Cure HHT Launches 22nd Center of Excellence
22nd HHT Center of Excellence in North America
University of Chicago Medicine HHT Center
“We are delighted that HHT multidisciplinary care will now be a reality in Chicago and the surrounding states,” said Cure HHT Executive Director Marianne Clancy.
The University of Chicago Medicine is the only facility in Illinois that specializes in the diagnosis, evaluation and treatment of HHT. This newest HHT Center of Excellence features a multidisciplinary team, led by Dr. Issam Awad, which coordinates care for adult and pediatric patients. Whether a patient needs genetic screening or a complex procedure, Dr. Awad’s team of specialists has the knowledge, resources and expertise to provide advanced and comprehensive care.
Dr. Awad is an internationally recognized leader in neurosurgery. As the John Harper Seeley Professor of Surgery, and Director of Neurovascular Surgery at The University of Chicago Medicine, he specializes in surgical management of neurovascular conditions affecting the brain and spinal cord, including 30 years of experience with managing HHT related problems. Dr. Awad is looking forward to a fruitful and contributive partnership with Cure HHT and the HHT patient community.
Dr. Umesh Dyamenahalli, Associate Medical Director
Dr. Awad Issam, Medical Director
Medical Director: Issam Awad, MD, MSc, FACS
Program Coordinator: Shannon Love, RN, BSN
Make an Appointment: 773-702-4452
HHT Specialties at U Chicago Medicine:
Cure HHT Welcomes New Board Members
Join us in Welcoming Alyson Conger, Sara Palmer and Jim Lapides!
We are pleased to announce the appointment of Alyson Conger, Sara Palmer and Jim Lapides to the Cure HHT Board of Directors, a role dedicated to guiding the global foundation toward new levels of awareness and finding a cure for HHT.
"I have personally watched the growth of the foundation since my childhood as my parents have been involved since the beginning. Our family has suffered great tragedies with the disease, but I have experienced firsthand the progress in screening, treatment and awareness for HHT patients. I look forward to being part of the movement for a cure and continued advances to benefit my children, grandchildren and the entire HHT community." Alyson Conger, Provo, UH
"Joining the board is way to deepen my involvement and work closely with other committed volunteers to improve education and awareness as well as to support research that leads to better treatments for HHT. My hope is Cure HHT can increase the rate of diagnosis; help develop drugs and other non-invasive treatments; and, ultimately find a cure for HHT.” Sara Palmer, Baltimore, MD
“I am fighting for a better life for me, my family and everyone else who suffers from this disease. Our organization and science are ready for a major leap forward, and we are closer to a cure than ever before.” Jim Lapides, Brookline, MA
> Full Board List
Continuing Medical Education
HHT for Clinicians at the 17th National Patient and Family Conference
CME Evaluation Form - Attendees who registered to receive continuing education credit need to print, complete and email the CME evaluation form to [email protected] by August 27, 2014. A certificate will be issued upon receipt of this documentation.
July 18-20, 2014
Santa Clara, California
Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu Syndrome, is a potentially life-threatening genetic disorder that, if properly diagnosed and treated, can be managed and tragedies can be averted. This program is designed for medical professionals who are likely to encounter HHT patients, among them: internal medicine, otolaryngology, gastroenterology, cardiology, interventional radiology, neurology, genetic counseling and nursing.
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Academy for Continued Healthcare Learning and HHT Foundation. The Academy for Continued Healthcare Learning is accredited by the ACCME to provide continuing medical education for physicians.
ACHL has been accredited as an Authorized Provider by the International Association for Continuing Education and Training (IACET). ACHL is authorized by IACET to offer 1.3 CEUs for this program.
Provider approved by the California Board of Registered Nursing, Provider Number 14803 for 12.4 contact hours.
Credit Designation Statement
ACHL designates this educational activity for a maximum of 15.5AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Upon conclusion of this conference, participants will be able to:
- Define the diagnostic criteria for HHT
- Identify treatment options for Pulmonary and Cerebral AVM
- Identify treatment options for Epistaxis
- Identify treatment options for Gastrointestinal and Liver AVM
- Discuss new potential therapies for the management of refractory HHT complications
Download the Conference Brochure
CDC Conference: HHT in the 21st Century
March 5-6, 2008
The Hereditary Hemorrhagic Telangiectasia (HHT) Foundation International, in conjunction with the Center for Disease Control and Prevention (CDC), held a landmark conference on March 5 – 6, 2008 at the Tom Harkin Global Communications Center in Atlanta, Georgia.
