Day 1 :
National Center for Advancing Transnational Sciences
National Institutes of Health
Time : 10:00-10:40AM
Dan Tagle is associate director for special initiatives at NCATS. He also recently served as acting director of the NCATS Office of Grants Management and Scientific Review and currently serves as executive secretary to the NCATS Advisory Council and Cures Acceleration Network Review Board. Prior to joining NCATS, Tagle was a program director for neurogenetics at the National Institute of Neurological Disorders and Stroke (NINDS), where he was involved in developing programs concerning genomics-based approaches for basic and translational research in inherited brain disorders.
There are fewer than 400 approved treatments for approximately 7000 rare diseases affecting more than 30 million Americans. The NIH have More than 30% of promising medications have failed in human clinical trials because they are determined to be toxic despite promising pre-clinical studies in animal models, and another 60% fail due to lack of efficacy. The challenge of accurately predicting drug toxicities and efficacies is in part due to inherent species differences in drug metabolizing enzyme activities and cell-type specific sensitivities to toxicants. These challenges are particularly acute for rare diseases where adequate tools and resources are severely lacking. To address this challenge in drug development and regulatory science, the Tissue Chips program aims to develop alternative approaches that would enable early indications and potentially more reliable readouts of toxicity or efficacy. The goal this program is to develop bio-engineered microdevices that mimic functional units of the 10 major human organ systems: circulatory, respiratory, integumentary, reproductive, endocrine, gastrointestinal, nervous, urinary, musculoskeletal, and immune. The opportunities for significant advancements in the prediction of human drug toxicities through the development of microphysiological systems, requires a multi-disciplinary approach that relies on an understanding of human physiology, stem cell biology, material sciences and bioengineering. This unique and novel in vitro platform could help ensure that safe and effective therapeutics are identified sooner, and ineffective or toxic ones are rejected early in the drug development process. These microfabricated devices are also useful for modeling human diseases, especially for studies in rare diseases, as well as precision medicine, environment exposures, reproduction and development, infectious diseases, microbiome and countermeasures agents.
King Saud Bin Abdulaziz University
Deputy Chairman, Intensive Care Department, Consultant, Pulmonary and Critical Care Medicine, Professor, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia, Dr.AlDawood graduate from College of Medicine in Kingdom of Saudi Arabia. Then he completed the Residency in Internal Medicine Program in McMaster University in Canada He obtained Critical Care and Respirology Fellowship Program in McMaster University, Canada (Jul 97-Jun 00). In July 2000, he joined King Abdulaziz Medical City, Riyadh, Saudi Arabia as a Consultant in Critical Care and Pulmonary Medicine up to the present. He is currently the Deputy Chairman of the Intensive Care Department and Professor in King Saud Bin Abdulaziz University for Health Sciences. In addition, he has more than 40 publications including articles in the New England Journal of Medicine (NEJM), JAMA, American Journal of Respiratory Critical Care Medicine, BMC Anesthesiology, and Critical Care Medicine.
Background: Since September 2012, 170 confirmed infections with Middle East respiratory syndrome coronavirus (MERS-CoV) havebeen reported to the World Health Organization, including 72 deaths. Data on critically ill patients with MERS-CoV infection are limited.
Objective: To describe the critical illness associated with MERS-CoV.
Design: Case series.
Setting: 3 intensive care units (ICUs) at 2 tertiary care hospitals in
Patients: 12 patients with confirmed or probable MERS-CoV infection.
Measurements: Presenting symptoms, comorbid conditions, pulmonary and extrapulmonary manifestations, measures of severity of illness and organ failure, ICU course, and outcome are described, as are the results of surveillance of health care workers (HCWs) and patients with potential exposure.
Results: Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a health care–associated cluster that also included 3 HCWs. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16 to 36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive.
Limitation: The sample size was small.
