Scientific Program

Conference Series Ltd invites all the participants across the globe to attend Annual Congress on Rare Diseases and Orphan Drugs Chicago, Illinois, USA.

Day 1 :

OMICS International Rare Diseases 2016 International Conference Keynote Speaker Rashmi Gopal-Srivastava photo
Biography:

Rashmi Gopal-Srivastava currently serves as the Director of the Extramural Research Program in the Office of Rare Diseases Research. She leads the Rare Diseases Clinical Research Network (RDCRN), a multidisciplinary national program. She collaborates with 10 NIH Institutes to manage 22 consortia and a central Data Management Coordinating Center. She has been the recipient of the NIH Individual Merit Award numerous times. She also has received recognition from the U.S. Department of Health and Human Services for outstanding community services and NIH’s Asian Pacific Islander American Organization’s outstanding achievement award for excellence in science. She is an advocate for women in science and has recently been interviewed for the “Women of Color Scientists at NIH” and featured and showcased in “Women in Science at the National Institutes of Health 2007-2008”.

Abstract:

Any disease which has a U.S. prevalence of less than 200000 is defined as a rare disease. There are several challenges and opportunities for doing research and drug development for rare diseases. To facilitate clinical research and development of treatments for rare and neglected diseases, the National Center for Advancing Translational Sciences (NCATS) has established several programs. This presentation will focus on the Rare Diseases Clinical Research Network (RDCRN) program for multi-site clinical research involving patient advocacy groups (PAGs) as research partners and will provide a brief overview of some other scientific programs that support therapeutic development for rare diseases. To facilitate natural history studies and clinical trials for rare diseases, the Office of Rare Diseases Research (ORDR) within NCATS has established the RDCRN program. The RDCRN is a successful, collaborative and innovative international clinical studies network of 22 distinct multi-site clinical research consortia and a central Data Management and Coordinating Center (DMCC). The research conducted in this network has involved 144 PAGs and explores the natural history, epidemiology, diagnosis and treatment of more than 200 rare diseases at 267 clinical sites in USA and 17 other countries. Each consortium is required to conduct two multi-site clinical studies on a minimum of 3 related rare diseases, develop a training program for new investigators involve patient advocacy groups as research partners and provide information about rare diseases to researchers, health care providers, patients and general public. The DMCC supports the consortia by supplying infrastructure; user-friendly resources for the public and Web-based recruitment and referral tools; logistical and administrative assistance and data coordination, management and sharing. The goal of RDCRN is to contribute to the research and treatment of rare diseases by working together to identify biomarkers for disease risk, disease severity and activity and clinical outcome, while encouraging the development of new approaches to diagnosis, prevention and treatment. Some other translational programs of NCATS include Therapeutics for Rare and Neglected Diseases (TRND), the Bridging Interventional Gaps (BrIDGs), NIH Chemical Genomics Center (NCGC), Tissue Chip or Microphysiological Systems (MPS) program and New Therapeutic Use program (NTU).

Keynote Forum

Timothy R Cote

Cote Orphan LLC, USA

Keynote: Inside track to an orphan designation

Time : 10:10-10:55

OMICS International Rare Diseases 2016 International Conference Keynote Speaker Timothy R Cote photo
Biography:

Timothy R Cote is a leading national Regulatory Expert in orphan drug development with 23 years of Federal Service at the FDA, NIH and CDC. He has recently served as the Director of the FDA Office of Orphan Products Development (OOPD) from 2007-2011. As an Anatomic Pathologist and Medical Epidemiologist, he has published 80 peer-reviewed articles on areas as diverse as HIV/AIDS-related malignancies, typhoid fever epidemics and the impact of bicycle helmet laws on injury statistics. He is the Founder and CEO of Cote Orphan; where he directs and trains staff to create compelling regulatory submissions that are finely tuned to each client's business strategy and to the unwritten rules within the FDA. He has received his Bachelor's degree from Syracuse University, Medical Doctorate from the Howard University College of Medicine and a Master's degree in Public Health from Harvard School of Public Health.

Abstract:

All too often, creators of new therapies for people with rare diseases will expend vast resources on drug discovery, manufacturing, clinical key opinion leaders and of course raising money but ignore regulatory affairs, assuming that will just itself somehow work out. In this presentation, Dr. Cote, previous Director of the FDA orphan drug office, will discuss the intricacies of the orphan drug designation in the US and in Europe, preparing for a winning pre-IND meeting, crafting clinical trials that make sense to regulators, special incentives like breakthrough therapy designation, the pediatric rare disease designation and the PRIME program will also be demystified.

