Abstract
Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, finding ways to increase drug delivery into the brain across the BBB remains a crucial challenge for researchers and clinicians in the field. Attempts have been made to boost brain uptake of enzymes by targeting various receptors (e.g., insulin and transferrin), and several other administration routes have also been tested. This review summarizes the available information on clinical trials (completed, ongoing, and planned) of novel therapeutic agents with efficacy against CNS symptoms in neuropathic MPS and also discusses the common associated challenges and pitfalls, some of which may help elucidate the pathogenesis of the neurodegeneration leading to the manifold CNS symptoms. A summary of current knowledge pertaining to the neuropathological progression and resultant neuropsychiatric manifestations is also provided, because it should be useful to ERT researchers looking for better approaches to treating CNS lesions in MPS.
Highlights
The advent of enzyme replacement therapy (ERT) for lysosomal storage disorders, spearheaded in 1991 by the introduction of glucocerebrosidase for Gaucher disease and followed in 2003 by that of laronidase (α-iduronidase) for mucopolysaccharidoses (MPS) type I [1], has paved the way for long awaited pharmacotherapies for these hereditary disorders
Patients with MPS with central nervous system (CNS) involvement have been unable to benefit from ERT, because the blood brain barrier (BBB) prevents large molecules, including enzymes, from penetrating the brain parenchyma, which in turn prevents ERT from acting against substrate accumulation in the CNS
Based on reports of completed, ongoing, and planned clinical trials, this paper summarizes recent advances in novel BBB penetrating ERTs to address neurodegeneration and CNS symptoms in neuropathic MPS
Summary
The advent of enzyme replacement therapy (ERT) for lysosomal storage disorders, spearheaded in 1991 by the introduction of glucocerebrosidase for Gaucher disease and followed in 2003 by that of laronidase (α-iduronidase) for mucopolysaccharidoses (MPS) type I [1], has paved the way for long awaited pharmacotherapies for these hereditary disorders. Research carried out to develop novel therapeutics for neuropathic MPS can shed light on the nature of progressive neurodegeneration itself: the basic etiology is clearly demarcated as a genetic deficiency in an enzyme that results in substrate accumulation, the progression of degeneration and the pathogenesis of the resultant manifold CNS symptoms are still in need of further elucidation, which is likely to come from research aimed at developing novel ERTs for neurodegeneration For this reason, this paper includes a brief summary of reported neuropathological findings and corresponding neuropsychiatric manifestations, with some suggestions on possible ways forward to better understand and address neuropathic MPS
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