L-cycloserine slows the clinical and pathological course in mice with globoid cell leukodystrophy (twitcher mice)

Abstract

Globoid cell leukodystrophy (Krabbe's disease) is an autosomal recessive disease that affects the lysosomal enzyme galactosylceramidase. Galactosylceramidase removes galactose from galactosylceramide and psychosine, which are derived from sphingosine. In the present study, L-cycloserine (an inhibitor of 3-ketodyhydrosphingosine synthase) was administered to the twitcher mouse, an authentic model of globoid cell leukodystrophy. Twitcher mice treated with L-cycloserine had a significantly longer life span and a delayed onset of weight loss than vehicle-injected twitcher mice. Pathological features such as macrophage infiltration and astrocyte gliosis also were less in treated twitcher mice. These results indicate that substrate reduction therapy may have therapeutic value for individuals with residual enzymatic activity, e.g., individuals with late onset disease or individuals with partial enzyme replacement via bone marrow transplantation. In these cases, a reduction in galactosylceramide and psychosine synthesis would enable residual enzymatic activity to keep up with the accumulation of these substrates that would otherwise lead to pathology.

Substrate-Reduction Therapy Enhances the Benefits of Bone Marrow Transplantation in Young Mice with Globoid Cell Leukodystrophy

“…Because L-cycloserine inhibits the synthesis of sphingosine, it is important to select a treatment regimen that does not completely inhibit the production of sphingosine as it is a key component of cells. Thus, mice did not tolerate doses of L-cycloserine that were much higher than those used in the present study (39).…”

“…Similar doses to the ones used in this study, however, did not result in any abnormal findings on routine pathologic examinations in control mice (39). Because L-cycloserine inhibits the synthesis of sphingosine, it is important to select a treatment regimen that does not completely inhibit the production of sphingosine as it is a key component of cells.…”

“…Substrate-reduction therapy (39,44) and enzyme replacement via BMT (25,42,45,46) have been used to successfully extend the life-span of twitcher mice. However, these treatments are limited in their ability to alter the disease course with the majority of treated mice dying before 100 d. In the present study, we explored the possibility that substrate-reduction therapy could be used as a supplemental therapy together with BMT to increase the life expectancy beyond that for either treatment alone.…”

“…Subcutaneous injections of L-cycloserine lowered the levels of sphingolipids including ceramide and sphingomyelin in the brains of normal mice (36,37), and galactosylceramide levels were reduced in myelin (38). When L-cycloserine was administered to twitcher mice, it prolonged the life-span and slowed the progression of clinical and pathologic signs (39). Substrate-reduction therapy is anticipated to have therapeutic value in adult-and juvenileonset GCL, in which low to moderate levels of residual enzyme activity still may be present.…”

Are animal models useful for understanding the pathophysiology of lysosomal storage disease?

“…While most of the experimental tests have been done with animal models of lysosomal storage diseases, in which glucosylceramidebased sphingolipids are stored, using inhibitors of glucosylceramide synthesis, this approach is not feasible for GLD because the disease does not involve impaired degradation of glucosylceramide-based sphingolipids. Instead, the use of cycloserine, which inhibits all sphingolipid synthesis, was suggested to treat twitcher mice in 1984 (59) and recent trials found it to be slightly effective (60,61). It should be noted that this approach cannot reverse the disease process unless mutant enzyme has residual activity or there is a minor metabolic bypass pathway.…”