Day 1 :
George Mason University, USA
Keynote: Rare diseases and orphan drugs: Passion and compassion or growing market with career opportunities for scientists and technologists?
Time : 10:30-11:15
Harsha K Rajasimha is internationally recognized in the field of life sciences consulting, systems biology, healthcare IT systems integration, BigData analytics, genomics of rare diseases and precision medicine. He is currently the Global Head of life sciences R&D at Dell Healthcare and Life Sciences (acquired by NTT DATA Inc.), Founder President of Jeeva Informatics and Founder Board Member of the non-profit organization for rare diseases India, Affiliate Faculty and Co-Director of the Center for Metabolic and Rare Diseases at George Mason University. He was the global Vice President at Strand Life Sciences, a precision medicine company that develops genomics-based clinical lab-developed tests for cancer and inherited diseases. In collaboration with Rare Genomics Institute, he has received the Sanofi Genzyme’s rare diseases Patient Advocacy Leadership award in 2016. He has authored over 15 peer-reviewed articles and is often invited speaker at conferences. He has earned Baccalaureate degree in Computer Science from Bangalore University, Master’s in Computer Science and Doctorate in Genetics, Bioinformatics and Computational Biology from Virginia Tech.
The words rare and orphan often generate a compassionate response from those affected but rarely generates any excitement among scientists or technologists or entrepreneurs. The progress in diagnosing or treating a disease has been largely driven by patient advocacy groups fighting against specific diseases. While this continues to be a driver, numerous recent trends indicate a thriving orphan drugs market with over 4000 orphan designations and ~600 orphan drugs approved by FDA since 1983. Until recently, only a handful of countries had a formal national policy on rare diseases or umbrella organizations advocating patients’ interests, clinical research involving rare diseases and patients registries to engage the biopharmaceutical industry. A number of new national and international organizations are spurring innovation and creating opportunities for collaboration and progress never before possible. The international consortium for rare diseases research, international collaboration of rare diseases, rare diseases international are examples of international organizations. The organization for rare diseases India (ORDI) and Chinese organization for rare diseases are examples of the umbrella organization representing the collective voices of all stakeholders of rare diseases in the most populous countries. Technology trends in clinical-speed, low-cost genome sequencing is enabling diagnosis of thousands of genetic diseases in a single test, BigData integration and analysis technologies are enabling unprecedented global patients access, wearable devices and real-world data extracted from EMRs are empowering patients with a 360o view of their health data and mobile apps are enabling them to participate in drug discovery and clinical development process. Collectively, these trends point towards a very promising area of research and development for young scientists and engineers to pursue as career options with much hope for patients globally. I will present how ORDI is tapping into these opportunities for India.
Keynote: Speeding up access to medicines for patients with unmet medical need: Integrating evidence and regulatory pathways
Time : 11:35-12:20
Stella Blackburn has spent over 30 years in Pharmacovigilance and Pharmacoepidemiology in both regulatory and industry environments. She was trained in Medicine at Cambridge and London Universities and has an MSc in Epidemiology from the London School of Hygiene and Tropical Medicine. At the European Medicines Agency, she was responsible for developing risk management for Europe and was the lead author of the guidelines. She is passionate about optimizing the benefit risk balance of medicines and to helping bring medicines to patients with unmet medical needs; particularly those with rare diseases. She is a Visiting Scientist at the Center for Biomedical Innovation, Massachusetts Institute of Technology where she continues to work on innovative methods for bringing medicines to market. She is a Fellow of the Royal College of Physicians of Edinburgh and a Fellow and Past President of the International Society of Pharmacoepidemiology.
Patients with life-limiting diseases and few or no treatment options want early access to medicines which show potential benefits. At the same time, regulators want reassurance that the potential benefits outweigh the potential risks; that the risks can be managed effectively and that comprehensive evidence will be provided. Getting a balance between these two stakeholders needs can be difficult. This can be compounded by the needs of payers who want evidence of cost-effectiveness. In the context of a rare disease, developing comprehensive evidence for all stakeholders is even more difficult when patients may be relatively scarce. In Europe, the European Medicines Agency (EMA) developed Adaptive Pathways as a means whereby a medicine could receive an initial authorization in a niche indication with a condition that development work would continue and that real world evidence would be gathered by close monitoring of patients receiving the marketed medicine. Regulators, HTA bodies, patients and healthcare practitioners are involved in the development discussions. Access to patients beyond those with most need would be gradually expanded as more evidence became available with the expectation that a “normal” marketing authorization would be achieved. This concept of using a combination of real world evidence along with clinical trials to optimize drug development is being further developed by the Center for Biomedical Innovation, part of the Massachusetts Institute of Technology. The purpose of this presentation is to explain the Adaptive Pathways concept and the multinational discussions which led to it and how early use of real world evidence can help drug development; particularly in the rare disease field. In particular, it will explore the use of disease registries as a means of speeding up trials, providing invaluable information on the natural history of the disease and monitoring patients in the post-approval setting.
