Research funded in 2021 by The Ehlers-Danlos Society

In 2021, The Ehlers-Danlos Society funded the following studies:

To view further research funded by The Ehlers-Danlos Society, please click here.

The Ehlers-Danlos Society aspires to offer grants annually, with calls for clinical research proposals early in the year and for basic science later in the year. We will also offer grants of varying value to reflect the different nature of researcher requirements, including microgrants.

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Molecular studies in hEDS and HSD

Insights into the mechanisms that cause disease in hypermobile EDS (hEDS) remain scarce. An important reason for this is the huge variation in clinical presentation among hEDS patients, which makes it unlikely that a single genetic defect will be responsible to cause this condition, but at the same time, it also makes it hard to pinpoint the exact molecular cause. Nevertheless, given the overlap of clinical symptoms with other EDS subtypes, that lead to abnormalities in the extracellular matrix (ECM), especially with classical EDS (cEDS), it is likely that the mechanisms underlying hEDS also affect the ECM to a certain extent.

Today, several technological advances make it possible to obtain and investigate large, complete datasets of all the DNA (genome), the RNA (transcriptome), and the proteins (proteome) in a particular tissue or cell type from an individual. It is known that in disease states, changes can be observed at these three levels. However, the extent of these changes in hEDS is currently not known.

In this study, we will perform these analyses on the skin and skin cells (fibroblasts) from two affected and one non-affected individual from 10 different hEDS families. In addition, we will also include skin and fibroblasts of 15 cEDS patients as a positive control since the genetic defect in these patients is known, and we will also include 10-15 healthy volunteers to compare the findings in hEDS and cEDS patients. Our approach is unique in the fact that we will investigate all datasets (genome, transcriptome, and proteome) for each of the selected individuals. To the best of our knowledge, this is the first time an integrative approach of this kind is applied to investigate this challenging condition.

The findings resulting from this research will be helpful to understand the defective mechanisms in hEDS, but also in cEDS. Moreover, this approach may result in the identification of (a) prognostic biomarker(s) for disease progression and the development of complications, such as chronic widespread pain or other symptoms. The knowledge obtained from these studies may also be useful for hypermobility spectrum disorder (HSD) patients and patients with other EDS subtypes. These findings may ultimately have an impact on the classification and/or grouping of these patients, eventually resulting in faster diagnosis, more effective management, and better counseling.

Primary Investigator:
Delfien Syx
Ghent University
Ghent, Belgium

Complex Chronic diseases account for nearly two-thirds of deaths worldwide and most health-care expenditure in the USA, thereby representing a major challenge to global health in the 21stcentury. With advances in technology, many promising tools have been created to better utilize precision medicine to improve diagnosis, treatment, and preventive strategies regarding complex comorbid conditions. However, there is a large gap between routine medical practice and the implementation of all these new tools and pipelines, creating a huge hurdle in treating patients with complex chronic conditions. Ehlers-Danlos syndrome, a group of related hereditary disorders that affect connective tissues are prototypical examples of complex chronic diseases, affecting millions of people worldwide.

EDS hallmark features involve joint hypermobility, soft and hyperextensible skin, abnormal wound healing, and easy bruising.  However, the genetic and epigenetic variation can affect the degree of skin hyperextensibility and joint hypermobility and also some additional clinical features that differ among EDS subtypes, such as the fragility of soft tissues, vessels, and hollow organs, early-onset periodontal disease, and involvement of the musculoskeletal system. Variation in clinical presentation and symptoms’ severity and the reduction in the degree of hypermobility due to factors such as aging, arthritis, and surgeries can cause ambiguities in clinical recognition between different classes of EDS. So far 14 classes of EDS have been identified, for those mutations in a handful of genes have been reported to be causal. However, the genetic causes of hypermobile EDS (hEDS), the most common type of EDS, and hypermobility spectrum disorders (HSD) are still unknown.

