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Title:  Use of leptin for treating human lipoatrophy and method of determining predisposition to said treatment
United States Patent: 
7,183,254
Issued: 
February 27, 2007

Inventors: 
DePaoli; Alexander M. (Santa Barbara, CA), Taylor; Simeon I. (Skillman, NJ), Oral; Elif A. (Ann Arbor, MI), Garg; Abhimanyu (Dallas, TX)
Assignee: 
Amgen, Inc. (Thousand Oaks, CA)
Appl. No.: 
10/623,189
Filed: 
July 18, 2003


 

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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.

SUMMARY OF THE INVENTION

The present invention provides for the use of leptin in treating humans with lipoatrophy and its associated metabolic abnormalities, and provides a method of determining a predisposition to leptin treatment. In one embodiment, human leptin is used in hormone replacement therapy in lipoatrophic patients having reduced serum concentration of leptin. Preferably, recombinant human leptin or leptin analog or derivative is used. Leptin proteins may be administered subcutaneously or systemically, or through any other routes including methods in gene therapy.

In assessing the predisposition of lipoatrophic patient to treatment with leptin, serum concentration of leptin may be determined. Preferably, patients with serum leptin concentration of less than 4 ng/ml, and more preferably, less than 2 ng/ml, and most preferred, less than 0.5 ng/ml, are subjected to leptin treatment. It is also preferred that treatment with leptin be given to female patients with <4 ng/ml of serum leptin concentration and to male patients with <3 ng/ml of serum leptin concentration. More preferably, leptin is given to male patients with <2 ng/ml of serum leptin concentration.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The adipocyte hormone leptin plays a central role in energy homeostasis. It was first discovered in the obese mouse as the missing serum factor that decreased food intake and body weight upon replacement (Zhang et al., 1994; Pelleymounter et al., 1995). Because of these initial observations, much of the earlier therapeutic attempt using this hormone has been in the treatment of obesity. Serum leptin concentrations in the majority of humans with obesity are high, and a state of leptin resistance is thought to exist (Mantzoros et al., 2000). Thus far, the effect of recombinant human leptin has been limited in causing weight loss in obese individuals except in the state of congenital leptin deficiency (Heymsfield et al., 1999; Farooqi et al., 1999).

The present invention provides for the feasibility of using leptin for the treatment of lipoatrophy and its associated metabolic abnormalities in humans such as hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, and insulin resistance. Results from studies in HIV patients have shown that decrease in serum concentrations of leptin is closely associated with the onset of acquired lipoatrophy. Furthermore, leptin replacement in lipoatrophic patients dramatically improves glucose and triglyceride metabolism even after all other potential therapies have been extinguished. In all these leptin replacement therapy cases, the baseline serum concentration of leptin was less than 4 ng/ml.

In one severe case of acquired lipoatrophy, the patient (having serum leptin concentration of <0.5 ng/ml) suffered from severe hypertriglyceridemia, diabetes, painful eruptive cutaneous xanthomata, and massive hepatomegaly. Leptin treatment over four months dramatically improved the patient's hypertriglyceridemia and hyperglycemia that allowed for discontinuation of plasmapheresis and other diabetes medications. The improvements were also accompanied by disappearance of the cutaneous xanthomata and the patient's liver volume decreased by 40%. Thus, these data show that leptin replacement therapy may effectively be used to treat acquired or congenital lipoatrophy and its associate metabolic abnormalities in human.

Furthermore, based on these data, it may be extrapolated that patients with less than 4 ng/ml serum concentration for leptin may be a preferred group of patients for replacement therapy with leptin. Leptin levels may be measured using a body fluid, most preferably blood or some portion thereof. Here, serums from individuals were used. Other body fluids may also contain measurable leptin, such as whole blood, cerebral spinal fluid, plasma, and possibly urine. The present measurements of 4 ng of leptin/ml of serum may be correlated to corresponding levels in other body fluids. For example, if whole blood is used, the leptin concentration will be diluted to account for the diluting effect of using unfractionated blood.

