Cunningham letter
UNIVERSITY OF CALIFORNIA, IRVINE
BERKELEY • DAVIS • IRVINE • LOS ANGELES • MERCED • RIVERSIDE • SAN DIEGO • SAN FRANCISCO
UC IRVINE MEDICAL CENTER
DEPARTMENT OF PEDIATRICS
333 CITY BLVD WEST, SUITE 800
ORANGE, CALIFORNIA 92868-4482
4/3/2021
North Carolina Awards Committee
N.C. Department of Natural and Cultural Resources
4601 Mail Service Center
Raleigh, N.C. 27699-4600
Dear Committee Members,
It is with great enthusiasm and pride that I nominate Dr. Priya Sunil Kishnani for the 2021 North Carolina Award in Science. Dr. Kishnani epitomizes the values and spirit set forth in the award criteria. She has dedicated her entire career to improving the lives of children and adults with genetic abnormalities through both research, clinical care and training the next generation of care providers. Dr. Kishnani is without peer in translational research and known worldwide for applying basic science discoveries to clinical trials and practice and leading development of new lifesaving therapeutics. Her impact on medical genetics, especially glycogen storage disorders (GSD), has transformed the life of countless individuals, young and old. In her role as the international principal investigator for pivotal clinical trials, she was critical in identifying the potential interventions and designing and leading the clinical studies that showed effectiveness. Her landmark discoveries led to the advent of the enzyme replacement therapy in Pompe disease. Her passion for mentoring a diverse and multidisciplinary group of future leaders continues to shape the discipline of clinical and biochemical genetics, promising to save countless lives for generations to come.
Scientific Achievements: Always Innovating Dr. Kishnani is a superb clinical and biochemical geneticist and pediatrician whose primary focus has been the translation of laboratory science into the clinic, especially in the area of enzyme replacement therapy, gene therapy, and small molecules. She has led a translational research program at Duke which has identified the molecular and genetic basis of rare diseases, developed potential interventions, brought those interventions into clinical trials and to licensure so that children and adults across North Carolina, the USA and the world can benefit from the treatments. This is exemplified by her work in Pompe disease, an otherwise lethal disorder, which, prior to the development of enzyme replacement therapy, resulted in death of untreated infants within the first year of life. Alglucosidase alfa is the therapy approved for Pompe disease and was a direct result of bench-to-bedside work done by Dr. Kishnani, Dr. Yuan-Tsong Chen, and their team at Duke.
Specifically, Dr. Kishnani’s role in decades of research is her identification of a naturally occurring canine model with glycogen storage disease type I (GSD I), cloning of the glucose-6- phosphatase gene, identification of the mutations in these Maltese dogs, and establishment of a breeding colony of dogs with these mutations. The genetic model established by these animals has been used as the foundation of numerous studies around the world, a better understanding of long-term complications of GSD I not previously recognized, and the development of clinical innovations, including small molecule and gene therapy approaches for this disease.
Among a host of other preclinical achievements, Dr. Kishnani and her lab colleagues created a knock-out model and identified the transporter role of the starch-binding domain-containing protein 1 (Stbd1) in glycogen metabolism. This was a key finding and an insight into how cytoplasmic glycogen enters the lysosome. Related study results using the Stbd1 KO model suggested a difference between the transport of cytoplasmic glycogen into lysosomes in muscle and liver. This finding has important implications for a potential therapeutic target in both cytoplasmic glycogen storage disorders as well as in Pompe disease.
Dr. Kishnani’s team was also responsible for identification of a naturally occurring canine model for glycogen storage disease type IIIa (GSD IIIa). This animal model has been extremely useful in developing a better understanding of the natural history of GSD IIIa. Subsequently, her team also built a KO mouse model of GSD IIIa. With the clinical knowledge gleaned from patient care, several preclinical experiments have been carried out in animal models to identify new treatment approaches for GSD IIIa, including a gene therapy approach for GSD III. This is now being translated in the canine model of GSD IIIa with a goal to clinical translation in the near future. Her lab also has mouse models for GSD IV and GSD IX. At this time there are no treatments for these diseases and her lab is currently focused on an AAV mediated gene therapy approach for these disorders.
