Treatment of Genetic Disease

ABSTRACT

The evaluation of improvements in the response to treatment of 65 inborn errors of metabolism reviewed in 1993 has been reviewed recently by Campeau and colleagues (see Supplement attached to this chapter). Improvements in the overall response to treatment have resulted from increased understanding of the pathophysiology of the conditions, improved diagnostic technologies, and acceleration of protein-replacement strategies with the increase in small-molecule treatments, including substrate-reduction therapy for the lysosomal disorders, chaperone therapy, and drugs causing stop-codon read-through.

TREATMENT AT THE METABOLITE LEVEL: METABOLITE INHIBITORS

For the treatment of lysosomal storage disorders owing to defects in the enzymes involved in glycosphingolipid degradation (including Gaucher types 1, 2, and 3; Fabry; Tay-Sachs; Sandhoff; and G_M1 gangliosidosis), an approach has been developed to decrease the number of accumulated glycosphingolipid substrates derived from glucosylceramide by reducing the biosynthesis of glucosylceramide by inhibition of glucosylceramide synthase, the enzyme that catalyzes the synthesis of the substrate and first step in biosynthesis of glycosphingolipids. Glycosphingolipids are found in the membranes of all eukaryotic cells and are proposed to function primarily at the cell surface and to participate in membrane microdomain/rafts essential for the signaling of certain proteins. The therapeutic effect of substrate-reduction therapy is related to the residual activity of the involved deficient protein (Platt et al.,³⁶; Cox,⁸).

Vunnam and Radin⁴⁸ first introduced the concept of glucosylceramide substrate reduction in 1980. The semiselective iminosugar N-butyl-deoxynojirimycin has been licensed since 2002 for the treatment of Gaucher disease. For Gaucher disease type 1, most patients are currently managed effectively by enzyme-replacement therapy (ERT) using recombinant human glucocerebrosidase (Weinreb et al.,⁴⁹). This treatment, however, is associated with the need for regular lifelong infusions and does not treat the CNS involvement in the neuronopathic forms of Gaucher disease types 2 and 3 (Schiffman et al.,³⁷). Inhibition therapy with the iminosugar N-butyl-doexynojirimycin (NB-DNJ) was approved recently for the treatment of patients with Gaucher disease type 1, for whom ERT is not a therapeutic option (Lachmann and Platt,²³; Lachmann,²²). Inhibition of glucosylceramide synthase potentially could treat other glucosylceramide-based glycosphingolipidoses such as Fabry disease, Sandhoff disease, and Tay-Sachs disease (Aerts et al.,¹). However, its efficacy is predicted to be best in Gaucher disease because the residual enzyme activity in these subjects is higher than in the other glycosphingolipidoses. NB-DNJ crosses the blood-brain barrier, and trials are in progress for Gaucher disease type 3, Niemann-Pick disease type C, and GM2 gangliosidosis. A number of gycolipids accumulate in Niemann-Pick type C cells that resemble those in glycosphingolipidosis patients. Lachmann reported the use of NB-DNJ in a patient with Niemann-Pick disease type C and showed that this drug reduced pathological lipid storage, improved endosomal uptake, and normalized lipid trafficking in peripheral blood B lymphocytes (Lachmann et al.,²⁴). This response suggests that glycosphingolipid accumulation is the primary ...