hEDS/HSD tends to run in families, suggesting a role for genetic predisposition in the development of the disease. Families with hEDS/HSD history also have a high burden of other comorbidities such as chronic fatigue syndrome, post-treatment Lyme disease syndrome, pediatric acute-onset neuropsychiatric syndrome, postural orthostatic tachycardia syndrome, GI disorders, small fiber neuropathy, craniocervical instability, sleep disorders, and anxiety. These indicate that family-based multi-omics studies are extremely valuable in understanding the genetic susceptibilities and molecular basis of hEDS/HSD, as the background genetic variation and environmental exposures are controlled to some extent. Here, we propose to conduct a comprehensive longitudinal multi-omics study on blood samples collected from multiple families with hEDS/HSD. This research will provide a deeper understanding of the underlying genetic and epigenetic risk factors associated with hEDS/HSD. Integrating the multi-omics data with participants’ clinical information will provide a causal mechanistic model of hEDS/HSD and help us to investigate key factors that can be therapeutically targeted or used as biomarkers, as well as insights into pathogenesis and heterogeneity. The long-term goal of this study is to develop novel blood-based biomarkers for more feasible and cost-effective diagnostic and/or prognostic assessment of hEDS/HSD and also identify therapeutic targets and strategies improving patients’ care; we have therefore assembled a team ideally suited to take on this challenge.

Primary Investigator:
Fereshteh Jahaniani
Stanford University
Palo Alto, USA

The Ehlers Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and genetic variation among the various thirteen subtypes. The initial genetic findings on EDS were related to changes in collagen but the causes of the many subtypes revealed several genes not involved in collagen production. However, the genetic basis of the hypermobile type of EDS (hEDS) is not known.

hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several co-morbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on a combination of age, gender, lifestyle, and the likely multitude of genes involved in hEDS.

Our studies initiated with a large family that presented with inherited hEDS. Through our genetic studies, we were able to identify a mutation in a putative causal gene. This mutation was found in each of the nine affected individuals throughout four generations of the family and none of the non-affected individuals. Since this initial discovery, we have successfully generated a mouse model with the corresponding human mutation. These mice have phenotypes consistent with hEDS, therefore validating the mutation as causative. In this proposal, we wish to add to these studies by uncovering not only how the mutation causes disease, but also identify additional causative mutations in large families with hEDS. These studies will identify why patients have defects in connective tissues and will indicate how we can develop treatments to help those with hEDS.

Primary Investigator:
Russell Norris
Medical University of South Carolina
Charleston, USA

Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, musculoskeletal pain, and other systemic manifestations without a known molecular basis. Therefore, its recognition remains an exclusion diagnosis based on a new set of strict clinical criteria. Patients with symptomatic joint hypermobility who did not fulfill these new diagnostic criteria are currently classified as hypermobility spectrum disorders (HSD).

The present proposal aims to unravel, by integrated molecular, biochemical/physical, and nanoscience approaches, bioactive key molecules, and pathophysiological mechanisms associated with these conditions. We previously demonstrated that hEDS and HSD cells shared a pro-inflammatory matrix-degrading phenotype with a range of cellular features that are typical of myofibroblasts. Cellular proteome profiling of hEDS myofibroblasts revealed changes in the expression of a subset of proteins mainly implicated in cellular metabolism, redox balance, extracellular matrix (ECM) homeostasis, cytoskeleton organization, protein folding into the endoplasmic reticulum, intracellular trafficking, and secretory pathway. Proteome analysis of hEDS cells-derived culture media (CM) discovered altered levels of several ECM structural components (including collagens, fibronectin, and proteoglycans), matrix metalloproteinases and their inhibitors, and further secreted proteins predicted to be located in extracellular vesicles (EVs), which likely contribute to the excessive ECM degradation and concomitant acquisition of the peculiar myofibroblast-like phenotype. Furthermore, preliminary data obtained treating control fibroblasts with patient cells’ CM-derived soluble factors and EVs suggested that both these fractions may act synergistically to induce the disease phenotype.

In the present project, we plan to corroborate and deepen our previous proteome and secretome findings through targeted in vitro functional studies on interesting, emerged biomolecules both in hEDS and HSD myofibroblasts, to decipher mechanisms of action and functional significance within specific disease pathways to support their diagnostic application and possible future use as therapeutic targets. We also project to dissect the secretome composition of hEDS and HSD myofibroblasts, by fractioning it into soluble macromolecular components (MCs) and different sized-EVs, to uncover specific RNA species (including miRNAs), secreted bioactive mediators, and associated disease pathways that may contribute to the hEDS and HSD pathomechanisms.