The purpose of this conference was to define and prioritize objectives to improve clinical outcomes, enhance the quality of life for those affected by HHT, and reduce intrinsic and extrinsic costs related to HHT treatment.
Please click on the following links to learn more about the Conference:
Over 60 health care professionals including: emergency medicine physicians, school nurses, family practitioners/internal medicine, pediatric specialists, physician assistants, dentists and dental hygienists, dermatologists, gastroenterologists, otolaryngologists, hematologists, pulmonologists, neurologists, cardiologists, radiologists, geneticists as well as representatives from governmental and non-governmental organizations attended this national conference. You can view participants by clicking on Participant List.
HHT is a long neglected national health problem that affects 75,000 Americans. HHT is a multisystem vascular genetic disorder producing arterioveneous malformations in the brain and lung which may result in stroke or hemorrhage. Twenty percent of children and adults with HHT die prematurely or may become disabled due to lack of recognition by the medical community. These outcomes are largely preventable with proper intervention. Timely diagnosis and treatment of HHT could improve outcomes and quality of life for people living with HHT while eliminating $6.6 billion in avoidable health care costs.
The conference was the first step in addressing this national health issue by identifying outreach programs that will increase surveillance, increase early recognition of people affected with this genetic condition, and support life saving interventions
For more information, contact Marianne Clancy, Executive Director of the HHT Foundation International, at 800-448-6389 or email her at [email protected] .
Our achievements in these areas during 2003-2006 were possible largely thanks to the support and generosity of our members and from grants received from John Abele on behalf of The Argosy Foundation.
NIH Workshop - HHT Vascular Biology & Pathophysiology
June 8-9, 2006
HHT Foundation in conjunction with the National Institute of Health (NIH) sponsored an HHT Workshop for basic scientific research. The conference provided an opportunity for NIH to formulate an HHT research plan. The workshop included a mix of keynote talks, platform presentations, and open discussion on several themes, including:
- Transforming Growth Factor-Beta Pathway and HHT
- Endothelial Biology and HHT
- Vascular Biology and HHT
- Chemical Genomics and HHT
- Organ Pathophysiology in HHT
- Click on the link below to view the Overview of the Program:
Clinical Practice Guidelines for HHT
November 15-16, 2006
The Consensus Development Conference consists of a group of experts in the field of HHT brought together to work collaboratively with professional facilitators to improve diagnosis and treatment of HHT. The goals of the conference are to review existing evidence on specific medical issues in a systematic fashion, to obtain expert consensus where scientific evidence is lacking, and to synthesize recommendations for Practice Guidelines
- To revise the existing Clinical Practice Guidelines for the diagnosis of HHT (Curacao Criteria) by incorporating the utilization of molecular genetic testing.
- To develop Clinical Practice Guidelines for the diagnosis, screening, and treatment of the major areas of clinical concern in HHT, including chronic epistaxis (nosebleeds), pulmonary arteriovenous malformations (AVMs), hepatic vascular malformations, cerebral AVMs, gastrointestinal bleeding, and skin telangiectases.
- To develop materials for and approaches to dissemination of the Clinical Practice Guidelines for health professionals. Examples include peer-reviewed publications, a site on the HHT Foundation International web page, and a multimedia presentation that would be available to individuals or educational and training programs that wish to teach about HHT.
- To develop recommendations for research priorities that will continue to improve the quality of evidence upon which the Clinical Practice Guidelines are based
At the conclusion of the Consensus Conference, the following will be identified and established:
- Clinical and genetic criteria by which a definitive diagnosis of HHT can be made
- Criteria for diagnosis and treatment of the most common symptoms and organ manifestations of HHT, including chronic nosebleeds, GI bleeding, pulmonary and cerebral AVMs, and liver vascular malformations.
- Protocols for routine follow-up by primary care and specialty physicians.
- Protocols for treatment of acute episodes.
- Recommendations for publication and broad distribution of Consensus findings and HHT Standard Practice Guidelines, and presentation at scientific and professional symposia.
- Strategies developed for implementation of the Practice Guidelines as the standard of practice and for assessment of the impact of Practice Guidelines on physician behavior and HHT care in North America.