Break: Coffee Break 10:55-11:15
  • Track 1: Different types of Rare Diseases| Track 2: Clinical Research and Public Awareness| Track 3: Mystery Diagnosis of Rare Diseases
Location: Chicago, Illinois, USA

Session Introduction

Amrik Sahota

Rutgers University, USA

Title: Tailored inhibition of cystine stone formation as a therapy for cystinuria

Time : 11:15-11:35

Speaker
Biography:

Dr. Sahota works at Rutgers University in the following capacities: (i) professor in the Department of Genetics, (ii) director of scientific programs and director of the Clinical Genomics Laboratory, RUCDR Infinite Biologics; (iii) clinical professor and laboratory director in the Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School (RWJMS); and (iv) clinical professor in the Division of Urology, RWJMS.

Abstract:

Background: Cystinuria, caused by mutations in SLC3A1 or SLC7A9 is characterized by excessive excretion of cystine in the urine and cystine stones in the urinary tract. Cystine stones are difficult to treat surgically and medical treatments have major side effects. Previous studies from our group have demonstrated that cystine analogs such as cystine dimethyl ester (CDME) inhibit cystine crystallization in vitro. Here we show that this analog also inhibits cystine stone formation in Slc3a1 knockout mice. Methods: CDME (200 μg per mouse) or water was administered by stomach tube daily for four weeks; higher doses were administered to assess organ toxicity. Urinary amino acids and cystine stones were analyzed to assess drug efficacy using several analytical techniques. Results: Treatment with CDME led to a significant decrease in stone size compared with the water group (p=0.0002), but the number of stones was greater (p=0.005). The change in stone size distribution between the two groups was evident by micro computed tomography. Scanning electron microscopy analysis of cystine stones from the CDME group demonstrated a change in crystal habit with numerous small crystals. L-cysteine methyl ester was detected by UPLC-MS in stones from the CDME group only, indicating that CDME is absorbed from the intestine and a metabolic product incorporated into the stone material. No pathological changes were observed at the doses tested. Conclusions: These data demonstrate that CDME promotes formation of small stones but does not prevent stone formation, consistent with the hypothesis that CDME inhibits cystine crystal growth. Combined with the lack of observed adverse effects, our findings support the use of CDME as a viable treatment for cystine urolithiasis.

Speaker
Biography:

Maite A. Castro is Professor in the Department of Biochemistry at the Universidad Austral de Chile since 2005. She obtained her PhD. in 2005 in Biological Sciences at Universidad Austral de Chile. In 2009, she did a postdoctoral training in Dr. Michael Levine`s laboratory at the University of California, Los Angeles, USA. During the last 15 years she has been making steady progress in the mechanisms of communication between neurons and glial cells and the way they regulate their metabolism. At the present time, her interest is to study the correlation between failures in brain energy metabolism and the progression of Huntington disease.

Abstract:

The brain makes up 2% of a person's weight. Despite this, even at rest, the brain consumes 25% of the body's energy. Most of the energy consumed in the brain is attributable to restoration of the membrane gradient following neuronal depolarization. Neurotransmitter recycling, intracellular signaling and dendritic and axonal transport also require energy. Even though neurons are responsible for massive energy consumption, the brain is made up of many cells, including neurons, glial and ependymal cells. Every brain cell has a specific function and thus every brain cell has different metabolic needs. Many of these specific functions are concerned with maintainance of neuronal transmission. Astrocytes play a central role in supporting neurons metabolically by producing lactate, through glycolysis and activation of glycogen catabolism. There have been several reports of metabolic impairment in a variety of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease, among others. Moreover, deregulation of energy metabolism could be implicated in an increased production of oxidative species. During the last 10 years we have been making steady progress in the mechanisms of communication between neurons and glial cells, the way they regulate their metabolism, and the use of ascorbic acid as inter cellular messenger. Here, we will described the regulation of neuronal glucose, lactate and ascorbic acid transporters under synaptic activity in mice models of Huntington's disease. Experiments demonstrating a failure in astrocytic ascorbic acid recycling and ascorbic acid-dependent modulation on neuronal metabolism in Huntington's disease will be discuss. Brain is an expensive organ in energetic terms so disruptions in energy production may affect neuronal transmission and thus, neuronal survival. FONDECYT1151206,DID-UACh.

