Ehlers Danlos syndromes (EDS) are a family of heritable connective tissue disorders causing a laxity of joint and spine ligaments. New models of hypermobile EDS (hEDS) are urgently needed to better understand how the body’s collagen production goes wrong and to explore potential treatments. This innovative proposal brings together a surgeon and a tissue engineer from Brown University in a collaborative effort to:   

1. Establish a bank of collagen producing (fibroblasts) cells from hEDS patients.
2. Test these cells in a new model of lab-grown human connective tissue, both towards the goals of studying as well as modifying the hEDS defective collagen and using the platform for the testing of potential therapies.

A recent National Academies of Sciences, Engineering and Medicine report, co-authored by Dr. Petra Klinge, an investigator on this proposal and a Professor of Neurosurgery at Rhode Island Hospital and Brown University, identified the urgent health need for better treatment options for hEDS patients. Dr. Klinge and her colleagues have shown that hEDS affects the filum terminale (FT), a fibrous structure anchoring the spinal cord to the coccyx. Her studies have shown that the filum is equivalent to a muscle or joint tending and the studies revealed that the FT mimics (or “mirrors”) the misalignment of collagen fibrils found in the connective tissue, i.e. joint ligaments and tendons, in hEDS, and her biomechanical testing showed a loss of elasticity. This loss of elasticity exposes the spinal cord to excessive stretch forces causing back and leg pain and bowel and bladder dysfunction. Dr. Klinge promoted the surgical excision of FTs for the treatment of TCS with and without hEDS comorbidity and routinely performs this surgical procedure on many patients each year. As such, Dr. Klinge has access to the excised connective tissues that normally would be discarded, but, the institutional Human Studies Committee has approved Klinge’s use of these tissues to grow fibroblast cells from these tissues and to use these cells to develop a novel test bed for new therapies. 

Dr. Jeffrey Morgan, Professor of Pathology and Laboratory Medicine at Brown University has developed a novel 3D in vitro model of human connective tissue. Professor Morgan is a pioneer in the development and the use of lab-grown human tissues as replacement for the use of animals. He is the Donna and Jason Weiss Director of the Center for Alternatives to Animals in Testing at Brown University. He routinely grows human fibroblasts and uses the cells to form ring-shaped human tissues that synthesize a highly aligned collagen rich fibrous extracellular matrix. Most importantly, his lab can measure the strength and stiffness of these ring-tissues by subjecting them to tensile testing. Defects in the strength and stiffness of connective tissues is at the heart of the clinical problems affecting hEDS patients and so these measurements of lab-grown tissues reflect the clinical problems and so can be used as testbeds for new therapies. 

Klinge and Morgan’s hypothesis is that the mechanical deficiency of hEDS resides in the fibroblast, the principal cell of connective tissue and this deficiency will be manifest and measurable in rings formed from fibroblasts isolated from hEDS patients versus non-hEDS patients. They propose to:

1. Isolate fibroblasts from FT specimens obtained from TCS surgery on hEDS and non-hEDS patients and use these cells to form ring-tissues.
2. Compare histology and organization of collagen fibers of hEDS versus non-hEDS rings.
3. Measure strength, stiffness and collagen content of hEDS versus non-hEDS rings.
4. Measure strength and stiffness of hEDS rings treated with varying doses of a growth factor (e.g.TGF-b1) known to increase strength, stiffness and levels of collagen.

This proposal will establish a collection of hEDS fibroblasts isolated from 20 patients, determine if the hEDS phenotype resides in the fibroblast by demonstrating that the biomechanical phenotype can be replicated in an in vitro model of lab-grown tissues. This human cell-based model will provide valuable insight into our understanding of hEDS, a resource of hEDS cells as well as a test bed to discover and evaluate new therapies for hEDS including drugs, growth factors, as well as cellular and gene therapies.

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