2004 Research Grant Recipients
Treatment of Disease
Laser Treatment for Nosebleeds: When Is It Likely to Work?
Elizabeth J. Mahoney, M.D.
Stanley Shapshay, M.D.
"New classification of nasal vasculature patterns in hereditary hemorrhagic telangiectasia". American Journal of Rhinology. Volume 20, Number 1. January-February 2006.
Over the years, a wide variety of treatments have been used to help manage nosebleeds in HHT patients including electro-cauterization, nasal packing, septodermoplasty (see article herein), arterial embolization, arterial ligation, and hormone therapy. While many of these interventions have achieved moderate success in the management of the HHT patient's nosebleeds, recent attention has focused on the use of lasers for the treatment of intranasal telangiectases in patients with HHT.
Finally, patients responses to therapy were evaluated.Patients were identified as a responder to the Nd-YAG laser treatment if they noted a 50% decrease in the severity and frequency of their nosebleeds for a period of greater than 6 months.
Interestingly, vascular pattern I was most common, while vascular pattern III was least common. Patients with vascular pattern I uniformly demonstrated a good response to the Nd-YAG laser. Conversely, nearly all of the patients with vascular pattern II were poor responders to the Nd-YAG laser treatments. Finally, 80% of patients with pattern III demonstrated a good response to the Nd-YAG laser photocoagulation treatment.
In addition to correlating vascular pattern with response to Nd-YAG laser photocoagulation, vascular pattern classification was also correlated with disease severity. Patients with vascular pattern I tended to be most mildly impacted by HHT, while patients with vascular pattern II were more severely impacted. Those with pattern III were more broadly distributed over the range of disease severity.
These findings are important for physicians caring for HHT patients as they may help to predict response to laser therapy. For example, when a patient with HHT is noted to have isolated intranasal telangiectases, he or she can be counseled to anticipate a good response to Nd-YAG laser photocoagulation, while patients with a more diffuse vascular pattern almost uniformly have a sub-optimal response to their Nd-YAG laser treatments. For patients with patterns I and III, treatment with the Nd-YAG laser will typically provide an improvement in the intensity and frequency of epistaxis for a minimum of six months. The procedure is simple, requires only local anesthesia with sedation, and has few risks or side-effects. To conclude, the findings in this study will allow otolaryngologists to better counsel HHT patients and improve stratification for therapy.
2005 Research Grant Recipients
Mechanism of Disease: $50,000 Research Grant
Primary Cultures of Endothelial and Monocytic Cells Derived from HHT Patients: An Open Window to Unravel the Pathogeniticy of HHT
Carmelo Bernabeu, PhD.
Centro de Investgaciones Biologicas, CSIC, Madrid, Spain
Blood vessels are lined with endothelial cells that express two proteins known as endoglin and ALK-1. Mutations in endoglin or ALK-1 genes interfere with the expression and function of these proteins in endothelial cells, affecting the vessels network and giving rise to the Hereditary Hemorrhagic Telangiectasia (HHT). Thus, isolation of endothelial cells derived from HHT patients to determine endoglin/ALK-1 levels and activity is crucial to understand how the disease develops. So far, most of the studies have been carried out in endothelial cells from umbilical veins of affected newborns. However, since the prevalence of HHT increases with age, probably these newborn endothelial cells are not a good model system. Instead, endothelial cells from adult patients with known HHT symptoms would be a more appropriate model of choice. In this project, we propose to isolate and characterize endothelial cells derived from blood samples of HHT patients. The same samples will be used to isolate the blood cells called monocytes, which have been shown to express endoglin, although at lower levels than endothelial cells. Both cell types will be used to determine whether the levels and function of endoglin and ALK-1 are affected in HHT patients and whether there is a correlation between these properties and the severity of the disease in the individual patient. Also, the impact of endoglin or ALK-1 mutations on endothelial gene expression using microarrays, will be assessed. These studies may help to understand the mechanisms of the disease, as well as to design new diagnostic methods.
Outcomes: According to Dr. Bernabeu, "Blood vessels are lined with endothelial cells that express two proteins known as endoglin and ALK-1. Mutations in endoglin or ALK-1 genes interfere with the expression and function of these proteins in endothelial cells, affecting the vessels network and giving rise to Hereditary Hemorrhagic Telangiectasia (HHT).