Conclusion: MERS-CoV causes severe acute hypoxemic respiratory failure and considerable extra pulmonary organ dysfunction and is associated with high mortality. Community-acquired and health care–associated MERS-CoV infection occurs in patients with chronic comorbid conditions. The health care–associated cluster suggests that human-to-human transmission does occur with unprotected exposure.
- Track 1: Rare Diseases and its Cause
Track 2: Pediatric Rare Diseases
Track 3: Rare Aging Diseases
Track 4: Rare Disease in Oncology
Track 5: Rare Ophthalmological Diseases
Track 6: Rare Metabolic Diseases
Track 7: Genetic Diseases and Disorders
Track 8: Neurological Diseases
Track 9: Rare Pulmonary Diseases
Track 10: Hematological Diseases
Track 11: Nursing and Rare Disease
Track 12: Therapies for Rare Diseases
Track 13: Potency of Orphan Drugs
Track 14: Strategies for Diagnosis &Treatment
Track 15: Legal Issues Related to Rare Diseases
Track 16: Current research on Rare Diseases
Location: London, UK
Nadia Ameen completed her medical degree from the University of the West Indies, Jamaica. She completed training in Pediatrics at Children’s Hospital Wisconsin and then pursued post-doctoral fellowship in gastroenterology at Yale University School of Medicine. She is the principal investigator of an NIH supported research laboratory at Yale University that studies CFTR and diarrheal diseases for over 20 years. She was the first to recognize a trafficking defect in MVID before a genetic defect was identified. She has authored more than 30 papers in reputed journals and serves as an editorial board member for several journals.
MVID is a rare congenital disease that results in severe secretory diarrhea (SD) and death in newborns. Brush border (BB) defects, villus atrophy and microvillus inclusions (MVIs) in enterocytes are associated with the diarrrhea. Loss of function mutations in the actin motor Myosin Vb (Myo5b) is responsible for most cases of MVID. How loss of Myo5b results in secretory diarrhea is unknown. The study used Myo5b loss of function human MVID intestine, polarized intestinal cell models of secretory crypt (T84) and villus resembling (C2BBe) enterocytes lacking Myo5b in conjunction with immunofluorescence confocal gSTED imaging, immunohistochemical staining, TEM, shRNA silencing, immunoblots, and electrophysiologic approaches to examine the distribution, expression and function of the major BB ion transporters (Na+ (NHE3), Cl- (CFTR) and Cl- /HCO3- (SLC26A3, DRA) that control intestinal fluid transport. NHE3 and DRA localization and function were markedly reduced on the BBM of human MVID enterocytes and Myo5bKD C2BBe cells, while CFTR localization was preserved. Forskolin-stimulated CFTR ion transport in Myo5bKD T84 cells resembled that of control. Conclusions: Preservation of functional CFTR in immature enterocytes, reduced functional expression of NHE3 and DRA contribute to Cl- and Na+ stool loss in MVID diarrhea.
National Center for Advancing Translational Sciences
National Institutes of Health
Dr. Wei Zheng received his Ph.D. in Pharmacology from the State University of New York at Buffalo. He had worked 12 years in pharmaceutical companies (Berlex, Amgen, and Merck) for drug discovery and development. Since 2005, Dr. Zheng has worked at National Institutes of Health for development of therapeutics for rare and neglected diseases. He has identified several drugs from drug repurposing screens and advanced two of them to clinical trials. Currently, Dr. Zheng is working on the therapeutics development for lysosomal storage diseases, drug resistant cancer and infectious diseases.
Zika virus infection with complications of microcephaly and other complications has emerged as a health threat in many countries the infection has been reported over 60 countries. Vaccines and therapeutics are currently unavailable for the Zika virus infection. We have developed several compound screening assays and carried out the drug repurposing screens to identify potential therapeutics for the Zika virus infection. The newest results on drug repurposing screens and Zika virus drug development will be presented in this talk.
