Vascular Ehlers-Danlos syndrome (vascular EDS) is an inherited connective tissue disorder caused by mutations in the type III collagen gene (COL3A1). The condition is characterized by a generalized weakness of the connective tissue that results in tissue fragility. Typical features include predisposition for rupture of blood vessels and hollow organs, joint laxity, easy bruising, abnormal wound healing, and translucency of the skin.

Furthermore, surgical repair of blood vessels and/or tissues, a mainstay of treatment for other connective tissue disorders, is considered a measure of last resort for people with vascular EDS due to their tissue repair described as trying to stitch together wet tissue paper. Additionally there is an alarming rate of life-threatening surgical complications post operatively.

Until very recently, the prospects for developing a meaningful therapeutic strategy for vascular EDS have appeared dismal. The prevailing view has been that the abnormal type III collagen leads to a deficiency in the amount of normal type III collagen that the body has to use, and thus results in an inherent weakness of the tissue. Yet by taking the undeniable parallels seen in two other connective tissue disorders, Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), it is believed that the same model––illustrating a failed matrix regulation of Transforming Growth Factor Beta––may also be in play for vEDS. In fact, there is currently a clinical trial underway for treatment of MFS.

This observation supports a very important question: Does vascular EDS simply reflect loss of tissue integrity imposed by a deficiency of type III collagen or might altered TGF signaling also be involved in this condition? If so, does the research being done for MFS show similar promise in the treatment of vascular EDS?

The results to this question were presented this fall at the 2008 American Society of Human Genetics Conference in an abstract entitled Altered Cytokine Signaling in Vascular Ehlers Danlos Syndrome (vEDS). This is the first published document presented that suggests that there is an increased signaling of the TGF-beta family seen in vEDS fibroblasts.

The results of this paper indicate the need for further investigation in a vEDS mouse model in which a mutated copy of the COL3A1 gene is present. The development of this mouse model will allow researches to explore the usefulness of medications that regulate the TGF-beta family. Additionally this research may enable the understanding of the mechanism involved in not only vEDS, but potentially all other types of Ehlers-Danlos syndrome and other disorders in which the collagen proteins are affected.

We feel that the best facility for this is Dr. Dietz’s laboratory at Johns Hopkins as he wrote a detailed research proposal to which over $50,000 has already been donated to get the vEDS research to this point. He feels that, “while ambitious, this proposal directly parallels the work that we have already accomplished for Marfan syndrome. All of the requisite expertise is already in place in my laboratory. Realistically, I believe that this work could get started with an initial investment of approximately $75,000. This would help cover the salary of a full-time postdoctoral fellow who is extremely committed to these studies, and would allow completion of the studies focused upon patient samples and cells. Initiation of the mouse work would require further investment, estimated at $200,000 per year for three years. It is our hope that the preliminary data developed with the initial investment will support successful applications to the NIH and other funding agencies that could supplement alternative sources of funding for this long-term research initiative.”

Selected References:

Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006 Aug 24;355(8):788-98.

Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7;312(5770):117-21.

Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar;37(3):275-81.

Ng CM, Cheng A, Myers LA, Martinez-Murillo F, Jie C, Bedja D, Gabrielson KL, Hausladen JM, Mecham RP, Judge DP, Dietz HC. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004 Dec;114(11):1586-92.

Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003 Mar;33(3):407-11.

Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991 Jul 25;352(6333):337-9.

Altered Cytokine Signaling in Vascular Ehlers Danlos Syndrome (vEDS). T. K. Cooper1,3, Q. Zhong1, U. Schwarze2, M. Pepin2, P. Byers2, H. C. Dietz3 1) Hershey Medical Ctr; 2) Univ of Wash; 3) Johns Hopkins