The primary function of ADAMTS-2 is the maturation of procollagen type I, II and III. Results obtained by in vitro testing, ex vivo model, and in vivo model support the hypothesis that ADAMTS-2 is an anti-angiogenic factor.

ADAMTS-2 (also called N-proteinase) belongs to a novel family of metalloproteases, the ADAMTS (A Disintegrin and Metalloprotease with ThromboSpondin type I repeats). The primary function of ADAMTS-2 is the maturation of procollagen type I, II and III by excising the amino-propeptide. This processing is required to generate collagen monomers that spontaneously self-assemble into fibrils. Deficiency in ADAMTS- 2 activity results in the formation of abnormal collagen fibers that are more susceptible to degradation than normal ones. Recently, it has been suggested that ADAMTS-2 could also modulate angiogenesis, as it contains sequences similar to those responsible for the anti-angiogenic activity of ADAMTS-1 and 8, which are 20-fold more anti-angiogenic than angiostatin and endostatin. Results obtained by in vitro testing (human endothelial cell proliferation), ex vivo model (mice or rat aorta pieces embedded in a collagen piece), and in vivo model (choroidal neovascularization) support the hypothesis that ADAMTS-2 is an anti-angiogenic factor. Mice without a functional ADAMTS2 gene have been created. Beside symptoms related to the absence of procollagen maturation, an unexpected observation was the sterility of males. The mechanisms causing this alteration have not been identified yet, but are most probably not related to the absence of normal procollagen processing.

Due to its anti-angiogenic effect, ADAMTS-2 could be used in various pathologies caused or favoured by an increased angiogenesis, such as cancer, diabetic retinopathy, and rheumatoid arthritis. Another application could be the development of inhibitors that would interfere with the procollagen processing and lead to the disorganization of the collagen fibers, but only in connective tissues undergoing a rapid remodelling process. These inhibitors should be well tolerated and could be used in anti-fibrotic therapies. Finally, study of ADAMTS-2 could lead to the identification of alterations causing male sterility and development of relevant therapy.

Early Stage

Granted: US 6,428,998  ; JP 4,027,984 ; CA 2,260,366

Pending: EP

Research collaboration for license agreement.