Tyson E. Dewsnup

Epilepsy Association of Utah, USA

Title: Epilepsy & rescue meds in schools

Time : 11:55-12:15

Speaker
Biography:

Tyson E Dewsnup has served as the Chairman of the Board of the Epilepsy Association of Utah since July 2016. Earlier he has served as the Associate Vice President of Programs. Outside of his service with the Epilepsy Association of Utah, he has served on various other non-profit boards in the public and private sector. He has a Bachelor of Science in Human Resource Management and is currently working on both his MBA and MHA. Aside from his board service, he is a Practice Supervisor for Intermountain Medical Group, a Physician and medical practice subsidiary of Intermountain Healthcare.

Abstract:

Statement of the Problem: While there are many other conditions, syndromes and diseases that both faculty & staff at public schools are comfortable and encouraged to administer rescue meds. Epilepsy remains a strange and scary thing. The over-all issue, especially in Utah is from school nurses not administering medications and not having enough nurses to cover schools.

Methodology & Theoretical Orientation: By encouraging staff buy-in and advocating with school nurses, the Epilepsy Association of Utah hopes to make seizure med training the norm in schools, not just in Utah, but across the country.

Findings: This does not seem to be a local problem only affecting those with epilepsy in Utah, but other states as well. Epilepsy affects more people than multiple sclerosis, cerebral palsy. Muscular dystrophy and Parkinson’s disease combined! Yet, epilepsy receives less funding than each of them individually. Just the use of the name “epilepsy & seizure disorders” creates a stigma for many people. Epilepsy still seems strange and foreign, even while 1 in 3 know someone with epilepsy. 1 in 10 will have a seizure in their lifetime. 1 in 26 will be diagnosed with epilepsy. By increasing public knowledge and awareness, through concerted efforts and outreach, we can show that not only are rescue meds important but also that failure to administer them endangers safety and violates various statutes and federal laws. Seizures can be scary for those who aren’t used to seeing them and those who are used to it. With a little training, however, our public schools can be more seizure-friendly. No parent should have to worry that while at school, their child may have a medical need that won’t be addressed.

Thomas C Chen

Keck School of Medicine of USC, USA

Title: Neo212: a new drug for temozolomide resistant malignant gliomas

Time : 12:15-12:35

Speaker
Biography:

Thomas C Chen has founded NEONC Technologies, Inc., in 2008 and serves as its Chairman, Chief Executive Officer and Chief Scientific Officer. He is an Executive Director at Cognos Therapeutics Inc., Co-Founder of Pharmaco-Kinesis Corporation and serves as its Chief Oncology Officer. He serves as a Scientific Advisor, Scientific Collaborator at Tocagen Inc. He serves as an Associate Professor of Neurological Surgery and Pathology at the University of Southern California (USC), Principal Investigator of an Independent Laboratory and Head of the Glioma Research Group at USC. He also serves as the Director of Surgical Neuro-Oncology at USC. He is a Member of Neurological Board, Member of Clinical Advisory Board at Magnetecs Corporation. He is a Physician and a board certified Neurosurgeon. He holds an MD from the University of California San Francisco, completed his Neurological Surgery Residency and PhD in Pathobiology at the University of Southern California. He has obtained Fellowship training in Spinal Surgery from the Medical College of Wisconsin and was graduated from the University of Illinois at Urbana-Champaign. He holds a Bronze Tablet Honors from University of Illinois at Urbana-Champaign and was inducted into the Phi Beta Kappa national academic honor society.

Abstract:

Although the alkylating agent temozolomide (TMZ) has become the standard of care in the treatment of malignant gliomas, its overall efficacy is still limited by development of drug resistance, limited blood brain barrier (BBB) penetrance and myelotoxicity. Recently, we have synthesized a TMZ analog by covalently linking the monoterpene perillyl alcohol (POH) to TMZ via a carbamate bond. This new compound (NEO212) has been tested in TMZ resistant malignant gliomas. U251 and U87 TMZ resistant gliomas were tested and implanted intracranially for in vivo model. NEO212 was administered subcutaneously using 10 day treatment, 7 day rest cycles; no significant toxicity on normal astrocytes and brain endothelial cells were detected. NEO212 revealed considerably greater therapeutic efficacy than TMZ, where a single cycle of treatment (10 days) extended median survival benefit from 6 days (in the case of TMZ) to 24 days with good tolerance. Pharmacokinetic analysis demonstrated that NEO212 has at least three times the brain concentration compared to TMZ when both agents are administered subcutaneously. Formal toxicity studies conducted at Charles Rivers (Montreal, Canada) demonstrated that it can be safely tolerated in both acute and chronic administration studies (up to 250 mg/kg). Long term toxicity appears to be myelotoxicity. NEO212 appears to be a promising well tolerated new agent with similar mechanism of cytotoxicity to TMZ. Its increased potency is most likely multi-factorial increased DNA damage, involving a broader scope of DNA repair mechanisms, linkage with POH, resulting in longer biological half-life and stability, increased lipophilicity, allowing for better penetration of the BBB and possibly cell membrane. This talk will emphasize the bench to bedside development in taking this drug to IND status.

