Role of the LPA-LPA₁ Pathway in Scleroderma Fibrogenesis

Andrew Tager, MD
Massachusetts General Hospital and Harvard Medical School

Project Summary:

The development of fibrosis, or scarring, in scleroderma contributes to the suffering and deaths caused by this disease. Current therapies have not been able to prevent the progression of the fibrosis (hardening) that develops in the skin, lungs and other internal organs of scleroderma patients, or improve these patients' survival. Finding effective therapies will require improved understanding of the chemical signals in the body that drive the development of fibrosis in scleroderma. The Tager laboratory discovered that a chemical called lysophosphatidic acid (LPA) is one of the most important signals driving the progressive and usually fatal fibrosis that develops in the lungs of patients with idiopathic pulmonary fibrosis (IPF). LPA contributes to the development of this lung fibrosis by activating a receptor present on the surface of many cells that specifically recognizes LPA, known as LPA₁. Using a mouse model of IPF, the Tager lab found that mice engineered to lack this receptor are markedly protected from the development of lung fibrosis and death. They also found evidence that LPA levels are increased and contribute to the development of fibrosis in the lungs of IPF patients.  In their SRF-supported project, the Tager lab has extended their investigations of LPA/ LPA₁ to scleroderma. They have found that LPA, acting through the LPA₁ receptor, also makes critically important contributions to the development of skin fibrosis in scleroderma. In the bleomycin mouse model of scleroderma, they found that the mice lacking LPA₁ are even more dramatically protected from the development of skin fibrosis than they are from lung fibrosis. The Tager lab is currently investigating the mechanisms through which LPA and LPA₁ contribute to the development of skin fibrosis in their mouse model of scleroderma. The lab is also pursuing studies using skin samples obtained from scleroderma patients to substantiate the relevance of their mouse studies to human scleroderma.

Project Update:

Based on the work in the Tager lab, Amira Pharmaceuticals developed a drug that targets the LPA₁ receptor. The Tager lab has found that administration of this drug markedly reduces the development and progression of skin fibrosis in their mouse model of scleroderma. A Phase 1 clinical study of this drug in normal, healthy human subjects, designed to understand its safety profile and to learn how the body metabolizes it, was completed and found no serious adverse events associated with taking the drug. Based on these positive results in animal models and safety results in human subjects, Amira was recently acquired by Bristol-Myers Squibb, which now plans to perform Phase 2 clinical studies of this LPA₁ receptor antagonist to determine whether it is effective in treating fibrotic diseases such as scleroderma.  In their studies using skin samples obtained from scleroderma patients and normal volunteers, the Tager lab has also found that the levels of autotaxin, the enzyme that is responsible for generating LPA, are significantly increased in the skin of scleroderma patients, suggesting that the LPA/LPA₁ pathway is activated in human scleroderma.

What this project means for people with scleroderma:

If successful, this project will both provide new insights into how LPA and LPA₁ contribute to development of skin fibrosis in scleroderma, and determine whether targeting this pathway has the potential to be an effective new therapeutic strategy for this devastating disease.

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