Image: Researchers have discovered a new biomarker that is associated with a rare metabolic disorder may facilitate better diagnosis and identification of new drugs for clinical trials (Photo courtesy of iStock).
Researchers have identified spermine as a potential biomarker associated with neuropathic forms of mucopolysaccharidoses (MPS), a family of rare metabolic disorders. Assaying for abnormally high levels of spermine may facilitate better diagnosis, monitoring, and identification of more effective drugs.
Development of monitoring assays and treatments for the neurological symptoms of MPS patients have been hindered by lack of objective measures of the extent of central nervous system (CNS) damage. The research team was led by senior author James Wilson, MD, PhD, of the Orphan Disease Center (ODC), Perelman School of Medicine, University of Pennsylvania Health System (Philadelphia, PA, USA), “This new biomarker for CNS symptoms in MPS patients may help families better understand their child’s diagnosis and prognosis and should help clinicians and regulatory agencies to evaluate the efficacy of new therapies,” he said.
Many of the forms of MPS share symptoms, such as vision and hearing problems, hernias, and heart problems. Patient life expectancy varies significantly, but individuals with the most severe form rarely live more than 10 years.
MPS I is the most common form of MPS diseases and is caused by a deficiency of the key enzyme IDUA needed to break down complex sugars in cells. The disorder eventually leads to the abnormal accumulation of sugar fragments and cell death. The two main treatments are bone marrow transplantation and intravenous enzyme replacement therapy; however, neither of these treatments cure the disorder, especially when the disease enters the CNS.
The ODC team screened metabolites from cerebrospinal fluid (CSF) in a canine model of MPS I. This assay revealed a marked elevation of spermine in affected animals. Gene therapy to reduce CSF spermine corrected brain lesions in these dogs. Additional studies with cultured neurons from MPS I mice showed that elevated spermine was responsible for the abnormal overgrowth observed in the mouse cells.
In humans, spermine is elevated in the CSF of 4 MPS subtypes in which cognitive declines are seen, but not in 2 subtypes in which cognitive function is preserved. In MPS I patients, elevated CSF spermine was restricted to patients with genotypes associated with CNS disease. CSF spermine in these patients was reduced following hematopoietic stem cell transplantation -- the only therapy currently capable of improving cognitive outcomes.
“Our findings offer new insights into CNS symptoms in MPS patients,” said first author Christian Hinderer, MD, PhD, “These studies suggest CSF spermine could be used as a biomarker to evaluate the outcome of novel therapeutics designed to treat the CNS manifestations of MPS diseases, which will greatly simplify clinical trials."
“The mission of the ODC is to enable the development of novel diagnostics and treatments for rare diseases,” said Prof. Wilson, “We are offering access to this biomarker to the orphan disease research community for all research purposes at no cost to enable labs to freely conduct assays for their own research and patients’ needs. The only way we will move ahead in our field is to openly collaborate in the pre-competitive space, during the early stages of development of biomarkers and treatments.”
The study, by Hinderer C et al, was published July 19, 2017, in the journal Human Molecular Genetics.
University of Pennsylvania Health System