Although disease progression in mucopolysaccharidosis type I (MPS-I) can be attenuated by hematopoietic cell transplantation (HCT), it is increasingly recognized that residual disease is substantial. Biomarkers that would allow us to evaluate the efficacy of HCT (and upcoming new therapies) in nonhematologic tissues are needed. Current biomarkers, including the iduronidase (IDUA) activity in leukocytes, are not suitable for this purpose because they are assessed in tissues of hematologic origin and may not reflect enzyme availability in nonhematologic tissues. Saliva is a nonhematologic body fluid that can be collected easily and noninvasively. We hypothesized that the extent of recovery of IDUA activity in saliva after HCT could provide a better understanding of the penetration of donor-derived enzyme into nonhematologic compartments. This study in 20 patients with MPS-I shows that the measurement of IDUA activity in saliva is possible and allows diagnosis of IDUA deficiency (P < .0001), with values a magnitude further deviating from the normal range than when assayed in corresponding dried blood spots (DBSs). Furthermore, it could possibly differentiate between phenotypes (P = .045). More importantly, patients exhibit strikingly low values of IDUA in saliva after HCT, far below the normal range of control subjects (P = .013), contrasting the normal IDUA levels in DBSs. We postulate that the limited recovery of donor-derived IDUA activity in saliva after treatment reflects the situation in poorly responding nonhematologic tissue compartments, unveiling enzyme delivery as a weak spot of the current therapy. Salivary IDUA activity could be used as a biomarker for the evaluation of the effect of new therapies in well-vascularized nonhematologic tissues.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbmt.2018.06.001 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Digital microfluidic platform for dried blood spot newborn screening of lysosomal storage diseases in Campania region (Italy): Findings from the first year pilot project.
Mol Genet Metab
December 2024
Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy. Electronic address:
Background: Newborn screening (NBS) is a simple, non-invasive test that allows for the early identification of genetic diseases within the first days of a newborn's life. The aim of NBS is to detect potentially fatal or disabling conditions in newborns as early as possible, before the onset of disease symptoms. Early diagnosis enables timely treatments and improves the quality of life for affected patients.
View Article and Find Full Text PDFHuman iPSC-derived neural stem cells engraft and improve pathophysiology of MPS I mice.
Mol Ther Methods Clin Dev
December 2024
Research Institute, Children's Hospital of Orange County, Orange, CA, USA.
Mucopolysaccharidosis type I (MPS I) is a metabolic disorder characterized by a deficiency in α-l-iduronidase (IDUA), leading to impaired glycosaminoglycan degradation. Current approved treatments seek to restore IDUA levels via enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). The effectiveness of these treatment strategies in preventing neurodegeneration is limited due to the inability of ERT to penetrate the blood-brain barrier (BBB) and HSCT's limited CNS reconstitution of IDUA levels.
View Article and Find Full Text PDFPrenatal diagnosis of mucopolysaccharidosis type I on hepatosplenomegaly and coarse features: a case-report.
BMC Pregnancy Childbirth
January 2025
Department of Clinical Genetics, Rennes University Hospital, Rennes, France.
Background: Mucopolysaccharidosis type I (MPS I - IDUA gene) is a rare autosomal recessive lysosomal storage disorder. Clinical symptoms, including visceral overload, are progressive and typically begin postnatally. Descriptions of hepatosplenomegaly associated with lysosomal pathology are uncommon during the prenatal period.
View Article and Find Full Text PDFFunctional assessment of IDUA variants of uncertain significance identified by newborn screening.
NPJ Genom Med
December 2024
Research Division, Greenwood Genetic Center, Greenwood, SC, USA.
With the expansion of newborn screening efforts for MPS disorders, the number of identified variants of uncertain significance in IDUA continues to increase. To better define functional consequences of identified IDUA variants, we developed a HEK293-based expression platform that can be used to determine the relative specific activity of variant α-iduronidases by combining a fluorescence-based activity assay and semi-quantitative western blotting. We employed the current platform to characterize over thirty different IDUA variants, including known benign and pathogenic variants, as well as multiple variants of uncertain significance identified through newborn screening.
View Article and Find Full Text PDFIntrathecal or intravenous AAV9-IDUA/RGX-111 at minimal effective dose prevents cardiac, skeletal and neurologic manifestations of murine MPS I.
Mol Ther Methods Clin Dev
December 2024
Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.
Article Synopsis
- Mucopolysaccharidosis type I (MPS I) is a rare condition caused by a deficiency in the enzyme α-L-iduronidase (IDUA), leading to the buildup of glycosaminoglycans and various health issues.
- Current treatments like stem cell transplants and enzyme replacement often fall short in addressing all patient symptoms.
- In a study with MPS I mice, administering a specific viral vector (RGX-111) at a minimal dose of 10 vector genomes showed significant metabolic improvement and reduced severe symptoms, suggesting a promising approach for human therapy.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!