This research, followed by targeted in vivo translational studies on patients’ serum/plasma, should contribute to the elucidation of the etiopathogenesis of hEDS and HSD, offer the possibility to identify potential biomarkers defining whether these disorders are part of a phenotypic spectrum rather than distinct clinical entities and, ultimately, pave the way to the development of targeted therapeutic strategies with a potential benefit for patients’ management. Considering the huge number of hEDS and HSD patients, the project could have a large social and economic impact. Indeed, reaching a definite and certain diagnosis will stop the expensive and lengthy diagnostic process and the development of targeted therapies will decrease the prescription of ineffective drugs and unnecessary evaluations, improve patients’ quality of life, and alleviate their disabilities.


Primary Investigator:
Marina Colombi
University of Brescia
Brescia, Italy

Many people consider Ehlers-Danlos syndrome to be one condition. However, our current understanding is more of a family of disorders, each with its own genetic cause and unique features. Recent advances in genetic technology have allowed for the discovery of the causes for several rare types of EDS. Hypermobility types EDS (hEDS) is the most common form of EDS, and although updates to the diagnostic criteria in 2017 improved our ability to appropriately diagnosis hEDS, they are not perfect. It would be extraordinarily helpful for patients if we were able to understand more about the underlying cause(s).

Earlier research trying to answer this question suggested that a gene known as TNXB may be responsible for both some cases of hEDS and a different type of EDS known as classic-like EDS (clEDS). It is likely that this is true, but this has proven to be a difficult gene to understand, and at best it represents a very small percentage of hEDS patients. Therefore, much remains to be learned about the causes of hEDS. Previous research has used a method known as whole-exome sequencing (WES) which analyzes only the parts of the human genome that code for protein products and has thus far not been successful in findings causes of hEDS. Current efforts to use whole-genome sequencing (WGS) to investigate the cause of hEDS offer additional potential for gene discovery, but the technology itself has limitations.

We propose asking the question of the cause of hEDS in diverse ways.

First, given the nature of our clinic, we can recruit significant numbers of entire families of affected patients and compare them to other unaffected relatives. This will increase the likelihood that helpful results will be obtained.

Second, we will use the existing infrastructure of the Genomic Answers for Kids program to evaluate for known genetic disorders which may look like hEDS but have different genetic causes. We have already found several such patients in this study but anticipate that there are more.

Third, genomic research thus far has generally used next-generation sequencing (NGS) technology for “short read” WES and WGS. NGS produces many small pieces of DNA that are then aligned by computer so that the entire sequence can be analyzed. Because the individual pieces of DNA are so small, there are many areas of the human genome that NGS cannot accurately analyze.

This study proposes using 3rd generation long-read WGS for patients with a clinical diagnosis of hEDS and no diagnosis found on standard short read WES. Having a longer length to each sequenced DNA strand is beneficial for analyzing areas that NGS is unable to accurately analyze. This includes certain types of spelling errors and larger changes to the structure of the DNA. Fourth, we will use a person’s individual sequence to compare to “normal” references to look for extra pieces of DNA. In conclusion, we feel that the expertise and novel approach that Children’s Mercy Kansas City brings to this project offers significant potential for discovering the causes of hEDS.

$ 200,000

Primary Investigator:
Tomi Pastinen
Children’s Mercy Hospital
Kansas City, Missouri

Basic Science Major Research

Vascular Ehlers-Danlos syndrome (vEDS) is caused by heterozygous mutations in the gene (COL3A1) encoding type III collagen. Patients are highly predisposed to spontaneous tear or rupture of arteries throughout the body, the intestines or the pregnant uterus, often leading to premature death. Puberty is a time of heightened risk for a catastrophic vascular event in vEDS, particularly in males. We developed a mouse model of vEDS by introducing a DNA change that was previously observed in patients with vEDS into the corresponding mouse gene. Our goal is to use this model to better understand how deficiency of type III collagen leads to the clinical problems seen in vEDS and to identify and test new treatment strategies. Using our mouse model, we observe a great acceleration of aortic rupture as they go through puberty, mirroring observations in young men with vEDS. As expected, this was particularly evident in male vEDS mice, but also seen to an extent in females. It is our firm belief that unraveling the mechanism of sex differences in vEDS will inform the fundamental basis of the disease process, with the strong potential of adding to therapeutic options for all vEDS patients.

