
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