One skilled in the art will be able to ascertain effective dosages by administering leptin, leptin analog or leptin derivative and observing the desired therapeutic effect. The goal of replacement therapy is to achieve near physiological concentrations of leptin in the plasma. It is estimated that the physiological replacement dose of leptin is about 0.02 mg per kilogram of body weight per day for males of all ages, about 0.03 mg per kilogram per day for females under 18 years and about 0.04 mg per kilogram per day for adult females. When attempting to achieve near physiological concentrations of leptin, one may, for example, treat a patient with 50 percent of the estimated replacement dose for the first month of treatment, 100 percent of the replacement dose for the second month of treatment, 200 percent of the replacement dose for the third month of treatment, etc. During the course of leptin replacement therapy, one can measure certain biochemical markers to monitor therapeutic effect of the leptin treatment. Glycosylated hemoglobin (HbA.sub.1c) levels and triglyceride (fasting) levels are among the preferred markers to measure therapeutic effect to monitor the efficacy of leptin treatment.

Alternatively, serum leptin levels can be measured using commercially available immunoassays, as further disclosed in the Examples below. In general, a diagnostic assay for measuring the amount of leptin in the blood (or plasma or serum) may first be used to determine endogenous levels of protein. Such diagnostic tools may be in the form of an antibody assay, such as an antibody sandwich assay. The amount of endogenous leptin is quantified initially, and a baseline is determined. The therapeutic dosages are determined as the quantification of endogenous and exogenous leptin protein (that is, leptin, leptin analog or leptin derivative found within the body, either self-produced or administered). Monitoring the leptin levels of a patient is continued over the course of therapy.

The present invention also provides methods of using pharmaceutical compositions of leptin, leptin analog or leptin derivative. Such pharmaceutical compositions may be for administration for injection, or for oral, pulmonary, nasal, transdermal or other forms of administration. Preferred methods of administering the leptin proteins include subcutaneously, systemically and by gene therapy methods.

In general, pharmaceutical compositions of the present invention comprise effective amounts of leptin, leptin analog or leptin derivative together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol); incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hylauronic acid may also be used, and this may have the effect of promoting sustained duration in the circulation. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the present proteins and derivatives. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435 1712 which are herein incorporated by reference. The compositions may be prepared in liquid form, or may be in dried powder, such as lyophilized form. Implantable sustained release formulations are also contemplated, as are transdermal formulations.

To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride. The list of potential nonionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the protein or derivative either alone or as a mixture in different ratios.

Additives that potentially enhance uptake of the leptin, leptin analog or leptin derivative protein are for instance the fatty acids oleic acid, linoleic acid and linolenic acid.

Controlled release formulation may be desirable. The leptin, leptin analog or leptin derivative protein could be incorporated into an inert matrix which permits release by either diffusion or leaching mechanisms e.g., gums. Slowly degenerating matrices may also be incorporated into the formulation, e.g., alginates, polysaccharides. Another form of a controlled release of this therapeutic is by a method based on the Oros therapeutic system (Alza Corp.), i.e., the leptin, leptin analog or leptin derivative protein is enclosed in a semi-permeable membrane, which allows water to enter and push the protein out through a single small opening due to osmotic effects. Some enteric coatings also have a delayed release effect.

Further, improved kits for determining the predisposition of a human patient with lipoatrophy to respond to treatment with leptin, leptin analog or leptin derivative are contemplated by the present invention. In one aspect, an improved kit may provide means for determining whether the leptin level of the patient prior to said leptin treatment is less than or equal to approximately 4 ng/ml. In a related aspect, an improved kit may consider the gender of a patient when determining a leptin level in the patient prior to said leptin treatment. Then, the kit may provide means for determining whether the leptin level of the patient prior to said leptin treatment is less than or equal to approximately 2 ng/ml if the patient is male, or less than or equal to approximately 4 ng/ml if the patient is female. Preferably, the kit comprises instructions for use. The kit may also comprise reagents, tubes, packaging, and/or other reaction components.
 


Claim 1 of 30 Claims

1. A method of treating a human patient with a condition of lipoatrophy, which comprises administering to the patient a dose of leptin, leptin analog or leptin derivative effective to treat the condition of lipoatrophy.

 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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