University of Alabama at Birmingham, USA
Time : 12:20-13:05
Ashwani K Singal is working as Associate Professor of Medicine in the division of Hepatology and Director of Porphyria Center at the UAB, Birmingham AL. His clinical research interests include alcohol and non-alcohol fatty liver disease, porphyria, and renal dysfunction in liver cirrhosis. He has over 110 publications, on editorial board of reputed journals, and research award committees of the AGA and AASLD. His research is funded by the Transplant Institute of the UAB, ACG, NIAAA, and NIDDK from the NIH, and pharmaceutical industry.
Porphyria is a group of metabolic disorders due to altered enzyme activities within the heme biosynthetic pathway. It is a systemic disease with multiple potential contributions to mitochondrial dysfunction and oxidative stress. Recently, it has become possible to measure mitochondrial function from cells isolated from peripheral blood (cellular bioenergetics) using the XF96 analyzer (Seahorse Bioscience). Using various inhibitors and activators of mitochondrial respiration, this technique measures various components of O2 consumption rate (OCR) in peripheral cells such as basal, ATP linked, proton leak, maximal, reserve capacity, non-mitochondrial, and oxidative burst, all measured as pmol/min./100,000 monocytes. We performed cellular bioenergetics on 18 porphyria (9 PCT, 6 acute, and 3 protoporphyria) patients and 39 age/gender matched healthy controls. Of porphyria cases, 5 were active (1 PCT and 4 acute) and 13 in biochemical remission. Monocyte bioenergetics was significantly decreased in active porphyria vs. porphyria in remission and vs. healthy controls. Among 6 acute porphyria, a negative correlation (-0.8 to -0.93) was observed between urinary porphobilinogen and various components of monocyte OCR. In two pseudporphyria patients, monocyte OCR was similar to healthy controls and higher than active porphyria. These novel and interesting preliminary findings suggest existence of mitochondrial dysfunction in porphyria and potential non-invasive biomarker for disease activity. Studies are suggested to examine mechanisms of these findings as basis for deriving mitochondrial based therapies in management of porphyria.
- Different types of Rare Diseases | Challenges in Rare Diseases Treatment | Mystery Diagnosis of Rare Diseases | Clinical Research and Public Awareness
Rutgers University, USA
Universite Laval, Canada
Jacques P Tremblay has received PhD in Neuroscience from the University of California at San Diego in 1974. Since that time, he has been at Laval University as a Post-doctoral Researcher, Professor and Director of the Department of Anatomy. He is currently a Full Professor in the Department of Molecular Medicine. He has published over 250 scientific articles on hereditary diseases. He has worked specifically on myoblast transplantation as a treatment for Duchenne muscular dystrophy. For the last 3 years, he also worked on gene correction with the CRISPR/Cas9 technology for Duchenne muscular dystrophy, Friedreich's ataxia and Alzheimer’s disease.
The new CRISPR/Cas9 technology permits to induce double strands breaks (DSBs) in the DNA at a specific sequence in the human genome selected by a guide RNA complementary to a 20 nucleotides sequence. These DSBs may be repaired by different process that either permits to knockout a gene or to repair a mutated gene responsible for a hereditary disease. This technique is used in our laboratory to develop therapies for 3 different diseases: duchenne muscular dystrophy (DMD), Friedreich ataxia (FRDA) and Alzheimer disease (AD). DMD is due to the deletion of one or several exons in the DMD gene that leads to a frame shift, a premature stop codon and the absence of the dystrophin protein. By inducing DSBs in the exons that precede and follow the patient deletion, we have been able to delete an additional segment of the gene leading to the formation of a hybrid exon that not only restores the normal reading frame but also restores the normal structure of the internally truncated dystrophin protein. This should thus permit to transform a DMD patient in a mild Becker muscular dystrophy patient. FRDA is due to an increased number of the trinucleotide GAA in intron 1 of the frataxin gene. This leads to a reduced transcription and a reduced production of the frataxin protein. We have used the CRISPR/Cas9 technology to induce DSB before and after the repeat to remove it. This treatment has led to a doubling of the frataxin mRNA and protein and this should be therapeutic in the patients. Hereditary AD is to point mutations in the amyloid precursor protein (APP) gene. Using the CRISPR/Cas9 system, have induced a DSB in that gene and replaced the mutated nucleotides. This could also lead to a potential therapy.