Philippe Jouvet

Sainte-Justine Hospital University of Montreal, Canada

Title: Management of life threatening hyperammonemia in Children

Time : 12:35-12:55

Speaker
Biography:

Philippe Jouvet has obtained his MD in 1989 at Paris V University and MD specialty in Pediatrics and MD subspecialty in Intensive Care at Paris V University. He has completed his PhD in Pathophysiology of Human Nutrition and Metabolism in 2001 at Paris VII University and joined the Pediatric Intensive Care Unit of Sainte Justine Hospital-University of Montreal in 2004. He is the Director of the Pediatric Intensive Care Unit and Scientific Director of the Health Technology Assessment Unit of the Sainte Justine Hospital-University of Montreal. He has a salary award for research from the Quebec Public Research Agency (FRQS). He currently conducts a research program on computerized decision support systems for health providers. He has published more than 130 papers in peer reviewed journals and gave more than 100 lectures in congresses.

Abstract:

Hyperammonemia is an acute life threatening situation encountered in the pediatric intensive care unit (PICU). Reduction in hepatocyte number or function in liver failure (LF) and inhibition or primary defect of urea cycle enzymes in inborn errors of metabolism (urea cycle defect UCD) are the main causes of hyperammonemia in children. Ammonia has been shown to affect brain function to modulate both excitatory and inhibitory neurotransmission and to contribute to cerebral edema. Ammonia direct neuronal toxicity coupled with an increase of cerebral blood flow can lead to cerebral edema. There are several demonstrations of a link between hyperammonemia and death or encephalopathy in either LF or UCD with threshold for risk of toxicity around 200-350 µmol/L. Targeting gut production of ammonia may be too slow and ineffective in lowering ammonia level and modulating its cerebral effects, in patients sufficiently ill to require PICU admission. The use of antibiotics remains controversial in the management of hepatic encephalopathy. Furthermore, there is no high-quality evidence to support the use of non-absorbable disaccharides. Ammonia scavengers are now widely used in patients with UCD and seem to improve outcome by efficient lowering of ammonia levels. The literature shows that few molecules have been tested in hyperammonemia. Possible treatment could include oral sodium benzoate, L-ornithine used in combination with L-aspartate, and phenylacetate, carglumic acid. When hyperammonemia is very high, an extracorporeal removal therapy is recommended. Recent advances in treating hyperammonemia suggest using synergistic combination treatments, broadening the indication of orphan drugs and developing novel approaches to regenerate functional liver tissue.

Break: Lunch Break 12:55-13:40
Speaker
Biography:

Laura K Sunderlin has 30 years of experience in the Insurance Industry; the last 15 of them insuring life sciences. She has insured biotech start-ups and some of the largest biotechs in the country, for clinical trials and products liability. She brings the experience of a decade and a half of defending against claims, analyzing risk, discussing exposures with risk managers and scientists.

Abstract:

Statement of the Problem: Scientists, medical researchers and their financial backers, particularly in the field of rare diseases and particularly with orphan drug development are entirely focused on the efficacy of the science and the impact of their work on the mitigation and cure of disease. Successful development however can come to grief because of alienation of affiliate groups, difficult or misunderstood clinical trials, public and legislator perception, unexpected lawsuits.

Methodology & Theoretical Orientation: A discussion of the cultural pitfalls surrounding drug development from 15 years of insuring life sciences companies. A discussion of growing distrust of clinical trials (from Constant Gardiner to distrust of results), perceptions on pricing and availability of product and alienation of orphan drug affinity groups, a tidal wave of public antipathy towards the drug industry and the critical role of a well-constructed informed consent, insurance and risk-management tactics and a look at what has put potentially successful companies out of business and ended promising research.

Conclusion & Significance: Attention must be paid to the cultural, social and legislative environment of drug development. Informed consents and monitoring in clinical trials, open and extensive communication with disease sufferers and their families, sensitivity to public perception and the use of insurance and risk management can assure that the focus can remain on the science.

Speaker
Biography:

Megan O’Boyle is the Principal Investigator for the Phelan-McDermid Syndrome Data Network (PMS_DN, PCORnet) and the Phelan-McDermid Syndrome International Registry (PMSIR). She is passionate about the value of the patient’s voice in research, drug development, clinical trial design, development of related legislation and quality of life decisions. She advocates for data sharing, collaborating with other advocacy groups, sharing resources and streamlining IRB practices and policies.

