High-dose enzyme replacement therapy in murine Hurler syndrome

Abstract

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease which leads to systemic disease, including progressive neurodegeneration, mental retardation and death before the age of 10 years. MPS I results from deficiency of α-L-iduronidase (laronidase, IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood-brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to transit across the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, we administered high-dose laronidase (11.6 mg/kg, once per week, 4 weeks) to adult MPS I mice. IDUA enzyme activity in cortex of injected mice increased to 97% of that in wild type mice (p<0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p<0.05). Further, immunohistochemical analysis showed that the treatment reduced secondary storage material GM3-ganglioside in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was surprisingly reduced (p<0.0001). In summary, these results indicated that repeated, high-dose ERT facilitated IDUA transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment.

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

“…This is in agreement with our previous studies16 showing that high enzyme doses are necessary to get sufficient amounts of enzyme into the CNS leading to a substantial reduction of brain storage when applied short term, suggesting a dose‐dependent uptake of the recombinant enzyme into the brain. Our studies are in agreement with other preclinical ERT studies in LSD animal models showing mostly beneficial effects of high‐dose injections of recombinant enzymes on primary lysosomal storage reduction and improvement of secondary pathological alterations such as neuroinflammation and behavioral deficits 29, 30, 31, 32, 33. Of note, in our preclinical study, the beneficial effect of ERT was most prominent for the 500 U/kg dosage but still significant at 125 U/kg for most of the parameters analyzed, suggesting that chronic treatment can at least to some extent compensate for lower enzyme activity.…”

“…Most ERT studies showing beneficial effects on the CNS reached only the sub‐endogenous enzyme activity level 32, 46, 48. In contrast, with the applied ERT regimen, we fully restored endogenous LAMAN activity levels in all CNS regions investigated.…”

Neuronopathic Types of Mucopolysaccharidoses: Pathogenesis and Emerging Treatments

“…Высокодозная ферментозаместительная терапия В течение последних нескольких лет исследователи изучали влияние высоких доз ФЗТ на моделях эксперимен-тальных животных некоторых лизосомных болезней нако-пления, в том числе МПС I, II, IIIA и VII [8,19,20]. Результаты большинства исследований демонстрируют возможность уменьшения степени выраженности патологического про-цесса в ЦНС, а также улучшения некоторых неврологиче-ских функций экспериментальных животных под влиянием высокодозной ФЗТ.…”

Long-term follow up of post-hematopoietic stem cell transplantation for Hurler syndrome: Clinical biochemical and pathological improvements

“…However, neurologic benefits are thought to be negligible because the blood brain barrier (BBB) blocks enzyme from reaching the CNS. At present, while available for some conditions, exogenous ERT cannot correct cognitive and CNS disease [3,4].…”

“…Skeletal manifestations observed in MPS IH has been known as dysostosis multiplex [3][4][5][6], consisting of abnormally shaped vertebrae and ribs, enlarged skull, spatulate ribs, hypoplastic epiphyses, thickened diaphyses, bullet-shaped metacarpals, hip dysplasia, genu valgum, and spinal cord compression [7].…”