Vision of correction for classic homocystinuria

Abstract

Inherited metabolic disorders are often characterized by the lack of an essential enzyme and are currently treated by dietary restriction and other strategies to replace the substrates or products of the missing enzyme. Patients with homocystinuria lack the enzyme cystathionine β-synthase (CBS), and many of these individuals do not respond to current treatment protocols. In this issue of the JCI, Bublil and colleagues demonstrate that enzyme replacement therapy (ERT) provides long-term amelioration of homocystinuria-associated phenotypes in CBS-deficient murine models. A PEGylated form of CBS provided long-term stability and, when used in conjunction with the methylation agent betaine, dramatically increased survival in mice fed a normal diet. The results of this study provide one of the first examples of ERT for a metabolic disorder and suggest that PEGylated CBS should be further explored for use in patients.

Figure 1. ERT for homocystinuria.

(A) In healthy individuals, methionine from dietary sources is metabolized into homocysteine, which is then converted into cysteine by the enzyme CBS. (B) Homocystinuria develops in individuals lacking CBS. Elevated homocysteine results in a variety of adverse effects, including thromboembolism, connective tissue disorders, Marfanoid habitus, osteoporosis, and cognitive impairment. Homocysteine and methionine are elevated to extremely high concentrations. (C) In this issue, Bublil and colleagues developed a strategy for ERT (5). In a murine model of homocystinuria, a PEGylated form of CBS provided long-term reduction of homocysteine levels. Moreover, the introduction of a C15S mutation reduced aggregation of the recombinant, PEGylated enzyme.