Abstract:

Phelan-McDermid Syndrome (PMS) is a rare genetic condition associated with autism spectrum disorder, seizure disorders and severe to profound intellectual disability. Today, there is no cure for PMS and patient interaction with health care and research is for the most part navigated by parents and caregivers. In 2011, the PMS Foundation launched the PMS International Registry (PMSIR), centralizing data about the PMS community and removing barriers for researchers studying the condition and its associated interventions. The PMSIR has been family-led since its inception. In 2013, the Foundation was awarded a PCORI contract to participate in PCORnet as a Patient Powered Research Network and establish the PMS Data Network (PMS_DN), integrating patient-reported outcomes from the PMSIR with concepts extracted from electronic health records of PMS patients. The PMS_DN, a collaboration between the PMS Foundation, Harvard Medical School Center for Biomedical Informatics and Boston Children’s Hospital, advances knowledge, care and treatment of PMS and related conditions by integrating diverse, complex data sources into a richly populated, high quality and centralized database to facilitate patient-centered research. The PMS_DN technical infrastructure is an i2b2/tranSMART data warehouse and web interface, which integrates patient reported outcomes (PROs), curated genetic testing results and knowledge extracted from clinical notes. The PMS_DN excels in engaging families in data sharing activities and prioritizing research questions, facilitating family communication and promoting transparency of patient data use in research, through the leadership of exceptional parents and the authentic engagement of patients and caregivers as champions for their families.

Yusuf Hovsep Eken

Elkerliek ziekenhuis, Netherland

Title: Fever of unknown origin: case study

Time : 14:20-14:40

Speaker
Biography:

Yusuf Hovsep Eken has completed his Medical education in Utrecht University, Netherlands.

Abstract:

Adult onset Still's disease (AOSD) is a rare disease in adults, in children also known as systemic juvenile idiopathic arthritis. We describe two patients with intermittent fevers without unknown origin. Patients were from Twenteborg Hospital Almelo affiliated with Academic Center Radboud Medical Center in Nijmegen and Catharina Hospital in Eindhoven affiliated with Maastricht Medical Center. 27 years man and 75 years old woman, who presented with lymphadenopathy and recurrent fevers, there has been used intensive serologic, radiologic, laboratory investigation to exclude infectious diseases and malignancy. All the investigation showed no diagnosis. The clinical disease described for the first time 105 years ago by Dr Still is finally diagnosed. Both patients received Anakinra with rapid response in hematologic, biochemical and cytokine markers with reduction of systemic and local inflammation.

Marise Abdou

Abo El-Rish Children’s Hospital, Cairo, Egypt

Title: A 20 days old patient with genital asymmetry

Time : 14:40-15:00

Speaker
Biography:

Marise Abdou has joined Diabetes, Endocrine and Metabolism Pediatric Unit (DEMPU) in 2010 and has completed her MD from Cairo University. She is an active Member of DEMPU which was founded in 1980 by Prof. Dr, Isis Ghaly. She is actively involved in many research studies that are carried out in DEMPU. She has one publication in the field of endocrinology.

Abstract:

A 20 days old patient reared as male was brought by his parents to Diabetes, Endocrine and Metabolism Pediatric clinic for atypical genitalia and bilateral undescended testis. On genital examination, the patient had underdeveloped right scrotal compartment, genital asymmetry, bifid scrotum, penoscrotal hypospadias and a phallus length of 3 cm. The left gonad could be felt at the medial end of the inguinal and it could be brought down to the scrotal sac and was of normal size and texture while the right gonad could not be felt along its course. The following investigations were ordered: Karyotyping, Basal hormones (17 (OH) progesterone, progesterone, DHEA, androstendione, testosterone, DHT, cortisol and ACTH) & Anti-Mullerian hormone and Abdominopelvic Ultrasonography. The result of the Karyotyping came back to show 45X0/46XY. Abdominal ultrasonography done revealed the presence of normal infantile uterus behind the urinary bladder, the vaginal canal was mildly dilated with fluid contents, a gonad mostly testis was seen on the left side measuring 12×7.2 mm and no gonad could be detected on the right side along its path of descent. The patient was prepared for laparoscopy at the department of Pediatric Surgery, Cairo University. During laparoscopy, specimens were obtained for histopathological examination and mullerian structures could be detected. The results of the histopathological examination revealed the presence of streak testis with male type ductal system which confirmed the diagnosis of mixed gonadal dysgenesis which is a variant of Turner Syndrome (Turner Syndrome with Y cell line).