Martine Zimmermann is a Executive Director in SVP Global Regulatory affairs in Alexion Pharmaceuticals Inc located in Switzerland
This track will discusses opportunities and challenges associated with developing drugs for rare and ultra-rare diseases, and the use of novel approaches to bridge these challenges and successfully bring important lifesaving therapies to patients in need.
Between 5,000 and 8,000 distinct rare diseases exist, affecting between around 27 million and 36 million people in the EU. Collectively these diseases represent a significant proportion of the population, and a growing healthcare concern since many of these rare disorders are serious conditions with no approved treatments.
Since roughly 80% of these diseases have identified genetic origin, our scientific understanding of and ability to target these diseases is growing. Technological advances and our increased understanding of underlying disease biology has aided in the development of several groundbreaking therapies over the past ten years. In addition, heightened public policy support and push to find treatments for patients with rare and devastating diseases has helped in the adoption of legislative vehicles and regulatory programs that compliment scientific discovery and provide important development and financial incentives to companies to bring new targets from bench to bedside. Among them include expedited development and approval programs that offer enhanced regulatory dialogue and support for developers from early stages of clinical development through to approval.
More and more we see appreciable regulatory support for innovative program design and increased regulator openness in applying regulatory flexibilities. All these factors have aided in the approval of important medicines for ultra-rare and devastating diseases. Yet challenges do still persist in the development process, chief among them is the absence of knowledge about the disease itself needed to inform important aspects of clinical development. Natural history for rare diseases is often poorly described or missing altogether given the small affected populations who themselves have variable phenotypes and clinical courses. For developers, it is important, early in the development process, to assess the depth and quality of this information so that a parallel study might better inform the development process.
In the this track we will discuss the pathway to development in rare diseases, starting with this most critical first step of assessing and acquiring knowledge of the disease itself through natural history studies. We will discuss endpoint selection, innovative design and leveraging expedited programs to help with small data sets. We will discuss ways in which frequent and early communication is essential. Finally, we will bring all these points together by using a real life example/case study.
Faculty of Health Sciences
Anahuac University North Campus
Diego Alvarez has his expertise on awareness, education, research and fundraising for Neglected Tropical Diseases. As a medical surgeon with interest and passion for infectious diseases, he is currently studying a Master’s degree of Medical Sciences at Anahuac University North Campus while he does laboratory research on Chagas disease at the Department of Microbiology and Parasitology of the National Autonomous University of Mexico. Also he has been working for several years on Antimicrobial Resistance at the Health Sciences Faculty of the Anahuac University North Campus. Nowadays he is working at the Coordination of Medical Services of the Mexican Red Cross PAR Huixquilucan Office and is a former member of the END7 Campus Leaders Council and of the Young Researchers Track of the Global Network for Neglected Tropical Diseases, an initiative of the Sabin Vaccine Institute. He just joined the American Society of Tropical Medicine and Hygiene.
Neglected tropical diseases (NTDs) are a diverse group of bacterial, parasitic and viral diseases that proliferate in tropical and subtropical enviroments through 149 countries. Currently, more than 1.4 billion people living in Africa, America and Asia are affected by at least 1 of the 17 NTDs recognized by the World Health Organization (WHO). NTDs are called “neglected” because they have been largely wiped out of the most developed areas, but they have persisted in the poorest and most marginalized societies, where inadequate sanitation due to the lack of clean water and poor hygiene, frequent contact with vectors and reservoirs and inadequate healthcare services prevail. If left untreated, NTDs may cause substantial illness and tremendous physical and emotional suffering, hampering children from attending to school and reducing adults economic productivity. As a result, families and communities become trapped in a cycle of disease and poverty. Fortunately, NTDs can be effectively managed if proper measures are implemented and while they have been around for centuries, the team effort to fight them is brand new. In 2011, the WHO Strategic and Technical Advisory Group for Neglected Tropical Diseases drew a roadmap for control, elimination and eradication for the 2012-2020 period and in 2012, a community of partners endorsed the London Declaration on Neglected Tropical Diseases to commit themselves to enchance a better and accelerated response by working in alliance. As we consider both events as an historic set point to change the course of NTDs and as we find ourselves at half of the way of the planned period, it is time to analize where does we stand on the roadmap and what areas of improvement should be reinforced. We still can achieve targets, but additional commitment is needed and each health professional should play its role to reach those left behind.
