Methods and materials for treating conditions associated with metabolic disorders

Abstract

Disclosed are methods for treating a subject suffering from phenylketonuria and/or phenylalanemia. The methods include, in part, enterally administering to the subject a LNAA supplement in which the weight ratio of Leu to Val is greater than 2:1; in which the weight ratio of Leu to iLeu is greater than 3:1; or which includes one or more LNAAs and which further includes Lys. LNAA supplements are also disclosed. Also disclosed are methods for treating a subject suffering from a condition involving a metabolic disorder involving the metabolism of a first amino acid X. The method includes enterally administering to the subject a composition which (i) is substantially free from the first amino acid X and (ii) which includes a second amino acid Y that competes with amino acid X at a gastrointestinal tract transporter.

Description

FIELD OF THE INVENTION The subject invention is directed, generally, to methods and materials for treating conditions associated with metabolic disorders and, more particularly, to methods and materials for treating conditions associated with metabolic disorders of particular amino acids. BACKGROUND OF THE INVENTION A number of conditions which afflict humans and other animals are attributable to disorders in metabolizing particular amino acids. In many of these conditions, treatment involves restricting the dietary intake of the particular amino acid or amino acids associated with the condition. However, therapies based on dietary restriction requires patient compliance and also requires that the patient know whether a particular food contains the particular amino acid or amino acids associated with the condition. For example, phenylketonuria (“PKU”) is hyperaminoacidemia of phenylalanine (Phe) associated with an inborn error of phenylalanine metabolism, mutation of the gene enc...

AI Technical Summary

Benefits of technology

The present invention also relates to a method for treating a subject suffering from a condition involving a metabolic disorder involving the metabolism of a first amino acid X. The method includes enterally administering to the subject a composition which (i) is substantially free from the first amino acid X and (ii) which includes a second amino acid Y that competes with amino acid X at a gastrointestinal tract transporter. As one skilled in the art will appreciate, the composition can further include (i.e., in addition to second amino acid Y) other components, such as other amino acids (e.g., one or more other amino acids which compete with amino acid X at a gastrointestinal tract transporter).

Problems solved by technology

(1980) (“Pardridge”)), untreated “classic” PKU patients have plasma Phe levels above 1 mM (e.g., plasma Phe levels of from about 1 mM to about 2.5 mM or more), and, although treatment with a low-Phe diet has a goal of reducing plasma Phe to below 0.3 mM, this is difficult to attain due to dietary compliance problems.

The excessive levels of plasma phenylalanine observed in PKU combined with the relatively high affinity of Phe for binding sites on carrier protein of the neutral amino acid transport system in the blood-brain barrier (“BBB”) leads to (i) accumulation of Phe and its neurotoxic metabolites (e.g., phenylpyruvate, phenylacetate, phenyllactate) in the brain and (ii) depressed levels of non-Phe neutral amino acids entering the brain, resulting in disturbed brain development and function, since key cerebral pathways of metabolism (e.g., synthesis of neurotransmitters) require precursor amino acids, such as tyrosine.

Although a diet low in phenylalanine can reduce plasma Phe levels in “classic” PKU below 0.3 mM and ameliorate the mental retardation associated with untreated PKU, dietary compliance becomes problematic as PKU patients reach adolescence, leading to a rise in plasma Phe levels and to both loss in intelligence and white matter changes in the brain.

Nutritional deficiencies can also result from Phe-restricted diets.

However, efficacy of these dietary amino acid supplement treatments has been controversial.

More particularly, tyrosinemia is a disorder caused by a defect in the terminal enzyme of the tyrosine metabolic pathway, leading to accumulation of fumarylacetoacetate, which converts to succinylacetone, which accumulates and is toxic to the liver.

However this is a difficult and expensive therapy.

However, safety issues regarding NTBC are unanswered to date, and dietary restriction of tyrosine and phenylalanine is dependent on patient knowledge and compliance, which, as mentioned above, can be problematic, especially in adolescents and adults.

However, safety issues regarding NTBC are unanswered to date, and dietary restriction of tyrosine and phenylalanine is dependent on patient knowledge and compliance, which, as mentioned above, can be problematic.

However, dietary restriction of methionine is dependent on patient knowledge and compliance, which, as mentioned above, can be problematic.

A defect in one step of a multistep metabolic pathway which converts the BCAAs to energy, results in accumulation of an intermediate metabolite of the BCAA to toxic levels, causing disease.

However, as discussed above, successful management of such diseases and conditions by dietary restriction of a particular amino acid or a particular set of amino acids is dependent on patient knowledge and compliance, which can be problematic.