We have isolated and characterized for the first time, circulating endothelial cells derived from blood samples of HHT patients. These cells show functional abnormalities that may explain the vascular lesions of those with HHT. To further investigate the altered function of these cells, we have analyzed the changes in their gene expression pattern (a sort of fingerprint of the cell). This study has allowed the identification of several genes specifically modified in endothelial cells from HHT patients. The genes affected are involved in different cellular processes relevant to the generation of the vascular lesion. Overall, these represent pioneer studies on the establishment of a culture method to isolate endothelial cells derived from HHT patients. Further studies on the genetic fingerprint of these cells will help to explain the molecular mechanism of the disease, which in turn may contribute to the design of novel therapeutic approaches to cure the disease.
Once a culture method to isolate endothelial cells derived from HHT patients is established, this method can be reproduced by other laboratories and these cells can be used for further biochemical and functional analyses. In addition, studies on the specific genes whose expression is affected in HHT cells are necessary. It is crucial to understand why these genes are disregulated and how the protein’s function is affected in the HHT cell.
This study constitutes a solid base to apply for a larger grant. In fact, at the end of this year, I will apply for a three- year grant on an HHT related subject to the Spanish Ministry of Education and Science for a total amount of approx. $300,000 USD.”
Treatment of Disease: $50,000 Research Grant
Identification of Risk Factors for AVM Formation in HHT
Douglas Marchuk, PhD
Although mutations in one of two genes, endoglin and ACVRL1, cause HHT, questions pertaining to vascular lesion formation in HHT remain largely unanswered. These vascular lesions in HHT develop in discrete locations, and often increase in number and size with age. The focal nature of these lesions and their age-dependent appearance suggests that yet undiscovered “factors” initiate lesion development. The identification of these initiation factors could lead to new approaches and therapies to reduce the incidence of vascular lesion formation.
According to Dr. Marchuk, "My laboratory has recently shown that older mice heterozygous for an engineered acvrl1 mutation show many features of the human HHT phenotype. Using a genetic approach, we will cross the ACVRL1 mutation into various genetic backgrounds that will enable us to test specific hypotheses concerning the nature of the initiation factor(s) for lesion formation. These genetically sensitized backgrounds are mutant mice that exhibit various potential physiological triggers for lesion formation, including (1) local alterations in blood pressure, (2) hypoxia of the surrounding tissue, (3) local inflammation of the endothelium, or (4) a second somatic mutation in the wild-type copy of the gene."
One (or more) of these sensitized genetic backgrounds may show an increase in AVM formation, lending further support for that particular trigger for lesion formation. Some of these physiological triggers can be reduced by currently-available pharmacological treatments, lending some hope of a long-term treatment outcome from this work. In addition, this work may lead to a more highly-penetrant animal model for HHT for further investigation into the mechanisms of HHT pathogenesis.
Outcomes: Despite the discoveries of the HHT genes, many questions remain unanswered concerning the role of these genes in the pathogenesis of HHT. The most critical question is an explanation for the focal nature of the vascular lesions associated with this disorder. Germline mutations only predispose the individual to the development of the discrete focal vascular lesions. The aim of our proposal was to identify the “trigger(s)” for vascular lesion development.
Various hypotheses have been proposed to explain the actual trigger for lesion development. These include:
- Elevated Blood Pressure (cross with Agt tg and eNos null mice)
- Tissue Hypoxia (cross with Csf2 and EpoR null mice)
- Local Inflammation (cross with IL2 and IL10 null mice) d. Loss of Heterozygosity at Acvrl1 (Cross with p53 null and Blm hypomorph mice)
According to Dr. Marchuk, “We did not find that loss of eNos, IL10, or p53 greatly exacerbated the phenotype of HHT mice. But we can say with some confidence that in the existing HHT mouse models, these various triggers do not appear to be the limiting factor in causing the HHT lesions. After performing the initial crosses to create the appropriate mutant mice, we began aging the mice. Here again we chose the 6 month end point to examine the mice. This final cross is ongoing and we have thus far analyzed only 9 of the double mutant mice. However, we are cautiously excited about our initial results with this cross. In about 1/3 of the mutant mice, we have found grossly dilated vessels on the surface of the liver. We have seen this level of dilation occasionally before, but we have never routinely seen this phenotype in HHT mice at such an early age."