Rare Disease Lead
Birmingham Children’s Hospital
Dr Larissa Kerecuk is the Rare Disease Lead at Birmingham Children’s Hospital and is developing the first Paediatric Rare Disease Centre in the UK for holistic patient care. Larissa also leads the 100,000 Genome Project at Birmingham Children’s Hospital.As Consultant Paediatric Nephrologist, Larissa specialises in treating children with kidney diseases including those on dialysis, which require a holistic approach.
At BWCH, everything we do is aimed at improving the care delivered to our patients. Given that we treat approximately 9000 patients with over 500 different rare diseases, it was very important to us to develop a rare disease strategy to address the keys improvement areas highlighted by RDUK. Therefore, BCH are developing the first holistic Paediatric Rare Disease Centre where multidisciplinary and multispecialty rare disease clinics will take place with coordination of care, peer support and better access to research, information and treatment. We are, and have been, consulting with patients and patient support organisations throughout the process. In the initial design process, families have told us that a large waiting area where they can interact with each other and patient support organisations is important so we have incorporated this into the design. We have also included a kitchen for our families to improve the quality of their stay as well to provide a facility for them to feed their children any special feeds that they are often on. Several of our patients have multiple sensory deficits, learning difficulties and/or may have autistic spectrum features so we have also ensured that we have a sensory room and a “chillout room”. As many of our patients and their families are wheelchair bound, all our doors are wider and the toilets are suitable for all our patients – including an adult changing room.
Whilst the rare disease centre is being built, we have applied for funding from the Roald Dahl Marvellous Children’s Charity to fund 3 posts to help to coordinate the care of children with rare diseases. We held a very successful Rare Disease Engagement Events which was very well attended by patients and families with a wide range of rare diseases. The aim of the days was to co-design the posts so that we address the concerns and needs of our families in a way that we can improve their quality of life. We now have 2 Roald Dahl Specialist Rare Disease Nurses and and one Roald Dahl Rare Disease Transition Sister.
Making a diagnosis is very important which is why we are also involved in the 100 000 Genome Project and we are actively recruiting families to this. We aer working with SWAN UK and have developed a bespoke clinic at BCH Rare Disease Centre for children with syndromes without a name.
At BCH, we believe that the first holistic paediatric rare disease centre will help to re-think the care we deliver to patients from a one-size fits all to a patient-centred approach in which we help patients and families with rare diseases lead the best quality of life possible thereby enabling to live their lives to their full potential. We envisage that the rare disease service will lead to development of patient guidelines to empower local teams. Transition to the UHB Rare disease centre will also make the service seamless.
We are also making research an integral part of the care of the children affected with rare diseases and we are able to recruit and discuss research at the same clinic appointment.
The World’s First Children’s Rare Disease Centre will open in December 2017 at Birmingham Children’s Hospital with a new vision in integrated healthcare delivery.
TriStem Corp Ltd
Dr. Ilham Saleh Abuljadayel: discovered the process of retrodifferentiation in the early nineties. This direct reprogramming of differentiated somatic cells is achieved through cell surface receptor contact of more mature adult human cells such as leucocytes. She was awarded worldwide patents on the methodology and device, enabling the production of unprecedented levels of pluripotent stem cells from differentiated cells. Based on her research, Dr. Abuljadayel co-founded the TriStem Group. During the period 1990 to 1995, Dr Abuljadayel worked as a consultant immunologist at the King Fahd Armed Forces Hospital in Jeddah, and from 1996-2000 headed the TriStem Research on retrodifferentiation at the London Hospital, Kings College, Downing College University of Cambridge and Addenbrooke Hospital
stem cells can offer cures to treat many rare diseases, which can be used to correct a plethora of genetic conditions or replenish damaged tissue and cells in acquired disorders, in allogeneic or autologous manners, respectively. The limiting factors for such applications are; the availability and quantity of the stem cell source, the identification of a suitable histocompatible donor and the aggressive nature of ablation therapies that enable engraftment . On the other hand, retrodifferentiation technology which is similar to epimorphic regeneration, albeit, occurs ex vivo, offers a rapid additional source of stem cells with high efficiency. The process involves dedifferentiation / retrodifferentiation of mature adult cells such as peripheral leukocytes into a heterogeneous population of stem cells belonging to a give tissue. Retrodifferentiation procedure produces unlimited supply of stem cells from patient or donor blood which have been shown to be safe as well as capable of long term engraftment.