Speaker
Biography:

Ramune Sepetiene is currently a PhD Student at Lithuanian University of Health Sciences. She has obtained her MD with medical laboratory specialization in 1999 from Lithuanian University of Health Sciences, Medicine Academy. She has more than 15 years of clinical work experience within immunology, hematology and genetics. She is a Junior Researcher in Laboratory of Molecular Cardiology, Institute of Cardiology, LUHS and part time laboratory MD position in patients’ clinic. Recently she has published 4 papers within PhD dissertation subject in reputed journals of cardiac surgery and genetics.

Abstract:

Transforming growth factor β1 (TGF-β1) is a cytokine that participates in a broad range of cellular regulatory processes and is associated with various diseases including aortic aneurysm. An increased TGF-β1 level is associated with Marfan syndrome (MFS) caused by fibrillin-1 (FBN1) mutations and subsequent defects in signaling system. FBN1 single nucleotide polymorphisms (SNPs) rs2118181 and rs1059177 do not cause MFS but are associated with dilatative pathology of ascending aorta. A purpose of the investigation was to test hypothesis does an association between FBN1 SNPs (rs2118181, rs1059177) and TGF-β1 level in human blood plasma exist among sporadic cases of dilatative pathology of ascending aorta. A study group was recruited from 312 patients who had undergone aortic reconstruction surgery due to dilatative pathology of ascending aorta and 741 healthy control subjects of Kaunas population (N=269) without cardiovascular disorders, except hypertension. Genomic DNA was isolated from potassium EDTA blood. Genotyping of FBN1 SNPs was carried out by using ABI 7900HT Real-time PCR Thermocycler with commercially available kits from Applied Biosystems. TGF-β1 quantitated detection was tested with eBioscience Platinum human TGF- β1 ELISA commercially available kit based on standard sandwich enzyme-linked immune-sorbent assay technology according manufacturers’ instructions. Non-parametric Kruskal-Wallis test was used for data analysis. The results showed a quantitative dependence of SNP genotype and TGF-β1 concentration. A presence of a single rs2118181 minor allele (G) increased the median amount of TGF-β1 level. Two copies of FBN1 rs1059177 minor allele (G) were required to give a significant rise of TGF-β1 level in blood plasma. We also found higher TGF-β1 concentrations in men compared to women (p=0.001). The results are indicating that presence of minor allele of FBN1 SNPs rs2118181 or presence of homozygous genotype of minor alleles of rs1059177 is associated with the significant increase in TGF-β1 blood plasma level but the mechanism of this association is still unknown.

  • Track 4: Challenges in Rare Diseases Treatment| Track 5: Rare Diseases in Cancer| Track 7: Rare Infectious Diseases and Immune Deficiencies
Location: Chicago, Illinois, USA

Session Introduction

Shinichi Takeda

National Institute of Neuroscience, Japan

Title: On-going exon 53 skipping clinical trial for Duchenne Muscular Dystrophy

Time : 15:20-15:40

Speaker
Biography:

Shin’ichi Takeda is currently the Director General of National Institute of Neuroscience in the National Center of Neurology and Psychiatry (NCNP). He initially trained as a Clinical Neurologist and received a PhD degree in Muscle Biology from Shinshu University, Graduate School in 1981 and has a long time laboratory experience including Paris Pasteur Institute (1987-1992). He focused his research on development of molecular therapy of Duchenne muscular dystrophy (DMD), since he came back from France and has gotten the position in NCNP in 1992. He has showed a proof of concept study of exon skipping in the colony of dystrophic dogs that he established and he recently finished the early phase clinical trial of exon 53 skipping of the dystrophin gene among DMD patients in Japan as a PI. He is working as an Associate Editor for review of J. Neuromuscular Diseases since 2013 and an Associate Editor of Am. J. Pathology since 2014.

Abstract:

Duchenne muscular dystrophy (DMD) is the most common childhood genetic disease, affecting one among 3500-5000 newborn boys, causing progressive muscle weakness, heart and respiratory failure and premature death. This disease is caused by the mutations of the DMD gene and there is no cure exists for this disease but a number of promising new molecular therapies are being intensively studied. Exon skipping by antisense oligonucleotides (AOs) is a novel method to restore the reading frame of the mutated DMD gene and rescue dystrophin expression. We have reported that systemic delivery of AOs targeting exon 6 and 8 of the canine DMD gene to CXMDJ, a dystrophin-deficient canine animal model, efficiently restored functional dystrophin proteins at the sarcolemma of these dogs and improved phenotypes of affected dogs without serious adverse effects. We, then, optimized AO sequences, which allow exon 53 skipping of the human DMD gene, together with Nippon Shinyaku Co. Ltd. After numbers of toxicology study of the AOs, NS-065/NCNP-01, we proposed an early phase clinical trial of exon 53 skipping of DMD patients, which was approved by Japanese Pharmaceutical and Medical Devices Agency (PMDA) and the trial, has been successfully carried as an investigator-initiated trial in NCNP hospital. Following the excellent results of the early phase trial, phase I/II trial in Japan and phase II trial in US are carrying by either Nippon Shinyaku Co. Ltd. or NS Pharma, Inc.