Dr. Marchuk's team is deeply grateful for this funding from the HHT Foundation which made their work possible. "We hope sometime in the future to leverage your investment in our work with a funded NIH grant proposal to continue our work on identifying the trigger for vascular lesion formation in HHT.”
2006 Research Grant Recipients
At the groundbreaking National Institutes of Health (NIH) HHT meeting in June 2006, it was our pleasure to award two new HHT research grants. There had been an extensive peer review of ten proposals. The two winning projects were:
Mechanism of Disease $50,000 Research Grant Award
TGF-B Activates eNOS and Regulates Vasomotor Function by an endoglin-and Alk-1' Dependent Mechanism
Dr. Michelle Letarte
Toronto Hospital for Sick Children, Canada
According to Dr. Letarte, “The genes mutated in HHT are endoglin and ALK1. The products of these genes, the endoglin and ALK1 proteins, are receptors for a potent factor called TGF-ß. We now have recent evidence that this TGF-ß factor may control the dilatation of blood vessels. We hypothesize that this normal process of regulation of vessel dilatation by TGF-ß is defective in HHT and can eventually lead to the clinical manifestations of disease. We will use the mouse models of HHT1 and HHT2 and test blood vessels isolated from these mice to see how they respond to TGF-ß compared to those of normal mice. We will then identify the molecules and pathways responsible for the effects of TGF-ß in cells from mice and patients with HHT. Our experiments should provide a better understanding of the mechanisms responsible for the early events in the disease and pave the way to novel therapeutic interventions.
Our specific objectives are:
- To measure the effects of TGF-b1 on eNOS-dependent vasodilation in small resistance arteries isolated from Eng+/- (HHT1 model) and control mice, using a perfusion myograph.
- To test whether TGF-b1 regulation of eNOS-dependent vasodilation is similarly altered in HHT2. Vasodilation will be measured on small resistance arteries from alk1+/- and control mice.
- To characterize the mechanism of TGF-b1-induced eNOS activation in murine endothelial cells (normal and deficient endoglin) and in human umbilical vein endothelial cells (HUVEC) from newborns with a molecular diagnostic of HHT1 or HHT2. We will measure the effects of TGF-b1 on eNOS enzymatic activity, eNOS-Hsp90 association, and eNOS phosphorylation using specific anti-phospho-eNOS antibodies. We will test for the association of ALK1 with eNOS and/or Hsp90 and see if its overexpression in endothelial cells amplifies the activation of eNOS by TGF-b1.
Dr. Letarte states, “We are very grateful to the HHT International Foundation for awarding us this grant and thank all of you for your kind donations. Our daily efforts are devoted to understanding the underlying mechanisms of HHT through basic research. We could not do it without your generous financial and moral support.”
Treatment of Disease $50,000 Research Grant Award
Differentiation of Eng-/- Embryonic Stem Cells in Embryoid Bodies, a Paradigm for Vascuaogenesis/Angiogenesis
Defects in HHT and a Potential Drug Screen
Professor Christine Mummery
Utrecht, The Netherlands
This study will examine the effects of Thalidomide on blood vessel structure. According to Professor Mummery, “By studying the effects of thalidomide on vessel stabilization, we propose (1) to validate the Eng-/vasculogenesis/angiogenesis assay as a useful method in screening potential HHT drugs, particularly those directed towards improving vessel robustness and (2) to determine the mechanisms underlying vessel stabilization. We will attempt to generate a human model of HHT development in vitro.”
(1) Mechanism underlying vessel stabilization. By using FACS sorting, ECs and SMCs will be isolated from 18 day Eng-/- EBs treated or otherwise with thalidomide. Transcriptional profiles will be compared both by microarray analysis and by real time RT-PCR to identify signaling pathways that may underlie the effects observed.
(2) Validation of the EB vasculogenesis/angiogenesis assay for screening HHT drugs. To date our experiments have been performed using only one of each wt, Eng+/- and Eng-/- ES cell lines. To validate our model, multiple new mES cell lines lacking or heterozygous for endoglin will be generated from blastocysts isolated from Eng+/- crosses and EB differentiation in presence of thalidomide will be repeated.
