In vivo alteration of a mutant human protein using the free thiol cysteamine

Inborn errors of metabolism in which there is a mutant protein due to a cysteine for arginine substitution may be amenable to treatment with the free thiol cysteamine. Evidence for this derives from patients with type III hyperlipoproteinemia, who are homozygous for apolipoprotein E2, which differs in charge and in vitro function based on a single such amino acid substitution. The plasma of a type III hyperlipoproteinemic patient, when made at least 50 microM with respect to cysteamine in vitro, demonstrated a charge shift of the apolipoprotein E isoelectric focusing pattern from the E2 to the normal E3 and E4 positions. Two children treated for cystinosis with cysteamine each exhibited some charge alteration of their apoE3 to a form migrating in the apoE4 position. The use of thiol reagents such as cysteamine to specifically alter selected mutant human proteins, such as antithrombin III Toyama, may be added to our therapeutic armamentarium in the treatment of life-threatening metabolic disorders.