Furthermore, the autologous retrodifferentiated stem cells have been shown to engraft human bone marrow in the absence of ablation, in a rare disease such as acquired aplastic anaemia. This presentation will focus on the production of multipotent stem cells prepared from mononuclear cells and its application in the treatment of aplastic anaemia, a rare condition if left untreated lead to rapid morbidity.
Jorge Ascencio is a medical surgeon with special interest on infectious diseases. He has been doing laboratory and clinical research on antimicrobial resistance and human gut microbiota for several years and recently he started doing laboratory research on Chagas disease at the Department of Microbiology and Parasitology of the National Autonomous University of Mexico. Currently he is working at the Coordination of Health Sciences at Anahuac University South Campus while he studies a Master’s degree of Directorate of Health Services at Anahuac University North Campus. He is a former member of the END7 Mexico Chapter of the END7 Campaign and of the Anahuac University Neglected Tropical Diseases Interest Group
Chagas disease or American trypanosomiasis is recognized by the World Health Organization as one of the 18 Neglected Tropical Diseases. It is estimated that there are between 7–8 million people infected, between 65–100 million people at risk of becoming infected and it causes nearly 12,000 deaths per year worldwide. Chagas disease is endemic of 21 Latin American countries, but the expanding migrational flows have male the disease an international health priority. It is a parasitic zoonosis caused by Trypanosoma cruzi, a protozoan with high genetic and phenotypic diversity that can be principally transmitted to human beings by the faeces of blood-sucking triatomines. Other mechanisms of transmission include; blood transfusions, organ or bone marrow transplants, from mother to child, by ingestion of food or drinks contaminated with triatomine faeces and due to occupational exposure. Chagas disease has a very broad-spectrum of clinical manifestations, depending upon the phase at where the patient is. Acute phase is characterized for passing unnoticed in 95% of the cases, unless Romaña’s sign or chagoma develops at the inoculation site. Chronic phase is characterized for developing cardiac or gastrointestinal disease that lead to increased morbi-mortality. Diagnosis can be done with the combination of epidemiological background and clinical manifestations, if present, but laboratory tests are required for confirmation. Benznidazole and Nifurtimox are the only drugs available for treating the disease and meanwhile the efforts to formulate vaccines remain insufficient, patients suffer from a preventable disease which main risk factor for acquiring it is living in poor and marginalised societies. Control of vector-borne transmission remains to be a challenge in endemic countries as it is related to low socioeconomic status, while serological screening at blood banks and monitoring of all pregnant women for non vector-borne transmission can be effective to control the disease in non-endemic countries
The Third Affiliated Hospital of Guangzhou Medical University
Xie Yingjun, Ph.D. Working in the Key Laboratory for Major Obstetric Diseases of Guangdong Province,China. Researching in clinical genetic disorders (such as down syndrome, microdeltion/microduplication syndrome, autism, DD and ID).
