A fusion protein that ferries a healthy version of a bone-related enzyme gone awry has shown early clinical success in treating a rare bone disorder with no known therapy, researchers reported earlier this month at the Endocrine Society's annual meeting in Washington, DC.

The drug -- which is essentially a protein-based enzyme delivery mechanism -- could open the door to treatments of other skeletal disorders that have so far been deemed untreatable.

"This is probably the most promising approach so far" for metabolic bone disorder therapies, Sundeep Khosla, an endocrinologist at the Mayo Clinic in Rochester, Minn., who was not affiliated with the work, told The Scientist.

The new therapy targets a rickets-like disease called hypophosphatasia (HPP), which is caused by a single mutation in the gene coding for an enzyme known as tissue non-specific alkaline phosphatase, or TNSALP. Developed by Enobia Pharma, a biotech company in Montreal, Canada, it is based on a fusion protein that contains the active portion of TNSALP merged with a small acidic peptide chain that targets the drug to bone, the site of enzymatic activity. In healthy people, TNSALP is normally tethered to the outside of bone- and cartilage-forming cells where it breaks down phosphate. But in HPP patients, the enzyme doesn't fold properly, which leads to a build up of several phosphate-containing compounds in blood and urine, and produces a range of clinical symptoms including softer bones, shorter limbs, respiratory problems, premature tooth loss, and often infant death.

Michael Whyte, a medical researcher at Washington University's School of Medicine in St Louis, Missouri, who consults for Enobia, announced the results of a Phase I trial involving afflicted adults and an ongoing efficacy trial in severely-affected HPP infants. In both studies, patients took to the medication well, and the first two infants to receive regular doses of the drug showed substantial bone mineralization and improved breathing abilities, Whyte reported at the meeting.

Enobia came up with the fusion construct in 2005. At the time, the company was working on a similar delivery vehicle to treat X-Linked Hypophosphatemic Rickets (XLH), a disease closely related to HPP that is also caused by a single aberrant enzyme. The XLH therapy, however, wasn't effective in a mouse model of the disease. They then switched to HPP and the enzyme replacement therapy "worked right from the first experiment," said Philippe Crine, Enobia's chief scientific officer. "It was really spectacular." Crine doesn't know exactly why the drug platform worked for one disease and not the other, but he is confident that the same bone-targeting technology should be effective in treating other related bone disorders.

In the past, clinicians have tried several approaches to tackling HPP, including vitamin D supplements and bone marrow transplants, but all these therapies failed. Researchers also injected TNSALP intravenously, but again with no success; the infused enzyme "kind of gets into the bloodstream, but it goes all over the place," said Khosla. "Being able to actually target therapeutic compounds to bone just hasn't been easy. Part of technical problem has been finding the right carriers, and [Enobia] seems to have found one."

Last year, a team led by Whyte, Crine, and José Luis Millán, a molecular geneticist at the Burnham Institute for Medical Research in La Jolla, Calif., published preclinical results showing that subcutaneous injections of their fusion protein drug mopped up phosphates floating in the blood and significantly improved survival and bone formation in knockout mice with a severe human infant-like form of HPP.

Enobia and its partners are now investigating the efficacy of different doses of the medication in their mouse models, as well as letting the mice develop for a couple of weeks before administering the drug, instead of treating them directly after birth. This is important because humans with the rare disorder often go months or years before being properly diagnosed. Early results show that the late-treated mice also have improved bone function and live longer, although not to the same extent as mice given the drug right away. "The bottom line," said Millán, "is that treatment is good even if conferred very late."

The drug -- which is being manufactured by Princeton, NJ-based Laureate Pharma -- was granted an orphan drug designation by the US Food and Drug Administration last October, and a fast track designation in May to help speed along its clinical development. The company plans to start Phase II adult trials later this summer.

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