Lisa Baumbach- Reardon

Translational Genomics Research Institute, USA

Title: Rare disease research – opportunities and challenges

Time : 15:40-16:00

Speaker
Biography:

Dr. Lisa Baumbach-Reardon completed her PhD at the age of 28 at University of Florida (Gainesville), and then entrenched her further training in Human Molecular Genetics at two subsequent post-docs at Baylor College of Medicine and University of Colorado. This lead to dual certification in clinical molecular genetics and biochemical genetics by the ABMG.. She has operated two CLIA molecular DX labs during her academic career, and joined TGEN in 2011 to operate a state-of- the art-CLIA lab, as well as pursue her further studies in XL-SMA.

Abstract:

Human Rare Diseases, also referred to as an orphan disease, is any disease that affects a small percentage of the population. Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30 percent of children with rare diseases will die before reaching their fifth birthday. No single cutoff number has been agreed upon for which a disease is considered rare. A disease may be considered rare in one part of the world, or in a particular group of people, but still be common in another. There is no single, widely accepted definition for rare diseases, which places constant demands on disease advocates, parents, clinicians and researchers to bring their concerns to national agencies regarding recognition of the disorder and treatment options for relatively rare diseases. Out research group has had the unique opportunity to identify a rare genetic disorder, X-Linked Spinal Muscular Atrophy (XL-SMA), and to work with clinicians and families throughout the world to identify these rare families. We have collected blood samples from family members to perform DNA linkage analysis, and finally, disease gene identification in a subset of these families. Surprising, as DNA identification technologies have developed, so has our sub-classification of even rarer “genetic” disorders evolved, demonstrating the additive strength of analyzing clinical phenotypes to causative genotypes which may well be overlapping in primary or secondary disease pathways.

Break: Networking and Refreshment Break 16:00-16:20
Speaker
Biography:

Prof Annemieke Aartsma-Rus obtained her PhD aged 27 at Leiden University (the Netherlands) in 2005. She became group leader in 2007 and is currently a professor of Translational Genetics at Leiden University Medical Center, the Netherlands. She currently chairs the TREAT-NMD Alliance (an infrastructure network for clinical trial readiness for neuromuscular disorders) and a networking Action (funded by Cooperation of Science and Technology (COST). She has published more than 100 papers in peer reviewed journals, has written multiple book chapters and has generated and maintains pages to explain Duchenne therapies in lay terms to the patient community. In 2009 she received the Duchenne award from the Dutch Duchenne Parent Project for her dedication to the field.

Abstract:

Duchenne muscular dystrophy (DMD) is a rare, progressive muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but multiple experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for the regulatory approval of any therapy. However, for DMD and other rare diseases, these were not in place when potential therapies entered the clinical trial phase. This has resulted in suboptimal trials for DMD therapy. To address this, a cooperative effort of DMD stakeholders, including representatives from patient groups, academia, industry and regulatory agencies aimed at identifying strategies to overcome challenges, developing the tools required and collecting relevant data. This is ongoing work, but already a huge effort has been made to develop new outcome measures, collect natural history data and to develop potential biomarkers. The open and constructive dialogue among stakeholders has positively influenced therapy development for DMD, and this should serve as a paradigm for rare disease therapies’ development in general.

Biography:

Dr. Prasanth Puthanveetil has done his PhD in Pharmacology especially in the area of cardiovascular diseases from the University of British Columbia. Following his post-doctoral training at NIEHS/NIH, University of Western Ontario and University of Michigan, he was selected for a full time tenure track faculty position at Roosevelt University School of Pharmacy. Till date, he has published more than 20 peer-review manuscripts, including 10 first-author publications.  He is an active member of many professional associations, including American Heart Association and Canadian Diabetes Association. He has and continues to serve as invited reviewer and editorial board member of several peer-reviewed journals.  At RUCOP, Dr. Prasanth Puthanveetil is setting up his research lab focusing on metabolic signaling in cardiovascular tissue especially during metabolic stress.  Also he has special interests in endocrine disorders like diabetes and Cushing’s syndrome and its impact on cardiovascular health.