Background: Expressivity is variable for most of the molecular defects. However, achondroplasia is a well-defined and common bone dysplasia an incidence of approximately 5-15 per 100,000 live births. Gain-off unction mutations in FGFR3 have been shown to cause both chondrodysplasias and craniosynostoses and to result in impaired endochondral ossification
A 2-year-old boy with clinical features consistent with achondroplasia and Silver-Russell syndrome-like symptoms. The patient exhibited features such as scoliosis and a trident configuration of the hands all of which can be explained by a mutations in FGFR3 at c.1138 G > A(p.Gly380Arg). However, prenatal onset growth delay, the speech delay, hypotonia and small triangular face phenotypes were not commonly reported in previous cases of ACH. We further detected a three-fold increase in GRB10 expression. Combining with previous other studies, the one unique feature of this patient that can be directly linked to a GRB10 duplication is the prenatal onset growth delay.
The data related to the patient described in the present study at least suggest that mutations in FGFR3 cause ACH but do not influence the effects of the duplication of GRB10 on prenatal onset growth delay in SRS. The results of our study also suggest that phenotypes are rarely “simple” or directly related to specific gene defects and that combinations of uncommon, rare and exceptional molecular defects, which can be explored and used in diagnoses, may explain the so-called variability observed in the expression of dominant traits.
Rizzoli Orthopaedic Institute
Time : Tiziana Greggi
1Spinal Tiziana Greggi working as a deformity Surgery Department in Rizzoli Orthopaedic Bologna, in Italy
Treatment of non idiopatic spine deformities in young children is very demanding.
Rare syndromes are various clinical conditions, heterogeneous in terms of clinics but associated with spinal deformities in a large percentage of cases. Scoliosis is the most common early onset deformity, sometimes present at birth and often rapidly evolving. Due to the complexity of its clinical aspects and early onset a multidisciplinary and timely approach is mandatory.
The purpose of this study is to describe an approach to spinal deformities in rare syndromes and assess the effectiveness of surgical treatment with growing systems (Growing rod, Magnetic rod and VEPTR-like system) at a young age.
A retrospective study of 11 paediatric patients (7 females and 4 males) treated at the authors’ department for early onset scoliosis associated with rare syndromes was performed. The patients had been surgically treated for scoliosis with growing systems, i.e. Growing Rod System, VEPTR and GSP, between 2006 and 2010 at the authors’ spine surgery department. Mean follow-up was 24 months (range, 12 to 36 months). Mean age at surgery was 7 years and the patients presented with the following clinical conditions: Escobar syndrome (1), scoliosis associated with congenital heart disease (1), Arnold-Chiari type 1 malformation (1), scoliosis associated with syringomyelia (1), type 1 neurofibromatosis (2), Prader-Willi syndrome (1), trisomy 8 (1), arthrogryposis (2) and spondylo-rib dysplasia (1). Each patient was investigated from the genetic point of view performing the following exams: brain and spine MRI, PFR, cardio-US and abdominal US, neuropsychiatric and neurological evaluation and a specific C0-C1-C2 CT scan to assess any instability, above all when some syndromes, such as arthrogryposis, were involved.
After a total of 11 lengthening procedures, performed 11 months after surgery on average, a correction of the thoracic curve of 63% was observed at the last follow-up and the Cobb angle on average had decreased from 61° to 31°. A total of 8 postoperative complications were encountered, 2 of which required a revision surgery not originally planned.
The growing systems are good devices which have proved effective in the treatment of early onset scoliosis associated with rare syndromes, when deformities are very aggressive on account of the peculiar features of the syndromes and, subsequently, are difficult to be controlled conservatively.
Both clinical and instrumental evaluation performed specifically for each patient were of the utmost importance, since the peculiar features of each syndrome had to be assessed together with the common characteristics of scoliosis shared by all patients.
PFR evaluates the young patients’ life quality indirectly; cardio-US and abdominal US are useful in the study of visceral malformations; brain and spine MRI can detect spinal cord malformation, that is to say contraindications to surgery, and is mandatory for thorough preoperative planning.
The indication for traditional Growing Rod, or Magnetic rod, rather than VEPTR/GSP should be given according to patient’s age and considering the presence of thoracic hyper kyphosis or chest deformities.