Cure HHT Research Roadmap
At Cure HHT, we are more than a patient advocacy organization. We are the catalyst for driving research and treatment forward. Everything we do is centered about solving problems that matter most to our patients, which is why we've worked diligently over the last two years to develop our "Research Roadmap."
Scroll down to learn more about how we have prioritized most important research initiatives over the next 3-5 years, and how we’ve brought together uniquely talented research teams to drive life-changing progress and breakthroughs.
Over 1,200 Patients Surveyed
Patients:
- HHT history
- Perceived gaps in research
- Most urgent treatment needs
Scientist & Clinician Input:
- State of HHT science
- Gaps in research
- Most urgent patient needs
Cure HHT Research Network (CHRN)
80 patients, scientists and clinicians form the CHRN and addressed patient priorities.
Workstreams:
8 groups from the CHRN evaluated the state of HHT science and clinical care to identify gaps, then they consolidated recommendations for high-impact focus.
Building the Roadmap
Through this global covening of the Cure HHT Research Network, a final actionable list of 31 questions were identified to build a 3 to 5-year roadmap to accelerate new treatments and a cure.
Needed Now to Make it Happen
Tools & Resources to Make it Happen:
- Centralized biosample repository
- A more refined patient registry
Innovative Research Fund:
- Preclinical collaborations
- Gene therapy task force
- Young investigator awards
- Investment in research
*Hover for more details
Patient Voices Matter: Identifying Critical Gaps in Care
Made possible through the support of a grant from the Chan Zuckerberg Initiative Rare As One Project, we surveyed 1204 patients, 96 clinicians, and 42 scientists to ensure our roadmap was grounded in what issues matter most to them.
Patient voices serve as our foundation. From our survey data, the Cure HHT Research Network came together and crafted recommendations and actionable strategies spanning critical areas of Research, Treatment, and Awareness to bring the Cure HHT Research Roadmap to life.
Check out our webinar to learn more about the survey results that shaped the start of the roadmap.
Research
______
Exploring the causes and factors aggravating HHT, and engaging with patients in shaping research to gain deeper insights.
Treatment
______
Developing transformative treatments for managing symptoms, restoring affected functions, and ultimately curing HHT.
Awareness
______
Raising awareness about HHT, empowering individuals to spot symptoms early, get the right care, and find the support they deserve.
Research
1
Develop a deeper understanding of what causes HHT.
Research
2
Explain the cellular and molecular factors that cause vascular malformations.
Research
3
Study donated tissues from HHT
patients.
Research
4
Study cells from blood vessels collected during HHT-related procedures.
Research
5
Use cells in the blood to understand more about mutations and how they impact HHT.
Research
6
Use advanced sequencing technologies to understand gene activity in HHT tissues.
Research
7
Explore long-term methods like RNA therapies and exosomes to boost proteins such as ENG/ELK1/BM9/10 and enhance blood vessel health.
Research
8
Increase ENG/ALK1/BMP9/10 as a therapeutic strategy through repurposed drugs and bioactive compounds.
Research
9
Increase ENG/ALK1/BMP9/10 as a therapeutic strategy through specially designed molecules/proteins/antibodies to force signaling.
Research
10
Develop highly efficient screening tools (using various cell types, iPSC-ECs, microfluidics, animal models, etc.).
Research
11
Involve patients in drug development for HHT.
Research
12
Determine which pathway is best to target for a new HHT therapeutic.
Research
13
Improve methods for measuring biological outcomes to aid in drug development, discovery, and clinical trials.
Treatment
14
Use imaging to examine small blood vessels.
Treatment
15
Develop a multidimensional bleeding severity score.
Treatment
16
Understand how things like genetics, environment, and diet affect bleeding severity.
Treatment
17
Use experimental models to determine if antiangiogenic drugs are effective for pulmonary AVMs.
Treatment
18
Study pulmonary AVMs of all sizes, locations, and of different ages to learn how they grow and react to treatment.
Treatment
19
Analyze growth rate of PAVMs (treated and untreated, during childhood, pregnancy, and adult life), to improve screening, treatment, and research.
Treatment
20
Investigate complicated liver vascular malformations and when a transplant is needed.
Treatment
21
Find predictors of symptomatic liver vascular malformations.
Treatment
22
Use experimental models to screen therapies that may be effective in treating HHT.
Treatment
23
Create a standard protocol for screening brain AVMs and use data to understand when to screen again.
Treatment
Treatment
25
Develop therapeutic strategies for brain AVMs based on patient selection, method, and evaluating results.
Awareness
26
Gain deeper insights into mutations in HHT-causing genes to better understand their significance.
Awareness
27
Update HHT diagnostic criteria and guidelines to better suit different ages.
Awareness
28
Standardize guidelines for genetic testing and minimal requirements needed to diagnose affected family members.
Awareness
29
Use whole genome sequencing to discover additional genetic data in HHT patients with initial negative tests.
Awareness
30
Identify HHT patients who have symptoms but negative genetic test results and those with positive tests but no symptoms.
Awareness
31
Examine if race, age, gender, or other factors affect HHT diagnosis and care, and identify solutions to overcome these barriers.
Route to Success: Key Questions Drive Action
We’ve heard what matters to patients. The world's leaders in HHT care and research have outlined exactly what we need to solve those programs. Now, with the Cure HHT Research Roadmap in hand, we are focused on driving these tasks forward to drive meaningful and life-saving progress forward faster.
A total of 31 recommendations were voted on to become the Cure HHT Research Roadmap. This roadmap will direct funding toward the most impactful, feasible, and important research priorities named by patients, scientists, and clinicians.
Below, you can find the three main categories guiding our roadmap.
Explore the Research Roadmap by selecting the key questions below to uncover detailed steps addressing the problem statements, critical gaps, and recommendations.
Research
Treatment
Awareness
Research
+ Problem
- Natural history and the factors influencing growth and development of AVMs is unknown
- Tools are missing to measure growth and response (imaging sensitivity may not be sufficient to measure in real-time)
+ Gap
We lack a validated preclinical pathway for screening therapeutic candidates
- What are the model system features predicting VM initiation that can be used to screen candidate therapies or pathways?
- Will screening based on EC phenotypes predict benefit in animal models?
- Will screening based on animal model phenotypes predict benefit in patients?
Requirement of BMP-ENG-ACVRL1 for VM progression/maintenance
- Animal models have not addressed restoration of BMP-ENG-ACVRL1 on phenotypes
- Will BMP ligand or ENG/ACVRL1 overexpression strategies be useful only to prevent novel lesions?
Cellular and molecular determinants of vascular malformations
- Studies suggest lesions contain mutant and WT cells
- Likely role of cross-talk between EC and surrounding cells (pericytes, etc)
- Technology exists to characterize single cell expression profiles
- Animal models and patient samples are available to explore biology
Inadequate therapeutic response to liver vascular malformations
Underutilization of liver transplantation
+ Recommendation
1. Understand BMP signaling and AVM maintenance.
2. Describe cellular and molecular determinants of vascular malformations.
+ Research Network Contributor(s)
AVM Progression Workstream
- S. Paul Oh, PhD [Neurobiology, Barrow Neurological Institute]
- Kevin Whitehead, MD [Cardiovascular Medicine, University of Utah Medical Center; HHT Center
- Helen Arthur, PhD [Cardiovascular Biology, Newcastle University, UK]
- Ethan Winkler, PhD [Endovascular Surgical Neuroradiology, Barrow Neurological Institute, US]
- Ann Eichmann, PhD [Cellular and Molecular Physiology, Yale Cardiovascular Research Center, US]
- Patrick Kamath, MD [Hepatology, Mayo Clinic MN; HHT Center
- Arndt Siekmann, PhD [Cell and Developmental Biology, University of Pennsylvania]
- Sanjay Misra, MD [Radiology; Vascular and Endovascular Surgery, Mayo Clinic MN; HHT Center
- Adrienne Hammill, MD PhD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center; HHT Center
- Jay Hoying, PhD [Cardiovascular Physiology, Advanced Solutions]
- Michael Ohliger, MD PhD [Radiology and Biomedical Imaging, University of California San Francisco]
- Karen Weissel, PhD [Patient]
- Gael Genet, PhD [Cell Biology, University of Virginia]
- Tania Competiello [Patient]
- Ann Trussell [Patient]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
+ Problem
- There is a need to understand the balance between primary and secondary mutations that contribute to the HHT phenotype.
- How does this vary between the different organs and tissues involved?
+ Gap
Second-hit somatic mutations in wild-type allele were identified in approximately half of muco-cutaneous telangiectasia resected from HHT1 and HHT2 patients. -Snellings et al., 2019.
Nearly all animal models require loss of both alleles for VMs, suggesting that loss of both copies of the gene is necessary, but not sufficient for VM.
- Are there “missing” somatic mutations in HHT with the two-hit genetic model?
- Is there evidence for somatic mutations in other (non-HHT) genes?
- Can these be targets for therapy?
- Is there evidence for somatic mutations in circulating cells in HHT?
+ Recommendation
3. Create an HHT-associated biorepsitory for vascular malformation and other tissues.
4. Harvest endothelial cells from vascular malformations and other tissues.
5. Search for somatic mutations in blood leukocytes and/or circulating cells.
+ Research Network Contributor(s)
Somatic Mutations & Mechanism of Disease Workstream
- Rosemary J. Akhurst, PhD [University of California San Francisco]
- Douglas Marchuk, PhD [Duke University]
- Joseph Shieh, MD, PhD [University of California San Francisco]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
+ Problem
- There are no FDA or EMA approved therapies for HHT patients
- Pre-clinical testing models need to be refined for efficient drug discovery & clinical trial prioritization
+ Gap
ALK1 signaling
- Better understanding of how ALK1 and its ligands are synthesized and mature to ultimately contribute to ALK1 signaling
- Better understanding of the role of endoglin in serving as an reservoir/container for ALK1 ligands
- Interfere/inhibit ALK5 signaling to push the balance towards more ALK1 activity
Understanding the role of endoglin shedding as a modulator of Eng/ALK1 signaling
Insight in the second hit hypothesis
Increasing Endoglin/ALK1/BMP9/10 as therapeutic strategy ->
Need to know more about what regulates their expression and how different endothelial/vascular beds respond as this is likely to be different
+ Recommendation
6. Create an HHT-associated biorepsitory for vascular malformation and other tissues.
7. Harvest endothelial cells from vascular malformations and other tissues.
8. Search for somatic mutations in blood leukocytes and/or circulating cells.
9. Increase ENG/ALK1/BMP9/10 as therapeutic strategy through engineered ligands and design proteins/specific antibodies to force signaling.
+ Research Network Contributor(s)
BMP Pathways Workstream
- Christine Mummery, PhD [Developmental Biology; Leiden University Medical Centre; Netherlands]
- M-J Goumans, PhD [Cardiovascular Cell Biology; Leiden University Medical Centre; Netherlands]
- Sabine Bailly, PhD [Cancer Biology; French Institution of Health and Medical Research; France]
- Andy Hinck, PhD [Structural Biology; University of Pittsburgh; US]
- Carmelo Bernabeu, PhD [Vascular Biology; Biological Research Center; Spanish National Research Center; Spain]
- Valeria Orlova, PhD [Cadiovascular Cell Biology; Leiden University Medical Center; Netherlands]
- Edda Spiekerkoetter, MD [Pulmonology; Stanford University; HHT Center; US]
- Anthony Canavicci, PhD [Patient; University of Toronto; Canada]
- Heather Mceldowney [Patient; US]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
+ Problem
- There are no FDA or EMA approved drug therapies for HHT patients
- Pre-clinical testing models need to be refined for efficient drug discovery & clinical trial prioritization
+ Gap
BMP Pathways
- Mechanisms involved in the regression of vascular lesions in animal models
- Identification of biological stimuli or triggers that contribute to regression
Antiangiogenics and Non-BMP Pathways
- Mechanistic pathways in HHT pathogenesis are only partially understood, which limit our ability to repurpose or discover new drugs.
- Genomics, transcriptomics, and proteomic approaches are often performed in isolation and not compared across different preclinical HHT models.
- Therefore, there is a need for continued refinement of basic and translational models for mechanistic studies, as well as for drug testing and development.
+ Recommendation
10. Develop high throughput screening tools (cell based, multiple stable endothelial cells line, iPSC-ECs, microfluidics, animal models, etc.)
11. Create more infrastructure for patient engagement during drug development.
12. Find promising pathways that can be used for novel drug development.
13. Develop and refine biological outcome measures to facilitate drug development and repurposing, drug discovery, and clinic.
+ Research Network Contributor(s)
BMP Pathways Workstream
- Christine Mummery, PhD [Developmental Biology; Leiden University Medical Centre; Netherlands]
- M-J Goumans, PhD [Cardiovascular Cell Biology; Leiden University Medical Centre; Netherlands]
- Sabine Bailly, PhD [Cancer Biology; French Institution of Health and Medical Research; France]
- Andy Hinck, PhD [Structural Biology; University of Pittsburgh; US]
- Carmelo Bernabeu, PhD [Vascular Biology; Biological Research Center; Spanish National Research Center; Spain]
- Valeria Orlova, PhD [Cadiovascular Cell Biology; Leiden University Medical Center; Netherlands]
- Edda Spiekerkoetter, MD [Pulmonology; Stanford University; HHT Center; US]
- Anthony Canavicci, PhD [Patient; University of Toronto; Canada]
- Heather Mceldowney [Patient; US]
Antiangiogenics and Non-BMP Pathways Workstream
- Aimee Nolan [HHT patient-advocate, Ireland]
- Denise Adams, MD [Pediatric Hem-Onc, Children’s Hospital of Philadelphia, USA]
- Alex Borst, MD [Pediatric Hem-Onc, Children’s Hospital of Philadelphia, USA]
- Sophie Dupuis-Girod, MD, PhD [Clinical Genetics; University of Lyon Hospital Center; Lyon, France]
- Franck Lebrin PhD [Leiden, Netherlands]
- Hanny Al-Samkari, MD [Hematology; Mass General, USA]
- Michael Lewis [HHT patient-advocate, USA]
- Stryder Meadows, PhD [Vascular biology, Tulane University; New Orleans, USA]
- Roxana Ola, PhD [Cardiovascular Pharmacology; University of Heidelberg; Heidelberg, Germany]
- William Sellars, MD [Cancer Biology and Cancer Genomics; Broad Institute; Boston, USA]
- Philippe Marambaud, PhD [Cell and Molecular Biology; Feinstein Institutes for Medical Research, USA]
- Vivek Iyer, MD [Pulmonology; Mayo Clinic Minnesota, USA]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
Treatment
+ Problem
- Individual HHT patients have a wide disparity in bleeding without obvious explanations.
- Tools are missing to measure severity and response to therapy.
+ Gap
Genetic determinants/modifiers (Somatic Mutations workstream overlap)
Impact of environmental factors on HHT phenotype
Effect of co-morbidities and their treatments
No global measure of disease severity (i.e. HHT phenotypic severity score) or global measure of bleeding severity
The widely used ESS has significant limitations
(not comprehensive or accepted by regulatory authorities)
A standardized approach to assess response to therapy is critical as we explore new therapeutic targets and therapies
Objective evaluation of telangiectasias is not a component of assessment of response to therapy
+ Recommendation
14. Evaluate capillary imaging methodologies in HHT
15. Develop a multidimensional bleeding severity score.
16. Understand modifiers of bleeding severity (environmental, genetic, and anatomic)
+ Research Network Contributor(s)
Bleeding Workstream
- Raj Kasthuri, MBBS [Hematology; University of North Carolina at Chapel Hill, USA]
- Hanny Al-Samkari, MD [Hematology; Massachusetts General Hospital, Harvard Medical School, USA]
- Franck Lebrin, PhD [Cell Biology; Einthoven Laboratories, Leiden University Medical Center, Netherlands]
- Claudia Crocione [Patient; Managing Director HHT Europe, Italy]
- James Gossage, MD [Pulmonology; Augusta University, USA]
- Jay Piccirillo, MD [Otolaryngology; Washington University, USA]
- Scott Olitsky, MD [Patient Advocate; CMO, Cure HHT]
- Marianne Clancy, RDH [Patient Advocate; Executive Director, Cure HHT]
- Maria Mavris [Patient Relations, Public Engagement Office, EMA]
- Mickael Tanter, PhD [Physics for Medicine Paris, INSERM, France]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
+ Problem
- There is a need to assess the role of antiangiogenic and other pathway-based therapies in the treatment of PAVMs (especially diffuse PAVMs and microscopic PAVMs) and PAH, using animal models and clinical trials.
- The determinants of outcomes and clinical significance of PAVM persistence, PAVMs in children, and PAH need to be identified
- There is a need to determine the growth rate of PAVMs during childhood, pregnancy and adult life which affects screening protocols, treatment recommendations, and outcomes
+ Gap
Little/no knowledge of how antiangiogenic therapies, other pathway-based therapies impact PAVMs.
For example, how does delivery/dynamics specific to lungs modulate impact/potential? No studies of role in severe forms, such as diffuse PAVMs.
Limited HHT animal models for PAVMs & PAH in HHT.
Limited information about outcomes (and their determinants) of PAVMs and of PAVM treatment (embolization, surgical, transplant, other) in some neglected groups:
Children, diffuse PAVMs, and PAH.
Limited information about the clinical significance of reperfusion, PAVM persistence after treatment to guide imaging and treatment recommendations.
Several screening and imaging modalities studied, but how do they predict risk of stroke, response to therapy, etc?
Limited information about outcomes and their predictors in patients with positive echo bubble but negative CT (microPAVMs) and small PAVMs.
Limited tools to measure accurately, efficiently, and prospectively the clinical impact on management of these patients, prevention, and follow-up imaging.
Limited data about growth of PAVMs, determinants of growth of PAVMs (existing and new).
Limited tools to measure accurately, efficiently, and prospectively the clinical impact on screening processes.
+ Recommendation
17. Assess the role of antiangiogenic and other pathway-based therapies in the treatment of PAVMs (especially diffuse PAVMs and microscopic PAVMs) and PAH, using animal models and clinical trials.
18. Identify determinants of outcomes of PAVMs, including groups where major gaps exist, such as AVM persistence, children, diffuse pulmonary AVMs and PAH.
19. Determine growth rate of PAVMs (untreated and treated, during childhood, pregnancy and adult life), and their determinants, to inform screening protocols, treatment recommendations, and outcomes research.
+ Research Network Contributor(s)
Unresolved Topics in Lung AVMs Workstream
- Marie Faughnan, MD MSc [Pulmonology; Toronto HHT Center]
- Miles Conrad, MD MPH [Interventional Radiology; University of California San Fancisco; HHT Center]
- Hans-Jurgen Mager, MD PhD [Pulmonology; St. Antonius Hospital; Netherlands]
- Hilary Dubrock, MD [Pulmonology; Mayo Clinic MN; HHT Center]
- Justin McWilliams, MD [Interventional Radiology; University of California Los Angeles; HHT Center]
- Murali Chakinala, MD FCCP [Pulmonology; Washington University St. Louis HHT Center]
- Scott Trerotola, MD [Interventional Radiology; University of Pennsylvania; HHT Center]
- Josanna Rodriguez Lopez, MD [Pulmonology; Massachusetts General Hospital; HHT Center]
- Clifford Weiss MD [Interventional Radiology; Johns Hopkins HHT Center]
- Mollie Meek, MD [Interventional Radiology; University of Arkansas]
- Stryder Meadows, PhD [Cell and Molecular Biology; Tulane University]
- John Dunn [Patient; US]
- Martina Mascioni [Patient; US]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
+ Problem
- Natural history and the factors influencing growth and development of AVMs is unknown
- Tools are missing to measure growth and response (imaging sensitivity may not be sufficient to measure in real-time)
+ Gap
We lack a validated preclinical pathway for screening therapeutic candidates
- What are the model system features predicting VM initiation that can be used to screen candidate therapies or pathways?
- Will screening based on EC phenotypes predict benefit in animal models?
- Will screening based on animal model phenotypes predict benefit in patients?
Requirement of BMP-ENG-ACVRL1 for VM progression/maintenance
- Animal models have not addressed restoration of BMP-ENG-ACVRL1 on phenotypes
- Will BMP ligand or ENG/ACVRL1 overexpression strategies be useful only to prevent novel lesions?
Cellular and molecular determinants of vascular malformations
- Studies suggest lesions contain mutant and WT cells
- Likely role of cross-talk between EC and surrounding cells (pericytes, etc)
- Technology exists to characterize single cell expression profiles
- Animal models and patient samples are available to explore biology
Inadequate therapeutic response to liver vascular malformations
Underutilization of liver transplantation
+ Recommendation
20. Understand more about liver transplant for complicated liver vascular malformations.
21. Find predictors of symptomatic liver vascular malformations.
22. Identify preclinical screening pathway.
+ Research Network Contributor(s)
AVM Progression Workstream
- S. Paul Oh, PhD [Neurobiology, Barrow Neurological Institute]
- Kevin Whitehead, MD [Cardiovascular Medicine, University of Utah Medical Center; HHT Center
- Helen Arthur, PhD [Cardiovascular Biology, Newcastle University, UK]
- Ethan Winkler, PhD [Endovascular Surgical Neuroradiology, Barrow Neurological Institute, US]
- Ann Eichmann, PhD [Cellular and Molecular Physiology, Yale Cardiovascular Research Center, US]
- Patrick Kamath, MD [Hepatology, Mayo Clinic MN; HHT Center
- Arndt Siekmann, PhD [Cell and Developmental Biology, University of Pennsylvania]
- Sanjay Misra, MD [Radiology; Vascular and Endovascular Surgery, Mayo Clinic MN; HHT Center
- Adrienne Hammill, MD PhD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center; HHT Center
- Jay Hoying, PhD [Cardiovascular Physiology, Advanced Solutions]
- Michael Ohliger, MD PhD [Radiology and Biomedical Imaging, University of California San Francisco]
- Karen Weissel, PhD [Patient]
- Gael Genet, PhD [Cell Biology, University of Virginia]
- Tania Competiello [Patient]
- Ann Trussell [Patient]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
+ Problem
- There is insufficient knowledge/information available to classify brain VMs as high risk vs low risk to identify those who need preventive treatment.
- Could there be a role for medical therapy for brain VMs?
+ Gap
No guidelines for screening and rescreening HHT patients for bAVM
- Regional and country variability in screening practices amongst HHT Centers of Excellence
- High rate of bAVM recurrence in children (21-33%) has prompted many groups to use non-invasive MRI for surveillance monitoring, but optimal imaging intervals remains unclear (how often, what age, what modality)
Understanding risk of hemorrhage by brain VM type and factors that influence risk
- “Lumping” low-risk capillary vascular malformations with high-risk shunting lesions -> low hemorrhage rate
- Other risk factors that influence hemorrhage risk, e.g., flow rates, family history, SES factors, biomarkers
Lacking treatment recommendations for bAVM due to insufficient outcome studies
Translating preclinical therapeutic studies to humans
- Limited clinical studies in HHT and sporadic bAVM patients (patient selection, safety and outcomes)
- Rigorous animal studies needed to test administration of single or multimodal drug therapy, dosing, and optimal drug delivery (oral or intravenous)
+ Recommendation
23. Develop standardized protocols for screening and rescreening HHT patients for brain AVM.
24. Determine the risk of hemorrhage in brain AVM and other brain VM types in HHT; and what factors influence risk.
25. Develop therapeutic strategies based on patient selection, delivery, and outcome assessment for BAVM.
+ Research Network Contributor(s)
Unresolved Topics in Brain AVMs Workstreams
- Helen Kim, PhD [Cerebrovascular Research; University of California – San Francisco]
- Steven Hetts, MD [Interventional Neuroradiology; University of California – San Francisco]
- Timo Krings, MD, PhD, FRCP(C) [Interventional Neuroradiology; University of Toronto, Toronto Western Hospital and Krembil Research Institute]
- Hua Su, MD [Cerebrovascular Research; University of California – San Francisco]
- Lauren Beslow, MD, MSCE [Neurology; Children’s Hospital of Pennsylvania]
- Christine Fox, MD [Pediatric Neurology; University of California – San Francisco]
- Beth Plahn [Patient Advocate; Avera Health]
- Michael T. Lawton, MD [Neurosurgery; Barrow Neurological Institute]
- Ralf Adams, PhD [Tissue Morphogenesis; Max Planck Institute for Molecular Biomedicine]
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
Awareness
+ Problem
- There is a significant proportion of HHT patients in whom we cannot confirm genetic diagnosis
- Updating Curacao diagnostic criteria
- Clinical manifestations of HHT with negative genetic testing and HHT-like syndromes
- Noncoding variants in known HHT genes versus new genes
+ Gap
Clinical Diagnosis (accuracy of which significantly affects calculated sensitivity of genetic testing)
- Detailed data regarding the presentation/characteristics of telangiectases, epistaxis, and AVMs in HHT versus those with CM-AVM, or other overlap disorders (includes GDF2 and BMPR2- related)
- Penetrance of HHT uncertain for manifestation and age
- Guidelines for imaging in the diagnostic evaluation for HHT
- Robust criteria for differential diagnosis of HHT versus overlap syndromes e.g. CM-AVM. Could RASA1 or EPHB4 mutation be used as exclusion criterion?
- How ancestry/ethnicity affects phenotype
Molecular Diagnostics
- Standardized protocol(s) for assessing VUSs
- Percentage of HHT patients meeting Curaçao diagnostic criteria without an identified HHT mutation & percentage of patients not meeting Curaçao diagnostic criteria with an identified HHT mutation
- Contribution of other genes, regions of known genes, or other molecular mechanisms causing HHT phenotype.
- Mutational “hotspots” within HHT genes
- Standardization in genes tested and methodology
- Standard guidelines regarding how age should influence testing strategy
+ Recommendation
26. Improve strategies for VUS interpretation in HHT genes.
27. Update clinical diagnostic criteria and guidelines for age and the application of clinical diagnostic criteria and genetic testing.
28. Standardize minimal acceptable components/approach for molecular diagnostic testing of proband.
29. Obtain further data from WGS (short and long reads) and/or RNAseq in patients clinically diagnosed with HHT whose initial genetic test results were negative.
30. Identify and describe patients with positive genetic test results who do not meet Curaçao Criteria & patients clinically diagnosed with HHT whose initial genetic test results were negative.
+ Research Network Contributor(s)
Genetic Considerations in HHT Diagnosis Workstream
- Jamie McDonald, MS [University of Utah, Salt Lake City, UT, USA]
- Miikka Vikkula, MD, PhD
- Sara Palmer, PhD [Patient, Cure HHT Board of Directors, Baltimore, MD, USA]
- Pinar Bayrak-Toydemir, MD, PhD [University of Utah/ARUP Laboratories, Salt Lake City, UT, USA]
- Ingrid Winship, MD [University of Melbourne, Royal Melbourne Hospital, Australia
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
+ Recommendation
31. Determine if there are any discrepancies in HHT diagnosis and access to HHT care regarding race, ethnicity, age, gender, socio-economic status, language, geography, or other factors and identify solutions to address barriers and related outcomes.
+ Progress Update
COMING SOON...
+ Publication(s)
COMING SOON...
Celebrating Milestones: Charting the Future of HHT
Empowering patients with actionable goals, the Cure HHT Research Roadmap paves the way for future endeavors, funding initiatives, and unparalleled collaboration among patients, clinicians, and researchers within the HHT community.