Abstract:

Statement of the Problem: The prediction of rare diseases  has always been a limiting factor associated with these complications.  By the time the presence of disease is confirmed the onset of disease must have been prominent leading to devastating and uncontrollable aftermaths.  Understanding the complexity of events occurring during these disease conditions would provide us with a better insight not only to treat these diseases but also to prevent the debilitating effects in the respective tissues and save the organ systems or prolong or hinder the damage. This study demands the need for understanding the metabolic and endocrine dysfunctions during a rare disease in detail and thus not only open up a new path for the scientists to explore the pathophysiological molecular mechanisms in detail but specifically help the clinicians/physicians to understand therapeutic strategies.

Hypothesis and Methodology: Wolff Parkinson White Syndrome is one of rare disease connected to the cardiovascular system.  Multiple factors have been shown to play an important role in the etiology of this disease.  A major share goes to PRKAG2 gene mutation leading to glycogen accumulation in the cardiac tissue and resulted in atrial fibrillation in patients.  Studies from preclinical data suggest that over activation of AMPK protein, the major energy sensor or metabolic switch could be playing an important metabolic role in bringing about this complication.  Some of my previous studies using glucocorticoid excess revealed that they were able to increase AMPK.  Thus using in vitro and in vivo model systems, I was able to see an increase in cardiac AMPK and glycogen accumulation.  This raises the concern that the pathogenesis of Wolff Parkinson White Syndrome can result from any other route rather than just PRKAG2 conclusion. 

Conclusion & Significance: Glucocorticoids in excess in heart resulted in uncontrollable AMPK activation with resulting glycogen accumulation in cardiac tissue.  Physiological situations like fasting and stress and pathological conditions like Cushing’s syndrome could result an increase in glucocorticoid excess release into the systemic circulation.  Now whether these metabolic changes associated with endocrine abnormalities could result in Wolff Parkinson White like syndrome or no is not fully studied and is one of the area I would like to shed more light upon and tried to minimize the detrimental effects. 

Nasir Afsar

Alfaisal University College of Medicine, Riyadh, KSA

Title: Tapping untapped: Exploring role of ALDH in pharmacogenetic and toxicogenetic studies

Time : 17:00-17:20

Speaker
Biography:

Born and raised in Pakistan, trained in Germany, Dr. Nasir Ali Afsar is a pharmacologist. He is a Member of (1) British Pharmacological Society, (2) Canadian Society of Pharmacology and Therapeutics (3) Association of Medical Education in Europe as well as Certified Researcher in Medical Education by American Association of Medical Colleges. He is affiliated to academia since 1999 in different capacities. His research interest includes pharmacogenetics, clinical pharmacology, clinical simulation, and medical education.

Abstract:

The response to a xenobiotic may be influenced by polymorphic genes of metabolizing enzymes and transporters. We had previously reported [1] selected genotype profiles for the breast cancer patients on fluorouracil, doxorubicin and cyclophosphamide (FAC) in a Pakistani set of population and compared them with allele frequencies in North America, Europe, Africa China and other regions as represented in HapMap database. Our current study explores the previously reported as well as additional genotypes in healthy adults from different population subgroups at Karachi which remains unreported so far. We included 155 healthy adults after informed consent and institutional approval. The DNA was extracted from saliva collected and stored in Oragene-DNA® kits. Relevant SNPs of genes involved in drug metabolism and transport were genotyped either through restriction fragment length polymorphism or pyrosequencing after PCR amplification. We genotyped selected drug metabolizing enzymes involved in Phase-I metabolism (CYP1A1 *2A/*3, CYP1A1*2C, CYP2B6*4, CYP2B6*6, CYP2C9*2, CYP2C19*2, CYP2C19*17, CYP2D6*4, CYP2D6*10, CYP3A4*22, CYP3A5*3), Phase-II metabolism (ALDH3A1, GSTA1 -69, GSTM1) and efflux transporters (ABCB1 1236, ABCB1 2677, ABCB1 3435, ABCC2 -24, ABCC2 3972, ABCC2 1249) along with such frequencies in other population sets represented in HapMap. Interestingly, we found that although there were certain differences in allele frequencies, most notably, ALDH2 variant allele frequency is much higher in our population, thus drawing possible implications regarding environmental toxicity, atherosclerosis and other situations marked by oxidative stress. The presentation would emphasize upon the fact that molecular research outcome from one field could be used in other disciplines because of biological overlap.