The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I
ABSTRACT Mucopolysaccharidosis I (MPS I, McKusick 25280) is caused by the deficiency or absence of the lysosomal enzyme, alpha-L-iduronidase (EC 184.108.40.206). This inherited disease causes progressive cellular, tissue and organ damage across the entire phenotypic spectrum. Disabling, multi-organ disease is the rule, and generally results in death between the first and fourth decades of life. Recently, laronidase (Aldurazyme) [Genzyme], a specific recombinant human alpha-L-iduronidase) became commercially available as long-term enzyme replacement therapy. Results from the Phase I/II and III extended clinical studies have shown that laronidase safely and effectively alleviates many systemic signs and symptoms of this progressive multisystemic disease. Clinically meaningful and sustained improvements in pulmonary function and functional capacity have been observed in Phase III study patients. Significant and sustained reductions in urinary glysosaminoglycan (GAG) excretion and hepatomegaly have also been observed. Improvements in sleep apnoea and joint range of motion occurred in patients with the most severe symptoms at baseline. Improvements in Disability Index scores as measured using the CHAQ and HAQ questionnaires were modest, which may have been related to the fact that these disability measuring tools are not disease-specific. Anecdotal reports of improvements in the performance of daily activities further add to the therapeutic benefits, as do case histories pointing at stabilisation or improvement of symptomatology in various organs, such as the eyes, heart, and muscles. With the availability of specific treatment, the importance of early recognition of the disease and appropriate therapeutic intervention has increased. The variability in clinical symptomatology is reviewed in detail and may allow for a better understanding of the diagnostic and therapeutic challenges. Results of the clinical trials and their initial extension periods, as well as the anecdotal experiences of physicians with laronidase in non-study settings, are discussed.
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- "approaches to enhance the overall therapeutic benefits . For example, current treatments for the lysosomal storage disease MPS I-H, such as hematopoietic stem cell transplantation (Aldenhoven et al., 2008) and enzyme replacement therapy (ERT) (Brooks, 2002; Wraith, 2005) are unable to alleviate abnormal lysosomal glycosaminoglycan storage in all tissues. In particular, ERT is unable to treat MPS I-H neurological defects because the exogenously supplied recombinant protein is unable to cross the blood-brain barrier. "
ABSTRACT: In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach.Critical Reviews in Biochemistry and Molecular Biology 06/2012; 47(5):444-63. DOI:10.3109/10409238.2012.694846 · 5.81 Impact Factor
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- "Recombinant human α-L-iduronidase (rhIDU) is commercially available for long-term enzyme replacement therapy (laronidase) , providing sustained and clinically meaningful improvements for some symptoms in patients with MPS I    . Unfortunately, peripherally administered rhIDU has no beneficial effects on the central nervous system (CNS) or skeletal manifestations of the disease such as scoliosis, kyphosis , cognitive deficits and spinal lesions including spinal cord compression caused by intervertebral disk compression and GAG accumulation in the meninges . "
ABSTRACT: The storage disorder mucopolysaccharidosis type I (MPS I) is caused by a deficiency in lysosomal α-L-iduronidase activity. The inability to degrade glycosaminoglycans (GAG) results in lysosomal accumulation and widespread tissue lesions. Many symptoms of MPS I are amenable to treatment with recombinant human α-L-iduronidase (rhIDU), however, peripherally administered rhIDU does not cross the blood-brain barrier and has no beneficial effects in the central nervous system (CNS). A feline model of MPS I was used to evaluate the CNS effects of rhIDU following repeated intrathecal (IT) administration. Twelve animals were randomized into four groups based on the time of euthanasia and tissue evaluation following three repeat IT administrations of 0.1 mg/kg rhIDU or placebo on Study Days 1, 4 or 5, and 9. Two days after the final IT injection, the mean tissue α-L-iduronidase (IDU) activity in the brains of the two treated animals were approximately 3-times higher (50.1 and 54.9 U/mg protein) than the activity found in normal cat brains (mean of 18.3 U/mg), and remained higher than untreated MPSI brain at 1 month (2.4 and 4.1 U/mg protein) before returning to near-baseline levels after 2 months. This activity corresponded with decreased brain GAG concentrations after 2 days (1.4 and 2.0 μg/mg) and 1 month (0.9 and 1.1 μg/mg) which approached levels observed in normal animals (0.7 μg/mg). Attenuation of GAG, gangliosides GM2 and GM3, and cholesterol reaccumulation was identified at both two days and one month following final IT injection. No adverse effects attributable to IT rhIDU administration were observed. IT rhIDU may be an effective means for providing enzyme replacement therapy for the central manifestations of MPS I.Molecular Genetics and Metabolism 07/2011; 103(3):268-74. DOI:10.1016/j.ymgme.2011.03.011 · 2.83 Impact Factor
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- "The more recently developed ERT with laronidase (Wraith et al. 2005; Wraith 2005) has been shown to improve respiratory and cardiac symptoms and some skeletal and joint manifestations, to reduce hepatosplenomegaly, and to improve overall quality of life (Wraith et al. 2004; Wraith 2005; Sifuentes et al. 2007; Clarke et al. 2009). However, ERT with laronidase at the labelled dose, 0.58 mg/kg, is not expected to prevent cognitive decline as the blood-brain barrier prevents the intravenously delivered enzyme from reaching the central nervous system in significant amounts (Kakkis et al. 2001; Wraith et al. 2005; Pastores et al. 2007). Early diagnosis and determination of phenotype are therefore of major importance to determine the best treatment option for each MPS I patient. "
ABSTRACT: Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world. Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n = 118) compared with patients from the rest of the world [ROW (n = 727)]. Phenotype distribution differed among patients in Latin America compared to ROW (Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). The frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%. These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.Journal of Inherited Metabolic Disease 05/2011; 34(5):1029-37. DOI:10.1007/s10545-011-9336-2 · 4.14 Impact Factor