Navigation Links
Novel treatment strengthens bones in genetic disease neurofibromatosis type-1
Date:8/14/2014

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 August issue of 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."


'/>"/>

Contact: Leigh MacMillan
leigh.macmillan@vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert  

Related medicine news :

1. Novel compound demonstrates anti-leukemic effect in zebrafish, shows promise for human treatment
2. Rutgers team discovers novel approach to stimulate immune cells
3. Novel drug candidates offer new route to controlling inflammation
4. Researchers present new findings for novel pancreatic cancer vaccine
5. Novel biomarkers reveal evidence of radiation exposure
6. VCU Massey Cancer Center sees potential in novel leukemia treatment
7. Study supports urate protection against Parkinsons disease, hints at novel mechanism
8. Novel Natural Sciences Repository Opens Web Portal
9. Novel Anti-Inflammatories May Offer a New Approach for the Treatment of Stroke
10. LA BioMed investigators, Drs. Kevin Bruhn and Noah Craft, develop novel treatment for melanoma
11. Novel radiation therapy safely treats prostate cancer and lowers the risk of recurrence
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Novel treatment strengthens bones in genetic disease neurofibromatosis type-1
(Date:6/27/2016)... , ... June 27, 2016 , ... ... mental health professionals, announced today its affiliation with Tennessee Counseling Association. ... to the network of the Tennessee Counseling Association, adding exclusive benefits and promotional ...
(Date:6/27/2016)... ... June 27, 2016 , ... TopConsumerReviews.com recently awarded their highest five-star rating ... Millions of individuals in the United States and Canada wear eyeglasses. Once considered to ... correct vision and make a fashion statement. Even celebrities use glasses as a way ...
(Date:6/26/2016)... ... June 26, 2016 , ... Pixel Film Studios Released ProSlice Levels, a Media ... give their videos a whole new perspective by using the title layers in ... Studios. , ProSlice Levels contains over 30 Different presets to choose from. ...
(Date:6/26/2016)... Clarkston, Michigan (PRWEB) , ... June 26, 2016 ... ... respect to fertility once they have been diagnosed with endometriosis. These women need ... but they also require a comprehensive approach that can help for preservation of ...
(Date:6/25/2016)... ... June 25, 2016 , ... The temporary closing of Bruton Memorial Library on June 21 due ... up a new, often overlooked aspect of head lice: the parasite’s ability to live away ... a common occurrence, but a necessary one in the event that lice have simply gotten ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... DUBLIN , June 23, 2016 ... the "Pharmaceutical Excipients Market by Type (Organic Chemical ... Preservative), Formulation (Oral, Topical, Coating, Parenteral) - Global Forecast ... The global pharmaceutical excipients ... 2021 at a CAGR of 6.1% in the forecast ...
(Date:6/23/2016)... June 23, 2016 Capricor ... ), a biotechnology company focused on the discovery, ... that patient enrollment in its ongoing randomized HOPE-Duchenne ... exceeded 50% of its 24-patient target. Capricor expects ... third quarter of 2016, and to report top ...
(Date:6/23/2016)... Ill. and INDIANAPOLIS , ... students receiving a Lilly Diabetes Tomorrow,s Leaders Scholarship is ... 2016 scholarship winners, announced today online at www.diabetesscholars.org ... let type 1 diabetes stand in the way of ... has supported the Foundation,s scholarship program since 2012, and ...
Breaking Medicine Technology: