An enzyme therapy may prevent skeletal abnormalities associated with the genetic disorder neurofibromatosis type-1, Vanderbilt investigators have discovered.
The researchers demonstrated in a mouse model of the disorder that the enzyme asfotase-alpha improves bone growth, mineralization and strength. The findings, reported in the journal Nature Medicine, “suggest that we can make bone stronger and better by injecting this drug, and possibly prevent fractures in patients with neurofibromatosis,” said Florent Elefteriou, Ph.D., director of the Vanderbilt Center for Bone Biology.
While he is excited about the results, Elefteriou emphasized the challenge of moving from mouse to human studies. “It’s very difficult to set up a clinical trial in patients with a rare disease; it will have to be an international effort to pool these patients,” he said.
Neurofibromatosis type-1 (NF1) is caused by mutations in the gene for neurofibromin, a protein that regulates cellular signaling pathways. The disorder causes nervous system tumors and skeletal pathologies including scoliosis, bone fragility, fracture and pseudoarthrosis (non-union of the bone following fracture).
Fractures are treated surgically to stabilize the bone and promote healing. Some families opt for amputation, to spare their children the pain of repeated surgeries, Elefteriou said.
“We wondered if there might be a way to prevent the fractures from happening in the first place,” he said.
It was difficult to even propose non-surgical preventive treatments, however, because it was unclear how mutations in neurofibromin cause skeletal pathologies.
To investigate the molecular pathology of NF1, Elefteriou and his colleagues, including first author Jean de la Croix Ndong, Ph.D., have studied a mouse model of the disorder. They noticed in histological stains of bone tissue that the mice had an accumulation of non-mineralized matrix, a condition called hyperosteoidosis.
They have now discovered that hyperosteoidosis in the mice is caused by accumulation of the molecule pyrophosphate, a strong inhibitor of bone mineralization. They found that in the absence of neurofibromin, the expression of certain genes is upregulated. These include genes that enable increased production and transport of pyrophosphate and a gene that prevents calcium and phosphate from depositing on collagen fibers.
In addition, the bone-forming cells fail to differentiate (mature) into “proper tenure-track osteoblasts,” Elefteriou said, which means the cells don’t produce alkaline phosphatase, the enzyme that normally breaks down pyrophosphate.
“That’s a fourth factor preventing mineralization and the formation of new good bone,” he said.
The investigators decided to try clearing the accumulated pyrophosphate by treating the mice with asfotase-alpha, an engineered form of alkaline phosphatase. Asfotase-alpha is currently in clinical trials for hypophosphatasia, another rare genetic disease affecting bone formation.
They found that asfotase-alpha treatment improved bone mass, mineralization and bone mechanical properties in the mouse model of NF1.
“This could be a drug that would prevent fractures and help these kids pass through the early rapid growth period and reach the point where they aren’t as likely to fracture the bone,” Elefteriou said.
To explore whether the molecular pathology of the disease is the same in humans as in the mouse model, the researchers studied pseudoarthrosis tissue biopsies from patients with NF1. They found that the gene that promotes pyrophosphate synthesis is upregulated, suggesting a similar molecular pathology and supporting the notion that asfotase-alpha may be a successful treatment in patients.
There’s much work to be done first, Elefteriou cautions. He notes that although the enzyme therapy corrects the functional defect of pyrophosphate accumulation, it does not correct the failure of osteoblasts to differentiate. This may indicate a need for long-term and combination drug therapy, which the researchers will examine in the mouse model.
They will also continue to collaborate with members of the Children’s Tumor Foundation Bone Consortium to develop clinical trials.
“I think we’ve made great progress in this area,” Elefteriou said. “It’s exciting that instead of fixing the bones after they break, we might have a drug now to prevent the fractures.”
Other Vanderbilt Center for Bone Biology contributors to the studies included Alexander Makowski, Sasidhar Uppuganti, Guillaume Vignaux, Ph.D., Koichiro Ono, Ph.D., Daniel Perrien, Ph.D., and Jeffry Nyman, Ph.D. Additional contributors included Simon Joubert, Ph.D., at Alexion Pharmaceuticals, Serena Baglio, Ph.D., and Donatella Granchi, Ph.D., at Istituto Ortopedico Rizzoli in Bologna, Italy, David Stevenson, M.D., at the University of Utah and Jonathan Rios, Ph.D., at University of Texas Southwestern Medical Center.
Leigh MacMillan, (615) 322-4747
Leigh MacMillan | Eurek Alert!
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy