DC in the News
DC Families in the News
The Mountains That Hold Me Up as I Parent a Medically Complex Child - Chantel Schieffer
A three in a million family - The Courier (Australia)
A bundle of hope after rare disorder claims Nelson man - Nelson Mail (New Zealand)
Statement on Unproven Stem Cell Interventions for Lung Diseases (Posted in the August 2016 Annals of the American Thoracic Society by the Respiratory Cell Molecular Biology Stem Cell Working Group)
A central component of the mission of medical societies is to translate new scientific information into patient education. The undersigned lung, respiratory, and thoracic societies, and patient advocacy groups strongly believe that patients and their families along with the general public should have at their disposal unbiased and scientifically sound information on new potential therapeutic options including stem cell-based treatments.
Continuing advances in stem cell biology have created justified excitement at the prospect of personalized stem cell-based therapies through the use of clinically relevant cell populations. We recognize the enormous potential of stem cells for disease management including acute and chronic ailments of the respiratory system. As we learn more about the therapeutic potential of stem cells and other cell therapies in clinical trials of non-lung diseases and in initial trials in lung diseases, we hope to move towards further consideration and potential implementation of these approaches.
However, as with all medical interventions, patient safety must be the top priority of any prospective stem cell-based therapy or treatment. As yet, there is very little known about the short- and long-term effects in terms of safety and efficacy of administering any type of stem cell-based therapy to patients with lung diseases. Until we know more, we must be strongly concerned that the treatment could cause adverse effects and could worsen the patient's condition rather than improve it.
At present, there are only a small number of peer reviewed and appropriately regulated approved clinical trials in the United States, Canada, the European Union, Brazil, Asia and Australia investigating cell therapy approaches for lung diseases. These can be found on the website of the National Institutes of Health at www.clinicaltrials.gov, of the European Medicines Agency at https://www.clinicaltrialsregister.eu/ctr-search/search, and of UMIN-ICDR in Japan at http://www.umin.ac.jp/icdr/index.html. We are watching these carefully to determine whether they will demonstrate that stem cell-based treatments could be effective and safe for treating lung diseases.
Thus, we are particularly wary of the ever-increasing examples of direct-to-consumer advertising of untested, unapproved, and potentially dangerous “stem-cell” treatments that take place in several countries. One may come across information on the internet or other sources about stem cells being administered to patients with lung diseases such as emphysema, pulmonary hypertension, cystic fibrosis, or pulmonary fibrosis in several locations worldwide including the United States. We fully acknowledge that patients with severe irreversible lung diseases are under extreme physical and emotional distress that provide the motivation to resort to expensive unproven treatments. Nevertheless, we strongly caution all patients that the claims of benefit being made by many of these programs have not been substantiated nor have they been reviewed by experts in the field or any regulatory agency. These programs are usually characterized by:
- Exorbitant fees
- Misrepresentation of risks and benefits
- Overreliance on, and advertisement of, patient testimony
- Poor patient follow-up
- Absence of regulatory oversight and objective clinical evidence for claimed benefits
Therefore, they differ substantially from therapies approved by legitimate regulatory agencies, from well-designed, controlled, and appropriately regulated clinical trials, and from regulated compassionate use of innovative cell therapies. Because of the potential for harm and the lack of any proven benefit, we strongly caution patients not to participate in these or any other comparable unauthorized or unapproved stem cell interventions, unless independent credible, reliable, and objective sources of information are available to substantiate the information and claims being made.
To better educate the lung scientific community about the complex issues of stem cell medical tourism, we propose the inclusion of relevant sessions, whenever possible, in future national and international conferences related to lung biology and disease. Representatives of regulatory agencies, patient advocacy groups, and bioethics and health policy scholars should be included as speakers and discussants. We also urge patient advocacy groups and foundations to work together with their national lung, respiratory, and thoracic societies, their local chapters, and with regulatory agencies on the issues of stem cell medical tourism and unproven stem cell interventions. Open channels of communication between these organizations and dissemination of reliable, evidence-based information through patient networks including social media, will ensure that lung disease patients make informed and safe decisions regarding cell-based treatments.
One such reliable source of information is the International Society for Stem Cell Research (ISSCR), which has developed an excellent web-based resource that includes the ISSCR patient handbook (http://www.isscr.org/home/publications/ClinTransGuide, http://www.closerlookatstemcells.org/stem-cells-and-medicine). The handbook provides information on mechanisms for monitoring or substantiating the claims being made by various organizations that purport to offer “stem cell therapies.”
Additional resources are provided by the International Society for Cellular Therapy (http://www.celltherapysociety.org/?page=PTF2015, http://bit.ly/1lAjOIV), the California Institute for Regenerative Medicine (www.cirm.ca.gov), the Canadian Stem Cell Network (http://www.stemcellnetwork.ca/) and the Canadian Stem Cell Foundation (stemcellfoundation.ca).
This Assembly on Respiratory Cell & Molecular Biology Stem Cell Working Group statement is supported by the following lung, respiratory, and thoracic societies and patient advocacy groups:
American Lung Association (U.S.A.)
Asian Pacific Society of Respirology
Brazilian Thoracic Society
COPD Foundation (U.S.A.)
Cystic Fibrosis Foundation (U.S.A.)
Dyskeratosis Congenita Outreach (U.S.A.)
European Lung Foundation
European Respiratory Society
The Japanese Respiratory Society
Macedonian Respiratory Society
Malaysian Thoracic Society
Pulmonary Fibrosis Foundation (U.S.A.)
Pulmonary Hypertension Association (U.S.A.)
South African Thoracic Society
Swiss Society of Respiratory Medicine
The Thoracic Society of Australia and New Zealand
The Transplantation Society of Australia and New Zealand
Turkish Thoracic Society
Dyskeratosis Congenita Outreach, Inc. part of announcement at Precision Medicine Summit with President Obama
PCORnet Patient Powered Research Networks Pledge Announced
Washington, DC (February 25, 2016) – Dyskeratosis Congenita Outreach, Inc., a member of the Community Engaged Network for All (CENA), is participating in the Precision Medicine Initiative Summit with President Obama today. Amidst several other ‘health data flow’ announcements, Sharon Terry, President and CEO of Genetic Alliance, announced that the Patient Powered Research Networks (PPRN) of the National Patient-Centered Clinical Research Network (PCORnet) will prioritize patient access to electronic health record (EHR) data in order to let it flow into research studies. CENA is a PPRN, and as such is changing the culture of medical research by involving participants, their families, and communities in all phases of research. Dyskeratosis Congenita Outreach, Inc., represented today by Sharon Terry, CEO and principal investigator of CENA, is thrilled to be involved in this commitment to help people more readily obtain their health information for advancing research.
The Community Engaged Network for All (CENA is quite novel in that it is a collaborative effort of 10 disease advocacy organizations, the University of California, San Francisco, the University of California, Davis and Private Access. CENA utilizes the Platform for Engaging Everyone Responsibly (PEER) built by Private Access and Genetic Alliance to enable individuals to share their health information according to their personal data access and privacy preferences.
“CENA has implemented the capability to receive EHR data transmitted using the Direct secure-email protocol within PEER, and their participants are giving CENA’s Direct address to their providers with the request that their EHR data be sent to CENA. We know the Argonaut Project’s progress and are eager to implement apps that will enable our participants to request the PCORnet clinical data elements through a FHIR-based API,” said Dixie Baker of Martin Blanck & Associates, who is assisting the PPRN in designing and implementing systems to extract EHR data.
To create a more robust network, all the PPRNs pledge to help participants access their EHR data and to make it available for research. This will greatly enhance the quality, sensitivity, and power of the available research data. The PPRNs will enable participants to retrieve their own EHR data through existing patient portals, giving them an immediate option to make these data available for research, while building toward data retrieval using apps to query OAuth 2.0 based APIs, and ultimately retrieval of FHIR resources. The first PPRN deployments are already in use.
“I am delighted to see these data flow! The goal for CENA is to empower people to ask for their health data from healthcare providers and receive it in the easiest and most useful way,” said Sharon Terry, CENA PPRN PI, and CEO of PXE International and Genetic Alliance. Terry is also a member of the Precision Medicine Initiative Cohort Program Advisory Panel.
“This EHR data, combined with information from self-reported data and other sources, will be critical in understanding health outcomes for millions of Americans,” Terry added.
About Dyskeratosis Congenita Outreach, Inc.
Dyskeratosis Congenita Outreach, Inc. was founded in 2008 to support individuals and families affected by Dyskeratosis Congenita and Telomere Biology Disorders. Principal to our mission is connecting families living with this rare disease to each other and to medical care providers and research specialists. We strive to educate families and clinicians, and bring awareness to the world. DC Outreach, Inc. works diligently to nurture hope and compassion for individuals and families around the world living with DC & TBD. Visit: https://www.dcoutreach.org
CENA is part of PCORnet, the National Patient-Centered Clinical Research Network, an innovative initiative of the Patient-Centered Outcomes Research Institute (PCORI). Genetic Alliance leads this project, which is a collaborative of ten disease advocacy organizations, the University of California San Francisco, the University of California Davis, and Private Access. For more information about CENA please visit: http://www.geneticalliance.org/programs/biotrust/cena
About Platform for Engaging Everyone Responsibly
Platform for Engaging Everyone Responsibly (PEER) is the world's first participant-controlled, cross-condition health registry. From the ground up, PEER is based on the principle that genuinely engaging individuals in medical research demands giving each individual (or their legally authorized representative) the power to decide for themself how, and with whom, they wish to share their health information. For more information: http://peerplatform.org/
About Genetic Alliance
Genetic Alliance engages individuals, families and communities to transform health. Founded in 1986, it is the world's largest nonprofit health advocacy organization network. Genetic Alliance's network includes more than 1,200 disease-specific advocacy organizations, as well as thousands of universities, private companies, government agencies, and public policy organizations. For more information about Genetic Alliance, visit www.geneticalliance.org.
About UC San Francisco (UCSF)
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital. More information is available at www.ucsf.edu.
About UC Davis Health System
UC Davis Health System improves lives by providing excellent patient care, conducting groundbreaking research, fostering innovative, interprofessional education and creating dynamic, productive community partnerships. It encompasses one of the country's best medical schools, a 619-bed acute-care teaching hospital, a 1,000-member physician practice group and the Betty Irene Moore School of Nursing. Together, they make UC Davis a hub of innovation that is transforming health for all. For information, visit www.healthsystem.ucdavis.edu.
About Private Access
Private Access is striving to make it safe for sensitive personal information such as medical records and genomic data to be accessible over the Internet. Through PrivacyLayer®, the firm ’s core services platform, Private Access empowers individuals to set granular privacy preferences and use dynamic consent tools to address a number of critical privacy concerns and related hurdles that have traditionally impeded privacy-protective sharing of this valuable information. In 2009, Forbes named Private Access as #12 on its list of America’s Most Promising Companies. More information is available at www.privateaccess.com.
The Patient-Centered Outcomes Research Institute (PCORI) is an independent, non-profit organization authorized by Congress in 2010. Its mission is to fund research that will provide patients, their caregivers and clinicians with the evidence-based information needed to make better-informed health care decisions. PCORI is committed to continuously seeking input from a broad range of stakeholders to guide its work. More information is available at www.pcori.org.
Genetics of Dyskeratosis Congenita
- The major cause of death in DC is bone marrow failure.
- The most common form of DC is X linked.
- In the X-linked form, females are not, or very mildly, affected, but they show extremely skewed X-inactivation, with cells expressing the mutated gene being outgrown by cells expressing the wild type gene.
- Dyskeratosis congenita is a disease caused by defective telomere maintenance.
- When the disease is caused by mutations in the core components of telomerase, TERT and TERC families show an increase in severity of the disease in later generations, a phenomenon known as genetic anticipation.
- Genetic anticipation is due to shortening of telomeres from one generation to the next.
- Some DC mutations are also known causes of pulmonary fibrosis, liver fibrosis and Coats retinopathy.
- Now that genes responsible for rare syndromes are being discovered, it is becoming evident that there is overlap between DC and several other rare syndromes that have been described.
New Gene Announced at ASH
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome that results from impaired telomere maintenance. The classic triad (dysplastic nails, skin pigmentation, and oral leukoplakia) is diagnostic of DC but significant clinical heterogeneity can exist, even within a family. Leukocyte telomere lengths less than the first percentile for age are diagnostic of DC. Patients with DC are at high risk of bone marrow failure (BMF), myelodysplastic syndrome, cancer, pulmonary fibrosis, liver disease and other complications.
Currently, germline mutations in 1 of 8 telomere biology genes (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53, and CTC1) are known to cause ~50-60% of DC cases. Our longitudinal cohort study conducts detailed medical record review and clinical examinations of patients with DC and their family members. DC is diagnosed based on the presence of the diagnostic triad or 1 of the triad plus BMF. All DC patients had telomeres <1st percentile. Patients are classified as DC-like if they have telomeres <1st percentile and other features, such as BMF or family history, suggestive of DC. All participants in this study were negative for mutations in the known DC genes.
We performed whole exome sequencing (WES) on two DC families using an enriched multiplexed sequencing library (Nimblegen v2) and sequenced on an Illumina HiSeqTM. Variants were removed from analyses if they did not pass quality control filters or were present more than 3 times in publically available databases (1000Genomes, ESP, Kaviar, and dbSNP). Since DC can be inherited in autosomal dominant, autosomal recessive, and X-linked manners, we evaluated all inheritance models in our families. Additionally, if healthy family members had very short telomeres, they were also evaluated as potential silent carriers, since this approach has facilitated the identification of other DC genes. Nonsynonymous variants were considered deleterious if SIFT, PolyPhen 2, and Condel predictions were consistent.
Family 1 has 2 siblings with the Hoyeraal Hreidarsson syndrome (HH) variant of DC, which includes features of DC plus cerebellar hypoplasia. In that family, WES revealed autosomal dominant inheritance of a nonsense mutation in RTEL1 (Regulator of Telomere Elongation Helicase 1), p.Arg1010Stop. Their mother, who has lymphocyte telomere lengths at the 1st percentile, is a clinically silent carrier of this mutation; the severe phenotypes present in her children are likely an example of genetic anticipation. In family 2, we found 2 RTEL1 mutations, a nonsense (p.Arg998Stop) and a deleterious missense (p.Glu615Asp) mutation, that were inherited from the father and mother, respectively. One clinically healthy child inherited only the missense mutation, but has telomeres <1st percentile. The other child has HH and extremely short telomeres; he is a compound heterozygote, having inherited both the missense and nonsense mutations in RTEL1.
We subsequently performed targeted sequencing of the entire RTEL1 gene in all of our mutation-negative DC (n=11) and DC-like (n=14) families. We identified missense mutations in RTEL1 in 2 additional families. Family 3 has 2 DC-like siblings, but only the proband’s DNA was available for sequencing. He was heterozygous for a deleterious missense mutation (p.Ala645Thr) in a conserved helicase domain of RTEL1. In family 4, a mutation was inherited in an autosomal recessive manner by a proband with HH. This mutation is intronic except for a read-through transcript of RTEL1-TNFRSF6B, which utilizes an alternative exon 34. If translated, this variant results in the amino acid change p.Arg1264His, which is likely deleterious; if not, this mutation may affect nonsense-mediated decay or induce a regulatory change in RTEL1 expression.
RTEL1 is an essential, evolutionarily conserved DNA helicase that is important for DNA replication and telomere elongation. Depletion of mRTEL1 from mouse embryonic stem cells results in telomeric loss and chromosomal instability. All individuals with germline RTEL1 mutations in this study have short telomeres, which underscores the functional importance of RTEL1 in human telomere maintenance. In summary, by employing WES followed by targeted sequencing, we discovered mutations in RTEL1 in 4 DC families, indicating that dysfunctional RTEL1 is a biologically plausible cause of DC.
A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells
Dyskerin gene is mutated in patients with X-linked dyskeratosis congenita (X-DC), which results in greatly reduced levels of telomerase activity. A genetic suppressor element (GSE) termed GSE24-2 has been isolated in a screening for cisplatin resistance. GSE24-2–expressing cells presented impaired telomerase inhibition following in vitro exposure to chemotherapies, such as cisplatin, or telomerase inhibitors. The promoter of the telomerase component hTERT was constitutively activated in GSE24-2 cells in a c-myc expression–dependent manner. Deletion analyses and mutagenesis of the human c-myc promoter demonstrated that the target sequence for activation was the nuclease hypersensitive element-III (NHEIII) site located upstream to the P1 region of the promoter. Further, expression of GSE24-2 in cell lines derived from patients with X-DC and in VA13 cells induced increased hTERT RNA and hTR levels and recovery of telomerase activity. Finally, expression of GSE24-2 was able to rescue X-DC fibroblasts from premature senescence. These data demonstrate that this domain of dyskerin plays an important role in telomerase maintenance following cell insults such as cisplatin treatment, and in telomerase-defective cells in patients with X-DC. The expression of this dyskerin fragment has a dominant function in X-DC cells and could provide the basis for a therapeutic approach to this disease.
Submitted April 8, 2007.
Accepted November 20, 2007.
© 2008 by The American Society of Hematology
The full paper can be viewed by clicking here:
For more information about this company and their work you can visit their website at: http://advmedprojects.com/
October 5th, 2009
Stockholm, Sweden -- Exciting news everyone! The Nobel Prize for Medicine has gone to three scientists whose work focused on telomere biology, a realm of science at the heart of recent research into Dyskeratosis Congenita (DC). As many of us know, recent work at the National Institutes of Health has led to the recognition that DC is a disorder of telomere biology. While the awarding of a Nobel may not mean a "cure" for DC is just around the corner, we at DC Outreach are glad to see research in this important field elevated to international prominence with this important recognition.
Here's the news, as described by the Nobel committee in an Oct. 5, 2009 press release:
Telomeres are structures on the ends of chromosomes that protect the strands of DNA, much like the plastic aglets that protect the ends of your shoelaces. Telomeres shorten naturally in everyone as they age. However, persons with DC have telomeres that are much shorter than expected for their age. While the research is ongoing, scientists over the years have found that DC is caused by a mutation in one of nine genes important in telomere biology However only about one-half of patients with DC have an identifiable mutation in one of these genes. Ongoing research aims to discover more DC-associated gene mutations, and to learn how telomere genes contribute to cancer development and aging.