Methods and compositions for the treatment of metabolic disorders

Abstract

The present invention is directed to a novel methods and compositions for the therapeutic intervention in hyperphenylalaninemia. More specifically, the specification describes methods and compositions for treating various types of phenylketonurias using compositions comprising BH4. Combination therapies of BH4 and other therapeutic regimens are contemplated.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation of U.S. patent application Ser. No. 10 / 991,573, which was filed on Nov. 17, 2004 and which claimed the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Ser. No. 60 / 520,767, which was filed Nov. 17, 2003. The entire disclosure of each of these priority applications is hereby incorporated herein by reference.BACKGROUND[0002]1. Field[0003]The present invention is generally directed to the therapeutic intervention of metabolic disorders, particularly those involving amino acid metabolism. More particularly, the present invention is directed to methods and compositions for the treatment of phenylketonuria, vascular diseases, ischemic or inflammatory diseases, or insulin resistance, or conditions and patients that would benefit from enhancement of nitric oxide synthase activity.[0004]2. Background of the Related Technology[0005]Phenylketonuria (PKU) is an inherited metabolic disorder that...

AI Technical Summary

Benefits of technology

The patent describes methods and compositions for treating metabolic disorders, particularly those involving amino acid metabolism. The invention is particularly useful for treating hyperphenylalaninemia, mild phenylketonuria, and vascular diseases, as well as other conditions such as insulin resistance, diabetes, and inflammation. The methods involve a combination of a protein-restricted diet and tetrahydrobiopterin (BH4) or a precursor or derivative thereof. The BH4 can be administered in a stabilized crystallized form or as a precursor or derivative of another compound. The invention can decrease the plasma concentration of phenylalanine by more than 600 μM. The protein-restricted diet can be a phenylalanine-restricted diet or a modified version of it. The invention can also be used to treat pregnant females with hyperphenylalaninemia. Overall, the invention provides effective methods for treating metabolic disorders and related conditions.

Problems solved by technology

Deficiencies in PAH in turn result in an excess of phenylalanine (Phe) in the brain and plasma.

Left undetected and untreated early in the life of an infant, PKU leads to irreversible damage of the nervous system, severe mental retardation and poor brain development.

Nevertheless, as mentioned above, these Phe levels are still significantly elevated in these individuals as compared to normal, non-PKU subjects and may present detrimental sequelae in at least pregnant women and very young patients.

HPA also results from defects in BH4 metabolism.

Thus, BH4 therapy either alone, or in combination with any other therapeutic intervention, has not being considered as a viable therapeutic intervention for the vast majority of individuals with HPA.

Despite the elucidation of the role of BH4 deficiency in HPA, treatment with BH4 has not been suggested because such treatment is very expensive, as high as $30,000 per year for an adolescent or adult, as compared with $6,000 for phenylalanine-restricted dietary therapy (Hanley, N. Engl. J. Med 348(17):1723, 2003).

Another significant problem with BH4 is that this compound is unstable and readily undergoes aerobic oxidation at room temperature (Davis et al., Eur. J. Biochem., Vol 173, 345-351, 1988; U.S. Pat. No. 4,701,455) and has a shelf-life of less 8 hours at room temperature (Berneggar and Blau, Mol. Genet. Metabol. 77:304-313, 2002).

Consequently, without supplementation, such a diet provides inadequate protein, energy, vitamins and minerals to support normal growth and development.

However, dietary protein restriction is at best an ineffective way of controlling PKU in many classes of patients.

For example, treatment is of paramount importance during pregnancy because high Phe levels may result in intrauterine retardation of brain development.

However, a low protein diet during pregnancy may result in retarded renal development and is thought to produce a subsequent reduction in the number of nephrons and potentially leads to hypertension in adulthood.

Poor patient compliance with a protein-restricted diet also is a problem.

The Phe-free protein formulae available are bitter tasting making it difficult to ensure that the patient consumes sufficient quantities of the protein to maintain the required daily intakes of protein, amino acids, vitamins, minerals, and the like.

This is particularly a problem with older children who may require up to 70 g, dry weight, of the formulas per day.

Many adolescent patients fail to rigorously follow the protein-restricted diet due to fears of peer attitude.

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