Diagnosis, hormone replacement therapy for HIV positive females, gene therapy; metabolic disorders; antidiabetic, anticholesterol, hypoglycemic agents
Inventors
DePaoli, Alexander M. • Taylor, Simeon I. • Oral, Elif A. • Garg, Abhimanyu
Assignees
Amgen Inc • University of Texas System • US Department of Health and Human Services
Publication Number
US-7183254-B2
Publication Date
2007-02-27
Expiration Date
2022-10-22
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Abstract
Leptin, leptin analogs, and leptin derivatives are used to treat patients with lipoatrophy. Leptin is effective against conditions of lipoatrophy for both genetic and acquired forms of the disease. A therapeutically effective amount of leptin can be administered in a variety of ways, including subcutaneously and using gene therapy methods. Methods of the present invention contemplate administration of leptin, leptin analogs, and leptin derivatives to patients having a leptin level of approximately 4 ng/ml or less before treatment.
Core Innovation
The invention relates to the therapeutic use of leptin, leptin analogs, and leptin derivatives to treat human lipoatrophy and its associated metabolic abnormalities. It provides methods to administer a therapeutically effective amount of leptin through various routes, including subcutaneous injection and gene therapy. The invention also includes a method to determine predisposition to leptin treatment by measuring serum leptin concentrations, particularly in patients with levels of approximately 4 ng/ml or less prior to treatment.
Lipoatrophy syndromes are characterized by loss or paucity of adipose tissue and are often associated with severe metabolic abnormalities such as hypertriglyceridemia, insulin resistance, and diabetes mellitus. These syndromes may be genetic, such as Dunnigan-type familial partial lipodystrophy or congenital generalized lipodystrophy, or acquired, for example in HIV positive patients treated with highly active antiretroviral therapy (HAART). Prior treatments to address insulin resistance and metabolic defects in lipoatrophy have been largely ineffective, and some, like troglitazone, have had serious adverse effects. There exists, therefore, a need for alternative treatments for lipoatrophy and its metabolic consequences.
The invention addresses this need by demonstrating that leptin replacement therapy improves metabolic abnormalities associated with lipoatrophy in humans, including HIV-associated lipoatrophy. It shows that administration of leptin to patients with low endogenous leptin levels improves glucose metabolism, insulin sensitivity, and lipid profiles, as well as reducing liver volume and hepatomegaly. This treatment is effective in both genetic and acquired forms of lipoatrophy, representing a novel and effective approach to managing this condition and its metabolic complications.
Claims Coverage
The patent includes multiple independent claims focusing on methods to treat lipoatrophy using leptin or leptin derivatives, and methods for determining patient predisposition to such treatments, outlining various conditions, patient characteristics, and combinations with other therapies.
Method of treating lipoatrophy with leptin or derivatives
Administering leptin, leptin analog, or leptin derivative at an effective dose to treat a human patient with lipoatrophy.
Selecting patients based on leptin serum levels
Treating lipoatrophic patients who have a leptin level of 4 ng/ml or less (and preferably 2 ng/ml or less) prior to administration.
Treatment of both genetic and acquired lipoatrophy
Applying the method to patients with acquired lipoatrophy, including HIV positive individuals undergoing HAART, and to patients with genetic forms such as congenital generalized lipoatrophy.
Addressing metabolic abnormalities associated with lipoatrophy
Treating metabolic abnormalities like hyperglycemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, and insulin resistance as part of the lipoatrophy condition.
Subcutaneous administration of specific recombinant leptins
Administering recombinant human leptin of SEQ ID NO: 1 or SEQ ID NO: 2 subcutaneously, optionally in pharmaceutically acceptable carriers or diluents.
Method of determining patient predisposition by leptin level and gender
Determining leptin levels prior to treatment and ascertaining thresholds of approximately 4 ng/ml for females and 2 ng/ml for males to predict treatment response.
Combination therapies including leptin
Administering a pharmaceutical regimen combining leptin, leptin analog or derivative with protease inhibitors or with compounds such as thiazolidinediones, fibrates, statins, and metformin to treat lipoatrophy.
The claims cover methods of treating lipoatrophy and its metabolic complications using leptin or derivatives, patient selection by endogenous leptin level (accounting for gender), routes of administration, specific recombinant leptin sequences, and combination therapies encompassing protease inhibitors and anti-diabetic or lipid-lowering agents.
Stated Advantages
Leptin replacement therapy dramatically improves glucose metabolism and triglyceride levels in patients with lipoatrophy.
Treatment reduces liver size and associated hepatomegaly in affected patients.
Leptin acts as an insulin-sensitizing and insulin-sparing agent in humans, improving metabolic control.
Leptin therapy can decrease patients' food intake and resting metabolic rate, aiding in metabolic improvements.
Provides an effective alternative to conventional therapies which have been largely refractory or have caused adverse effects.
Documented Applications
Treatment of human lipoatrophy, including genetic forms such as congenital generalized lipodystrophy and acquired forms such as HIV-associated lipoatrophy related to HAART therapy.
Treatment of metabolic abnormalities associated with lipoatrophy, including hyperglycemia, diabetes, insulin resistance, hypertriglyceridemia, dyslipidemia, hypercholesterolemia, atherosclerosis, and vascular restenosis.
Use in hormone replacement therapy to patients with low serum leptin concentrations.
Diagnostic use determining predisposition for leptin treatment by measuring serum leptin levels in patients.
Combination therapy regimens including leptin and protease inhibitors or anti-diabetic and lipid-lowering agents such as thiazolidinediones, fibrates, statins, and metformin.
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