One candidate event that attends puberty in males is the release of high levels of male sex hormones (called androgens) such as testosterone. Androgens also rise in females at puberty, but to a lesser extent than males. We tested the hypothesis that androgens are contributing to puberty-associated vascular rupture by treating male and female vEDS mice with a potent inhibitor of the androgen receptor called bicalutamide in combination with hydralazine, a drug that prevents vascular events prior to puberty; dramatic protection was observed in both sexes. Given the potential for side effects related to use of a potent androgen blocker, we tested a drug called spironolactone that also inhibits androgens, albeit more gently, and is used to treat a variety of disorders in people of both sexes. The combination of hydralazine plus spironolactone prevented vascular events in male and female vEDS mice through puberty and beyond.

We are just beginning to learn about how androgens contribute to the risk of vascular disease in vEDS. Our ongoing and future studies will comprehensively address this critical issue using the most advanced molecular methods to define the detrimental response of vascular cells to a deficiency of type III collagen, to elucidate how androgens amplify these abnormalities, and to characterize molecular changes that attend successful treatment of vEDS with androgen blocking agents. We will also determine the precise cell type or types that are responsive to androgens in the vessel wall. This will be accomplished by selectively removing the androgen receptor gene in specific cell types in vEDS mice using powerful genetic strategies. Our expectation is that we will observe overt protection when the androgen receptor is deleted in one or more critical cell types. This will allow future efforts to develop new treatments for vEDS to focus on events and cells that specifically contribute to disease.

Primary Investigator:
Dr. Harry Dietz
John Hopkins University
Baltimore, Maryland

Major bleeding caused by tearing of large blood vessels is a serious complication in Ehlers-Danlos syndrome (EDS). However, many patients also suffer from mild-to-moderate bleeding such as easy bruising, abnormal uterine bleeding, or excessive bleeding after surgical procedures. The ability of the body to stop bleeding, called hemostasis, depends on the normal function of blood cells called platelets. These are small cells that flow through blood vessels along with red blood cells, and whenever there is damage to a blood vessel, platelets stick to the damaged area to plug the hole and stop bleeding.

Several subtypes of EDS are caused by changes in the molecules that make up blood vessels, which is what can cause them to break easily. However, these molecules are also important for allowing platelets to stick to the injured vessel, so this causes platelets to function less effectively in some EDS patients. However, there are studies that suggest that even when you test patient platelets in a test tube, they still show signs of dysfunction. If the platelets themselves are dysfunctional, on top of the changes to the blood vessel molecules, this could worsen bleeding in some EDS patients. The objective of this proposal is to determine whether platelets are dysfunctional in EDS using both a mouse model and patient samples and determine how this impacts the effectiveness of certain therapies to prevent or treat bleeding. The big picture goal is to identify other bleeding risks in EDS patients to better predict and treat bleeding.

Primary Investigator:
Robert Lee
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, USA

Chronic pain is a main symptom in patients diagnosed with Ehlers-Danlos syndromes or hypermobility spectrum disorders and is an important reason to seek medical attention. It has a larger impact on quality of life and psychosocial well–being of EDS/HSD patients. Despite its high prevalence, little is known about the precise origins and mechanisms contributing to EDS–related pain, and the pain is usually refractory to currently used treatments. An important reason for this is the lack of studies investigating the mechanisms and pathways that initiate and maintains pain associated with EDS.

Animal models can give valuable insight into mechanisms and pathways that are affected in human disorders. Several mouse models exist for different EDS subtypes. Our previous work demonstrated for the first time the presence of pain-related phenotypes in mouse models for classical; EDS due to defects in type V collagen and also showed accompanying changes in the interaction of the skin.

To better understand EDS-associated pain, more insights are needed including for example if the pathways leading to pain are similar or distinct in different EDS subtypes. Therefore, the general aim of this proposal is to document pain-related behavior in mouse models for dermatoparaxis EDS, caused by defects in ADAMTS-2, the enzyme that cleaves the N-propeptide of type 1 collagen. This model was chosen because patients with dermatoparaxis report progressive chronic widespread pain. To obtain this information, several behaviors and responses of these mice will be carefully monitored and analyzed. If pain-related behavior is observed, we will try to reverse the observed pain-related behavior by administering serval types of pain medication. In addition, the dermatoparaxis EDS mice will be crossed with specific reporter mice allowing them to visualize and study the nervous system in more detail. Finally, the obtained results for dermatoparaxis EDS mice will be compared with the available results for a classical EDS mouse.


Primary Investigator:
Delfien Syx
Ghent University
Ghent, Belgium

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