Maria Shkrob has 7 years of experience in the bioinformatics industry, working on the solutions for text and data mining. At Elsevier, she works as a Consultant for Elsevier Professional Services applying the rich R&D Solutions portfolio to address customers’ needs.
Statement of the Problem: One of the pressing challenges in drug repurposing for rare diseases is a limited amount of scientific information needed to discover new targets and suggest new treatments. In this field, it is particularly critical not only to aggregate all available evidence about the rare disease but also to be able to fill the gaps with the knowledge from other research areas to generate new ideas and propose new therapeutic approaches.
Methodology & Theoretical Orientation: Elsevier is collaborating with a rare disease charity, Findacure, to provide information about congenital hyperinsulinism to the patients, researchers and doctors, to help finding new treatments, support applications for drug repurposing programs, increase awareness, streamline information exchange and education. Using an integrative approach of automated and manual curation of literature, we provided an overview of the mechanisms, targets, drugs, key opinion leaders and institutions studying the disease. An automated pipeline to generate such summaries was designed to expand the use of the approach and provide scalability.
Findings: Suggested approach was applied to several rare diseases to automatically generate ranked lists of drug repurposing candidates, targets and key opinion leaders.
Conclusion & Significance: We developed a framework to retrieve and aggregate information required to support drug repurposing decisions, facilitate clinical trials and bring together stakeholders. Suggested approach was applied to congenital hyperinsulinism and was replicated two more rare diseases.
Rutgers University, USA
Amrik Sahota is a Professor in the Department of Genetics, Rutgers University, Piscataway, NJ. He is also a Clinical Professor in the Department of Pathology and Laboratory Medicine and in the Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. He is a fellow of the American College of Medical Genetics and Genomics, National Academy of Clinical Chemistry, Royal Society of Biology (UK), and the Royal College of Pathologists (UK). He is board-certified in Clinical Molecular Genetics by the American Board of Medical Genetics and Genomics and in Molecular Diagnostics by the American Board of Clinical Chemistry. His research interests are in genetic disorders of urolithiasis, mouse models for human disease, and molecular diagnostics.
Background: Cystinuria is characterized by excessive excretion of cystine in the urine and cystine stones in the kidneys and, to a lesser extent, in the bladder. Cystine analogs such as cystine dimethylester (CDME) inhibit cystine crystal growth through binding to specific crystal surfaces, thus providing a novel therapeutic approach for cystinuria. We synthesized a series of L cystine diamides as cystine crystal growth inhibitors that would have greater stability and bioavailability compared with CDME. The most effective inhibitor to date is L cystine bis(Nʹ-methylpiperazide), denoted LH708. Here, we evaluate the effectiveness of LH708 in inhibiting cystine stone formation in Slc3a1 knockout male mice, which serve as a model for cystinuria.
Methods: Mice age three months were screened for bladder stones by computed tomography (CT). Only mice that did not have stones were used for this study. Mice were treated with LH708 (150 µmol/kg) or water alone by stomach tube daily for 60 and CT scans were done on days 30 and 60. Bladder stone volume was determined using image analysis software.
Results: Nineteen mice were treated with LH708 and five of them showed stones at day 30. The same mice were stone-positive at day 60, and there was a significant increase in stone volume between the two scans (28.15 versus 64.70 mm3, p=0.0005). Twenty-four mice were treated with water alone and 15 of them showed stones at day 30. Five of these mice died between the two scans, but an additional three were stone-positive at day 60. There was a significant increase in stone volume at the second scan (20.74 versus 52.67 mm3, p=0.0001). Overall, 26% of mice formed stones in the LH708 group versus 75% in the water group.
Conclusion: These data strongly support the evaluation of LH708 as a potential therapy for cystinuria.
University of California San Francisco, USA
Janel Long-Boyle is a Translational Scientist with research interests that include pediatric cancer therapeutics, pharmacokinetics, pharmacodynamics, pharmacogenomics, and clinical trial design. The majority of her research resides within the complex setting of hematopoietic cell transplantation (HCT) and focused around chemotherapeutic and immunosuppressive agents used in the preparative regimens of pediatric HCT and gene therapy. More recently, her work aims to facilitate the adoption of population pharmacokinetic models into routine clinical practice to improve patient care. Professionally, she has an established clinical pharmacy practice within the UCSF Pediatric Bone Marrow Transplant Service. She also directs an advanced clinical pharmacology consultation service utilized by members of the UCSF Pediatric Bone Marrow Transplant, Immunology and Oncology Services as well as many external clinical centers worldwide.
