Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model.
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 (approximately 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.
Madhavarao
C N
CN
Department of Anatomy, Physiology and Genetics, Program in Neuroscience and Program in Molecular and Cell Biology, USUHS, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Arun
P
P
Department of Anatomy, Physiology and Genetics, Program in Neuroscience and Program in Molecular and Cell Biology, USUHS, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Anikster
Y
Y
Metabolic Disease Unit, Safra Children Hospital, Sheba Medical Center, Tel-Hashomer, and Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
Mog
S R
SR
Division of Comparative Pathology, AFRRI, Bethesda, MD, USA.
Staretz-Chacham
O
O
Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
Moffett
J R
JR
Department of Anatomy, Physiology and Genetics, Program in Neuroscience and Program in Molecular and Cell Biology, USUHS, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Grunberg
N E
NE
Department of Medical and Clinical Psychology, Program in Neuroscience, USUHS, Bethesda, MD, USA.
Gahl
W A
WA
Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
Namboodiri
A M A
AMA
Department of Anatomy, Physiology and Genetics, Program in Neuroscience and Program in Molecular and Cell Biology, USUHS, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA. anamboodiri@usuhs.mil.
D000085:Acetates / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D017825:Canavan Disease / Q000188:drug therapy*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D014202:Tremor / Q000188:drug therapy* / Q000473:pathology; D014215:Triacetin / Q000008:administration & dosage* / Q000009:adverse effects*; D014280:Triglycerides / Q000737:chemistry
D000085:Acetates; D014280:Triglycerides; D014215:Triacetin
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