TY - JOUR
T1 - Glyceryl triacetate for Canavan disease
T2 - A low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model
AU - Madhavarao, C. N.
AU - Arun, P.
AU - Moffett, J. R.
AU - Namboodiri, A. M.A.
AU - Anikster, Y.
AU - Mog, S. R.
AU - Staretz-Chacham, O.
AU - Grunberg, N. E.
AU - Gahl, W. A.
N1 - Funding Information:
Acknowledgements C. N. Madhavarao was supported by the Rosalind Poss Rosen Clinical Research Training Fellowship sponsored by the American Academy of Neurology Foundation, St Paul, MN and Canavan Foundation, New York, NY. The study was supported by Jacob_s Cure Foundation, NTSAD, Boston, Samueli Institute and NIH R56 grant NS039387 for A. M. A. Namboodiri. GTA for the clinical trials was provided gratis by Cognis Oleo Chemicals, Germany. The authors thank the National Bio Resource Project for the Rat, Kyoto University, Kyoto, Japan, for providing breeding pairs of tremor rats.
PY - 2009/8/17
Y1 - 2009/8/17
N2 - Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (∼90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted.
AB - Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (∼90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted.
UR - http://www.scopus.com/inward/record.url?scp=70350347765&partnerID=8YFLogxK
U2 - 10.1007/s10545-009-1155-3
DO - 10.1007/s10545-009-1155-3
M3 - Article
AN - SCOPUS:70350347765
SN - 0141-8955
VL - 32
SP - 640
EP - 650
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 5
ER -