The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother
ABSTRACT Mucopolysaccharidosis I (MPS I, McKusick 25280) is caused by the deficiency or absence of the lysosomal enzyme, alpha-L-iduronidase (EC 220.127.116.11). 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.
- SourceAvailable from: David M Bedwell
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- "This suggests that both NMDI-1 and gentamicin cross the murine blood brain barrier, and the combination of suppression therapy with NMD attenuation may potentially moderate the neurological defects associated with MPS I-H. This is a particularly important finding, since current MPS I-H treatments such as enzyme replacement therapy do not improve the neurological aspects of the disease . In addition, this approach could potentially be used to treat other neurological diseases attributable to nonsense mutations. "
ABSTRACT: Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order to restore expression of functional protein. However, the process of Nonsense-Mediated mRNA Decay (NMD), which reduces the abundance of mRNAs containing PTCs, frequently limits this approach. Here, we used a mouse model of the lysosomal storage disease mucopolysaccharidosis I-Hurler (MPS I-H) that carries a PTC in the Idua locus to test whether NMD attenuation can enhance PTC suppression in vivo. Idua encodes alpha-L-iduronidase, an enzyme required for degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. We found that the NMD attenuator NMDI-1 increased the abundance of the PTC-containing Idua transcript. Furthermore, co-administration of NMDI-1 with the PTC suppression drug gentamicin enhanced alpha-L-iduronidase activity compared to gentamicin alone, leading to a greater reduction of GAG storage in mouse tissues, including the brain. These results demonstrate that NMD attenuation significantly enhances suppression therapy in vivo.PLoS ONE 04/2013; 8(4):e60478. DOI:10.1371/journal.pone.0060478 · 3.23 Impact Factor
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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 · 7.71 Impact Factor
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- "Hurler syndrome is considered to be incurable; however, as multiple organs are involved a multidisciplinary approach is needed to sustain and improve the quality of life. There are currently two different well-established approaches for the treatment of Hurler syndrome if diagnozed early, and these includes Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy with alpha-L iduronidase enzyme to stabilize or reverse many aspects of Hurler syndrome. "
ABSTRACT: Mucopolysaccharidosis type I (MPS I H, Hurler syndrome) is a rare autosomal recessive inborn deficiency in the metabolism of glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, resulting from deficiency of Alpha-L-iduronidase enzyme. This condition is characterized by accumulation of incompletely degraded glycosaminoglycans into various organs of body, which leads to impairment of organs and body functions. Such children appear nearly normal at birth; however, if left untreated, show a progressive mental and physical deterioration leading to death due to cardiorespiratory failure before the second decade of life. Pedodontists have a role for early diagnosis, rendering corrective and preventive treatment to the developing dentition, and referring the patient to the concerned specialities. An interesting case of a seven year old boy with a combination of skeletal, neurological, ophthalmologic, oro-dental and radiological findings of this diverse and devastating clinical entity with MPS I-(Hurler syndrome) has been presented here in this case report.04/2012; 3(1):86-9. DOI:10.4103/0976-237X.94554