(3) Since we have expertise in the differentiation of multiple human ESC (HESC) lines into mesoderm derivatives, including vascular cells, in EBs we will test the effects of thalidomide in an analogous model to validate and extend our findings on vessel stabilization to human. Time permitting and the context of other studies to optimize siRNA-mediated knockdown in HESCs, we will attempt to generate a human model of HHT development in vitro.
OUTCOMES published in Nature Medicine
2007 Research Grant Recipients
David and Clara Bartley Jordan Epistaxis Research Grant Award
Development of a Standardized Epistaxis Severity Score (ESS) in HHT in Order to Validate Therapy Efficacy
Dr. Jeff Hoag
Johns Hopkins University School of Medicine and Drexel University School of Medicine
This study is awarded to Dr. Jeffrey Hoag of Drexel University School of Medicine and will develop a uniform epistaxis severity scoring system. This system will be used to assess the effectiveness of specific treatments for HHT-related epistaxis. HHT-Epistaxis Severity Scores will help to validate current treatment algorithms, and serve as a benchmark for the development of future medical and surgical treatment strategies. The study will involve a population of 245 participants with a varying range of epistaxis severity which will provide an adequate representation of the population of patients with HHT-related epistaxis.
Specific Aim 1: The study will try to determine the factors associated with epistaxis in HHT. A standardized list of patient perceived important variables combined with provider perceived important variables will provide a comprehensive list of factors associated with HHT-related epistaxis. This list will be developed with patient care providers from HHT Centers of Excellence and Patient Focus Groups through the support of the HHT Foundation International.
Specific Aim 2: (Epistaxis Severity Score) This study will develop a uniform epistaxis severity scoring system.
Specific Aim 3: To validate the HHT-Epistaxis Severity Score through correlation with standardized quality of life (QOL) assessments and statistical models.
Specific Aim 4: (Assessment of Epistaxis Treatment) To use the HHT-Epistaxis Severity Score to assess the effectiveness of specific treatments for HHT-related epistaxis. HHT-Epistaxis Severity Scores will help to validate current treatment algorithms, and serve as a benchmark for the development of future medical and surgical treatment strategies.
Outcome: Dr. Hoag presented his research at the HHT Scientific Meeting held in Santander, Spain in 2009 and published his findings in the April 2010 edition of Laryngoscope. The Epistaxis Severity Scoring Tool developed by Dr. Hoag is used by ENT's at HHT Treatment Centers around the world to determine severity of nosebleeds and improvements realized from laryngology treatments, including the 2011 NOSE Study.
ESS Published Article - Laryngoscope 120: April 2010
Epistaxis Severity Scoring Tool (ESS)
This study was made possible through a generous donation from David and Clara Barley Jordan and many other HHT Foundation members who made donations to the HHT Epistaxis Fund.
Mayo Clinic Team Leverages $50K HHT Foundation Research Award to $1 Million
Dr. Karen Swanson, D.O., Director of the Mayo Clinic HHT Center
Dr. Swanson has been approved for funding from the Office of Orphan Products Development within the Food and Drug Administration (FDA) for an interferon protocol. Dr. Swanson's budget is now $1 million over three years. The study, entitled "Interferon-2B Treatment in Hereditary Hemorrhagic Telangiectasia," was directed towards determining whether interferon may provide a safe and effective treatment for HHT. A certain type of interferon has already been shown to have anti-angiogenic properties and is currently used in the treatment of infantile hemangiomas and liver hemangiomas. Both of these are diseases of abnormal blood vessel formation similar to the teleangiectases and AVMs that occur in HHT. To everyone who donated generously to the HHT Foundation so that we could provide that initial $50,000, without which the larger grant would never have been approved, we offer our wholehearted thanks on behalf of all of those with HHT.
2008 Research Grant Recipients
HHT FOUNDATION AWARDS 3 RESEARCH GRANTS FOR 2009 TOTALING $150,000
In August, the HHT Foundation received nine applications for one $50,000 grant. The research applications were outstanding! The research review committee scored each application and presented their recommendations to the Board of Directors at the Patient and Family Conference in Chicago. The HHT Board of Directors, upon the recommendation of the Research Review Committee, chose to fund the top ranked study. However, over the course of a few hours, three very generous donors came forward and we were able to raise an additional $100,000 so that the work of three scientists could be funded to advance critical HHT Research!!