Statement of the Problem: Quantitative science is a multidisciplinary approach to studying therapeutics, which emphasizes the integration of the relationships between diseases, drug characteristics, and individual variability across studies/drug development. Historically, the adoption of complex pharmacokinetic models into mainstream clinical practice has been hampered by complicated software and the tendency to develop complex models impractical for clinicians to utilize quickly. However, with recent advancements in technology model-based dosing algorithms can be easily implemented into clinical protocols and used to individualize therapy. For pediatric therapeutics this signifies an important paradigm shift from a pre-defined dose (e.g. mg/kg or mg/m2) to a more tailored, individualized approach to therapy.
Methodology & Theoretical Orientation: The overarching goal of model-based dosing is to effectively treat diseases without acute toxicity and to prevent long-term side effects of drug therapy. In pediatrics the pharmacokinetics of drugs in infants can differ widely between children and adults. Within the first year of life, age-related changes can lead to altered drug disposition. Additionally, the relationship between drug concentration and outcomes may be highly variable across different age groups or disease states. Intervention with hematopoietic cell transplantation (HCT) early in life is often critical to effectively treat several childhood diseases including immunodeficiencies and genetic metabolic disorders. Newborn screening allows for diagnosis and thus interventions such as HCT or gene therapy to be offered early when outcomes are superior. Examples of how model-based dosing can be applied to infants, including the commonly used agents used in the setting of pediatric HCT, will be described.
Conclusion & Significance: Moving away from traditional dosing intensity strategies to model-based dosing allows for tailored drug exposure. Further development of model-based dosing in the setting of HCT has the potential to minimize toxicity while maximizing efficacy, resulting in superior outcomes for children with rare diseases.
The Research Institute at Nationwide Childrens Hospital, USA
Shipra Agrawal is an Investigator in the Center for Clinical and Translational Research at The Research Institute at Nationwide Children's Hospital and a Research Assistant Professor in the Department of Pediatrics at The Ohio State University College of Medicine. She is trained in Molecular, Cellular and RNA Biology and mechanistic aspects of human diseases and her research interests have both basic and translational components with a committed focus on kidney disease. Her basic research direction is the identification and modulation of molecular signaling pathways involved in glomerular and podocyte biology and injury, which can potentially translate into novel therapeutic targets for nephrotic syndrome and other glomerular diseases. Her additional translational research focus is on the identification of biomarkers to predict and define steroid resistance in nephrotic syndrome. Her contributions have been published in high impact journals: NEJM, JBC, KI, JASN, HMG, AJHG, JVirol, Virology and NRN.
Statement of the Problem: Nephrotic syndrome (NS) is a kidney disease characterized by proteinuria, edema and increased risk for complications such as infection, acute kidney injury, thrombosis and dyslipidemia. Glucocorticoids (GC) induce remission of NS in most children, though ~20% present with or develop GC resistance. The predictive biomarkers and molecular basis for differences in GC efficacy between steroid-sensitive (SSNS) and steroid resistant (SRNS) children remain largely unknown. This study seeks to determine the predictive biomarkers and mechanisms responsible for differential responses to GC in children with SSNS and SRNS.
Methodology & Theoretical Orientation: Paired plasma samples and total mRNA from leukocytes were collected at presentation (P) and 6-8 weeks later after the first course of GC therapy (F) from children with SSNS (n=30) and SRNS (n=15). Transcriptome profile was generated by deep RNA seq and differentially expressed genes identified by volcano plotting followed by extreme learning machine algorithm. The plasma samples were enriched for low-abundant serum proteins and analyzed by LCMS for generation of proteomics profile. Broad spectrum HNMR data were acquired, binned, and concentration fit for metabolomics analyses. Cytokine profile was generated using a 27-cytokine panel on immulite system.
Findings: Each sample produced ~100 million sequence reads of ~50 bases/read by RNAseq. Transcriptome profile could identify 15,418 genes after filtering, 28 of which were differentially expressed at presentation and 84 upon treatment between SSNS and SRNS. Curation of 215 identified proteins in the samples resulted in 13 predictor and 67 steroid resistance defining markers following Wilcoxon and Mann-Whitney testing. Metabolites most perturbed by treatment included lipoproteins, adipate, tyrosine, valine, alanine, glutamine, glucose, pyruvate and creatine. These could be differentiated in SSNS but not SRNS. Also, elevated malonate levels increased the odds of GC response. Cytokine profile was also altered in the two patient population specifically for IL-8, RANTES and PDGF.
Conclusion & Significance: Different omics approaches could identify candidate biomarkers that can differentiate between the SSNS and SRNS groups at baseline and after treatment.