Lab-made protein shows arthritis potential

By Wai Lang Chu

- Last updated on GMT

Related tags Rheumatoid arthritis Signal transduction Protein

Scientists have synthesised a lab-made version of a human protein,
which alleviates symptoms of both acute and chronic arthritis. The
study opens new research avenues to better understand and develop
drug treatments for rheumatoid arthritis.

Although there's no known cure for the stiffness, swelling, joint pain, and fatigue of rheumatoid arthritis, millions of people who live with the disease now receive better diagnoses and have access to new medications.

This new research aims to thwarting the joint inflammation characteristic of rheumatoid arthritis, one of the most common autoimmune diseases.

"Rheumatoid arthritis is a condition that causes suffering in more than two million Americans,"​ said National Institute of Allergy and Infectious Disease (NIAID) director Anthony Fauci.

Investigators from NIAID's Laboratory of Immunology have been focusing on a protein, which prevents the assembly of a cell surface receptor, thus blocking transmission of chemical signals that lead to arthritis symptoms.

Interest in the protein, called pre-ligand assembly domain protein or PLAD, grew out of their research on a very rare autoimmune disease called autoimmune lymphoproliferative syndrome (ALPS).

Previously, lead researcher Michael Lenardo, and his colleagues showed that in ALPS a form of PLAD blocked a cell surface receptor and prevented a chemical signalling pathway from functioning correctly.

In ALPS, the signal pathway interrupted by PLAD leads to disease symptoms. But, the scientists thought that PLAD might also block a related cell surface receptor- one involved in passing signals that lead to inflammation.

In theory, inhibiting this pathway might benefit people with rheumatoid arthritis, who suffer from excessive inflammation.

What is currently known about arthritis is that a key promoter of the characteristic inflammation is a chemical called tumour necrosis factor alpha (TNF-alpha).

TNF-alpha starts a chemical chain reaction leading to inflammation by binding to two cell surface receptors, TNFR-1 and TNFR-2.

Naturally occurring PLAD helps both forms of TNFR assemble and prepare to receive TNF-alpha.

Synthetic PLAD, the scientists hypothesized, would bind to its natural counterpart and prevent it from performing its usual task.

The scientists used a variety of techniques (including injection of TNF-alpha) to induce arthritis symptoms in mice. Researchers also injected some of the animals with lab-made PLAD (P60 PLAD).

"We found that P60 PLAD protein powerfully inhibited the symptoms of TNF-alpha-induced arthritis,"​ said Lenardo.

P60 PLAD also lessened the effects of arthritis induced by other means. He added that P60 PLAD also appeared to inhibit disease symptoms in mice with established as well as acute arthritis.

The scientists did not detect any obvious toxicity in the PLAD-treated mice.

"We're very hopeful that this could be good news for arthritis sufferers,"​ said Lenardo.

In particular, the researchers are intrigued by P60 PLAD's apparent specificity. It seems to block the binding of TNF-alpha to TNFR-1, while allowing TNFR-2 to continue to function.

This is important, said Lenardo, because it may represent an advantage over some currently used arthritis drugs, which directly block TNF-alpha by binding to both TNFRs and thereby inhibit beneficial actions mediated by TNFR-2.

The scientists next aim to develop a more stable form of P60 PLAD. Ultimately, they hope to test the protein in clinical trials.

Related topics Preclinical Research

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