Genetic Modification of HHT
Rosemary Akhurst, PhD, University of California – San Francisco
Summary: This study will open up a whole new area of investigation and it addresses a fundamental question in HHT, what gene(s) act in concert with endoglin and ALK1 to predispose certain patients to the development of PAVMs? This modifiable gene, in stark contrast to the original two genes (which are receptor genes and difficult to target for the formulation of therapeutic agents), may give us an easier pathway for treatment. It is the first study to be funded that partners basic laboratory research with clinical research. This study will be conducted in collaboration with HHT Centers in France and The Netherlands.
Outcome: According to Dr. Akhurst, "This is a basic study in molecular mechanism. We have identified a gene that differs between individuals and, depending on which form of the gene is inherited, this influences the risk for PAVM in HHT patients. We have also shown that this gene connects into the ACVRL1 and EphrinB2 Pathways. This tells us more about molecular pathways downstream of ACVRL1, which is essential for future drug development or drug strategies (for HHT and for angiogenesis in general). "
READ (pdf) the paper entitled, "Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary hemorrhagic telangiectasia", that was published online on January 10, 2012 in nature communication (scroll to the bottom of the page). Dr. Christopher Hughes was a collaborator on this publication since his work, also funded by the HHT Foundation, was sited in Dr. Akhurst's findings.
SUMMARY (pdf) of paper published in nature communication.
Mouse Model Drug Research
Therapeutic Potential of VEGF Blockade in HHT Pathogenesis
S. Paul Oh, PhD, University of Florida
Summary: The drug (Avastin) blocks a protein (VEGF) that advances the development of artery formation, called angiogenesis. It is Dr. Oh’s hypothesis that subjects with HHT produce more of this VEGF protein, and that this continued promotion of vessel development is key to the expression of the multiple defects. This would provide much needed additional insight to advance this particular drug for HHT therapeutic options (and perhaps warn us of potential risks). In addition, this study will investigate the relevance of this parameter in the disease process, give us disease understanding, and outline potential alternative targets for treatment pathways.
Outcome: Mid-Year Review by Paul Oh
3D Model of Vessel Development
Cross-talk between Alk1/ Endoglin and Notch Signaling in HHT
Christopher Hughes, PhD, University of California – Irvine
Summary: This is a new area of HHT study! It is clear that people from families with identical gene defects (specifically in ALK1 and endoglin) experience multiple clinical types and levels of disease severity. In multiple previous experiments, a certain series of proteins called “notch” have also been demonstrated in animals to produce defects in the walls of arteries, quite similar to those observed with ALK1 and endoglin. Might it be that “notch” influences the clinical presentation of ALK1 defects in humans? To investigate this idea, Dr. Hughes proposes to use an elegant 3D system of vessel development. In a dish on the bench of a laboratory, developmental cells called “stem cells” (or the more matured “endothelial cells” which form the lining of our arteries) are injected into a gel substance after which these cells begin to curve together and form tubes; just the way our arteries begin to develop in our bodies. Dr. Hughes has already demonstrated that defects in notch proteins alters this tube development. By altering the cells, for either or both ALK1 and notch, he can actually observe if there are interactions in the formation of these arterial tubes. If notch is relevant, we can begin to find drugs that affect notch, and see if it makes a difference in this very same tube-development model.
Outcome: Dr. Hughes has presented a mid-contract summary of his results.
2008 Young Investigators Grant Recipient
Dr. Pinar Bayrak-Toydemir
It is with great pleasure that we congratulate Dr. Pinar Bayrak-Toydemir for her award of $20,000 for the 2008 Young Investigators Grant sponsored by the HHT Foundation International. Dr. Bayrak-Toydemir's research is seeking to identify a causative mutation, gene, or loci in patients/families with HHT for whom linkage to HHT1 and HHT2 loci have been excluded. Her proposal is focused on the discovery of gene(s) not yet identified as a molecular cause for the HHT disease. It is designed to identify molecular genetic characteristics of the HHT disease and thus additional genes involved in blood vessel development. The results of this research will provide new insight into blood vessel development by adding one piece to the puzzle that represents current understanding of vascular development and dysfunction. This information will also be important for molecular diagnosis of HHT patients and identification of at risk family members.
Dr. Bayrak-Toydemir's proposal was deemed the strongest of all of those submitted and in the words of the evaluators, "We were impressed by the commitment of the applicant to the field of HHT research., the research environment, and the design of the study. Investment in this work may lead to the identification of a fourth HHT causing gene."
