Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New engineered drug may offer prolonged arthritis relief

17.10.2006
Researchers at Duke University have devised a new way to significantly prolong the effects of an anti-inflammatory drug, potentially making it useful for providing longer-lasting treatment for osteoarthritis, the most common form of arthritis.

The modified drug, which would be injected directly into arthritic joints, could last for several weeks rather than just the few hours the unmodified drug would last, the researchers said.

In their study, the researchers modified a drug called interleukin-1 receptor antagonist (IL1RA). They found that the drug, which is a protein, could be improved by attaching a second protein that clumps together at normal body temperatures. The combined drug likewise would assemble into clumps in the body to serve as "drug depots" that gradually release active drug particles, the researchers said.

"Although the conventional drug is being used for autoimmune diseases, no one yet knows how much of it would be needed to achieve a therapeutic effect for osteoarthritis," said Lori Setton, associate professor of biomedical engineering and surgery. "Current estimates suggest it would require perhaps two injections per week of the unmodified drug.

"With this advance, we believe treatments could go from twice a week to perhaps twice a month, and that would be a huge clinical gain," she said.

By remaining at the site of disease, the drug also might cause fewer negative side effects than the unmodified drug, the researchers added.

The team reported an initial proof-of-concept study on Saturday, Oct. 14, at the Biomedical Engineering Society annual meeting, in Chicago. The team also has reported related findings online in the Journal of Controlled Release.

The work was supported by a Coulter Foundation Translational Research Partnership award to the biomedical engineering department at Duke's Pratt School of Engineering, and by the National Institutes of Health and a United Negro College Fund-Merck graduate dissertation fellowship.

Osteoarthritis is a degenerative joint disease that affects an estimated 21 million adults in the United States. It is the nation's most prevalent musculoskeletal disorder and the leading cause of disability, the researchers said, adding that as the average age of the population continues to rise, the incidence of osteoarthritis will increase.

Osteoarthritis had been attributed primarily to the gradual wear and tear of joint surfaces. More recently, however, scientists have discovered that inflammation sparked by the immune system also plays an important role in the worsening of the disease.

Specifically, scientists have linked a key molecule involved in inflammation, called interleukin-1 (IL-1), to osteoarthritis. IL-1 heightens the activity of enzymes that damage joints by breaking down their collagen "framework," Setton explained. She credits team member Virginia Kraus, professor of rheumatology and immunology at Duke University Medical Center, for focusing on IL-1 as a major mediator of osteoarthritis in the joint.

Given the immune system's suspected role in osteoarthritis, scientists have suspected that the interleukin-1 receptor antagonist drug, which is known to block IL-1 activity, might have value in diminishing the severity of osteoarthritis, said Mohammed Shamji, a neurosurgery resident pursuing his Ph.D. in Setton's laboratory.

However, trials of IL1RA for osteoarthritis have had limited success, primarily because the drug tends to break down quickly, according to the researchers.

"Physicians can inject large amounts of this drug systemically, but it's cleared very rapidly and there is no evidence that it reaches the joint space," said Helawe Betre, who performed these studies for his doctoral work at Duke and now works at Zimmer Orthobiologics. "We set out to develop a modified version of the drug that when injected directly might stay in the joint long enough to be effective."

To build in such durability, Betre turned to a class of proteins called elastin-like polypeptides (ELPs). Once ELPs in solution reach a certain threshold temperature, they assemble into protein aggregates. Study collaborator Ashutosh Chilkoti, a professor of biomedical engineering at the Pratt School, previously had investigated the use of ELPs that clump at temperatures higher than normal body temperature for treating cancers.

ELPs aren't recognized by the body's immune system as foreign substances, and thus they have some unique advantages for biomedical applications, according to the researchers. Also, ELPs can be joined directly to genes that control the production of various proteins in cells, with the combination forming "fusion proteins." As the proteins degrade, they yield simple amino acids, which are the building blocks of all proteins.

By experimenting with composition, molecular weight and concentration of various ELPs, Betre developed a protein for use in joints that would precipitate out of solution and clump at normal body temperature.

When he injected the sticky ELP into the knees of rats, the protein proved to have a 25-fold longer half-life in the joint than a similar soluble protein, Betre reported in the journal article. Half-life is the time required for half the quantity of the protein to be broken down and eliminated from the joint space.

"At 12 hours, the soluble protein was already at a concentration in the joint below 10 percent of the injected dose," Setton said.

In contrast, the sticky ELP took about two weeks to fall to the 10 percent level in the animals' joints -- a "really substantial increase," she said.

Moreover, rats injected with the clumping ELP contained lower blood levels of the protein, suggesting that a protein drug paired to the ELP might also have the benefit of fewer side effects, Shamji said. This would be important, he said, because IL1RA can weaken the immune system and make patients more susceptible to infection.

Such vulnerability to infection is a particular problem for patients treated for chronic diseases such as osteoarthritis, and this vulnerability suggests the need for a local treatment, Shamji added.

Based on the initial investigation, the team paired the ELP with the IL1RA drug in a second study, to test whether the fusion protein would retain the ability to suppress IL-1 activity and fight inflammation.

The researchers treated human white blood cells with either the original or the modified drug. White blood cells are responsible for mounting the body's immune response and normally react to IL-1 by growing in numbers and releasing molecules that further activate the immune system. Active IL1RA therefore serves to dampen the immune cells' rate of proliferation, Shamji said.

White blood cells treated with the modified drug increased in number at a slower than normal pace, evidence of the drug's activity, Shamji reported at the Biomedical Engineering Society meeting. But its potency dropped by a factor of about 20 compared to the pure drug.

Further studies, however, suggested the fusion protein might do better in an arthritic joint, Shamji said. The researchers were surprised to find that the same inflammatory enzymes that destroy joint collagen also chew ELP from the original drug protein, thereby restoring its activity.

"With the ELP tag gone, you get back your originally active drug," Shamji said.

"That finding was pretty unexpected," Setton added. "We hadn't intentionally designed it to have that feature at all."

The researchers now plan to work with collaborators to test the modified drug's ability to interfere with the progression of disease in the joints of animals.

Kendall Morgan | EurekAlert!
Further information:
http://www.duke.edu

More articles from Health and Medicine:

nachricht Biofilm discovery suggests new way to prevent dangerous infections
23.05.2017 | University of Texas at Austin

nachricht Another reason to exercise: Burning bone fat -- a key to better bone health
19.05.2017 | University of North Carolina Health Care

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>