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.
Metabolic Disease Unit, Safra Children Hospital, Sheba Medical Center, Tel-Hashomer, and Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
J Inherit Metab Dis. 2009 Oct;32(5):640. doi: 10.1007/s10545-009-1155-3. Epub 2009 Aug 15.
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.
Canavan 病（CD）是一种致命的脑白质营养不良遗传疾病，与天冬氨酸酰基酶缺乏有关，导致大脑中的乙酸盐水平降低和髓鞘脂质合成减少。在这里，我们测试了一种有效的乙酸盐前体甘油三乙酸酯（GTA）在两个被诊断患有 CD 的婴儿（8 个月和 13 个月大）中的低剂量耐受性。在 CD 的震颤大鼠模型中评估了更高剂量的 GTA 的毒性。GTA 以 25mg/kg 的剂量每天口服两次给婴儿服用，每周增加一倍，直到达到最高 250mg/kg。野生型和震颤大鼠幼崽每天口服两次 GTA，从出生后第 7 天到第 14 天开始，剂量为 4.2g/kg，从第 15 天到第 23 天，剂量为 5.8g/kg，此后在食物（7.5%）和水中（5%）中添加。在试验结束时（约 90 至 120 天），分析大鼠的血清和组织以了解血液化学和组织病理学的变化。GTA 治疗没有引起可检测的毒性，患者的临床状况没有恶化。在高剂量动物研究中，治疗组和未治疗组之间的平均血液化学值没有显著差异，在检查的任何组织中都没有发现表明毒性的病变。在低剂量试验中，两名 CD 患者和高剂量动物研究中都没有 GTA 毒性，这表明在人类 CD 患者中进行更高、有效的剂量研究是合理的。