As a second year Assistant Professor of Pathology at the University of Utah, she states, "It is an honor to be the recipient of the 2008 Young Investigator's Grant sponsored by the HHT Foundation International. I will work hard to find the fourth HHT causing gene!"
2010 Research Grant Recipient
North American Study of Epistaxis (NOSE Study)
Sponsored and Conducted by Cure HHT
PUBLICATION: Journal of American Medical Association; JAMA. 2016;316(9):943-951. doi:10.1001/jama.2016.11724
Principal Investigator: Dr. James Gossage, Cure HHT Medical Director
Important Update on the NOSE Study Funded by Cure HHT
The North American Study of Epistaxis in HHT completed enrollment with the last patient having been evaluated in July 2014. Between August 2011 and March 2014, Cure HHT enrolled 121 patients at six of the US HHT Centers of Excellence.
Interest in the treatment was actually so high that enrollment was slowed because patients were concerned about being placed on placebo. If it hadn't been apparent before, this observation further confirmed how important research is to finding treatments and a cure for our community.
While the preliminary results of the study were presented at the HHT scientific conference in June 2015, the study must be officially published before results can be shared with the public. The focus is now on featuring the study in a major medical journal so HHT experts around the world can critically review and draw their own conclusions.
The article was submitted to a renowned medical journal this week, and if accepted will hopefully be published in the next four months. Though we cannot release specific results at this time, we can say the study was well conducted and there were no significant side effects from the drugs. The majority of patients also noted some degree of symptom improvement!
At it's core, this study has taught us which drugs work and which don’t. Hopefully, we can build on this with even greater and quicker research participation in future studies. The more that patients get involved, the sooner we get results that impact the treatment of HHT.
Overview: The HHT Foundation has been listening to its members and over the last two years, the largest clinical study to date involving several North American HHT Centers of Excellence has been carefully designed. The North American Therapeutics Group (NATG), led by Dr. James Gossage, conducted a systematic review of published research published on different nosebleed therapies. The group had a list of agents that was honed down to a study of three and a placebo. The U.S. Federal Drug Administration (FDA) reviewed the application and asked for testing to ensure the agents were safe and stable in the spray bottles. The agents were tested and we received approval from the FDA.
This will be the largest multi-centered study of nosebleed treatment ever conducted and will be funded by members who have donated through the years to a special Epistaxis Fund.
Summary: The purpose of the NOSE Study is to carefully examine the benefit and safety of 3 nasal sprays for patients with HHT related epistaxis and definitively determine which of these are overall beneficial. Each of these sprays will approach the problem from a different mechanism of action. 140 patients with moderate to severe nosebleeds secondary to HHT, will be randomized to receive one of four intranasal sprays for a period of 12 weeks and then followed for an additional 12 weeks off therapy. A placebo arm has been included to allow an accurate estimate of both benefit and safety. The primary measure of effectiveness will be the frequency of epistaxis. Other measures of effectiveness will include the Hoag Epistaxis Severity Score (ESS), a quality of life survey, satisfaction with treatment, hemoglobin level, and transfusion requirements.
The spray agents are:
- Saline spray (Placebo);
- Estriol (a low dose estrogen);
- Tranexamic acid (a drug that promotes clotting), and
- Bevacizumab (also known as Avastin, a drug that might actually reverse abnormal blood vessel growth). The dose that will be used in the NOSE Study is 4mg per day, about 1% as potent as the intravenous dose. We expect that side effects will be minimal.
The HHT Foundation International is very grateful to the members who have contributed and continue to support this research. While it may appear that this clinical trial has taken a long time to develop, it is important to recognize that it needs to be done with scientific rigor so that the results provide the important treatment information that is so needed in HHT. One key element of our mission is to ad- vance therapeutic treatments for HHT patients. We take this commitment seriously and look forward to updating you on the progress!
The NATG Groups consists of the following members: James Gossage MD, Georgia Health Sciences University; Marie Faughnan MD, University of Toronto; Reed Pyeritz MD PhD, University of Pennsylvania; Paul Oh PhD, University of Florida; Michelle Letarte PhD, Toronto Hospital for Sick Children; Dennis Sprecher, MD, Cure HHT Board Member; Scott Olitsky, MD, Cure HHT Board Member; Marianne Clancy, Cure HHT Executive Director