Pompe disease breakthroughs. Dr. Kishnani was involved in preclinical work at Duke demonstrating that the recombinant human enzyme acid alpha-glucosidase worked in vitro and in vivo in an animal model. These results were used to secure FDA Orphan Drug designation for alglucosidase alfa, facilitating initiation of phase I clinical trials at Duke. Dr. Kishnani led in the design and conduct of subsequent trials. This work resulted in FDA approval of the therapy alglucosidase alfa (LumizymeTM/MyozymeTM) in 2006. Through the years, her work resulted in a better understanding of treatment challenges, including age and stage at diagnosis, negative prognostic factors such as immune response factors (cross-reactive immunologic material (CRIM) and anti-drug antibodies), inadequate delivery of enzyme to skeletal muscle, challenges with autophagic build-up of material in skeletal muscle, and sanctuary sites not responsive to enzyme replacement therapy.
She and her team worked through these problems, finding a solution for each of them. She used the bedside-to-bench approach, for example, in patients with infantile Pompe disease treated with alglucosidase alfa who develop sustained high antibody titers. She completed preclinical work with the drug bortezomib to show the proof of concept that this plasma cell
targeting agent could reduce the high antibody titers in the Pompe KO mouse model. These data were instrumental in allowing of the novel use of bortezomib on a compassionate basis for patients with Pompe disease who were poor responders due to development of high and sustained antibody titers directed against the therapeutic enzyme. This work represents a first in the field—the ability to overcome the entrenched antibody response to a therapeutic agent—and resulted in a landmark paper. Lessons learned from Pompe disease have built a valuable model for other diseases such as mucopolysaccharidosis Types I and II, hypophosphatasia and acid lipase deficiency, to name a few.
Building on her work, Dr. Kishnani was successful in having Pompe disease added to the recommended uniform screening panel for babies born in the United States in 2015 by showing the impact of early treatment in the animal model as well as in patients with Pompe disease. Her work also helped with getting approval of SEEKERTM, the first FDA-approved device for newborn screening for Pompe disease and other lysosomal storage diseases. Related discoveries include the utility of urinary glc4 (glucose tetrasaccharide) as a biomarker for, and the development of a blood-based assay to enable a rapid diagnosis of, Pompe disease. Always moving forward, her team is now looking at the role of AAV gene therapy as a treatment for cytoplasmic GSDs, including GSD III, IV and IX.
Her team has also successfully launched an investigator-initiated NIH-supported study to explore the role of low-dose methotrexate as an immune-modulating agent. In 2017, she published her creative methods of mitigating the deleterious impact of CRIM-negative status on ERT outcomes through induction of immune tolerance, a paper that has already stimulated fundamental research and established a paradigm for the biopharmaceutical therapy of other rare diseases. She has also co-authored a white paper, developed in collaboration with the FDA and other stakeholders, emphasizing the need to understand the role of antibodies in ERT treatment response and disseminating an algorithm for diagnosis and treatment of Pompe disease. In the clinical arena, her work has dramatically improved the natural history of children with infantile Pompe disease.
More recently, in collaboration with her colleague Dwight Koeberl, there is now an AAV gene therapy for Pompe disease in Phase I clinical trials. All the bench work was done at Duke and the clinical translation efforts were led by Dr Kishnani.
Always Moving Forward. Building on her accomplishments in Pompe (GSD II), Dr. Kishnani added an animal model for GSD type IV and type IX to those previously developed for types I, II, and III. At this time, her team is working closely with pharmaceutical partners to advance proof-of-concept work using an AAV gene therapy approach, which has shown preclinical success. Through work in genome-wide association studies (GWAS) and microRNA studies, she has identified potential biomarkers to predict cancer risk in patients with GSD type I. Other highlights of her work include a key role in designing end points for clinical trials for other rare diseases such as Gaucher, Fabry, hypophosphatasia, GSD types I, III, IV, mucopolysaccharidosis, Wolman disease, and Down syndrome.
Impact on Careers: An Inspirational Mentor. Dr. Kishnani emphasizes continued research into these devastating conditions via a multidisciplinary and multicultural team approach. Her team, in fact, comprises clinical and research professionals practicing in a wide range of specialties, from cytogenetics and molecular genetics to cardiology, pathology, pulmonology and a myriad of other subspecialties. To fulfill her commitment to global health, she cultivates students and mentees from all over the world, including India, Lebanon, and various Latin American countries. This reflects her emphasis on the real-world impact of the work done every day in the Division of Medical Genetics at Duke and her drive to expedite translation of research results into clinical practice. Currently, there are more than 100 collaborators in different subspecialties working closely with Dr. Kishnani’s team in rare diseases. Dr. Kishnani has served as a research mentor to more than 80 individuals spanning a range of educational levels—high school students, undergraduates, medical students, residents, fellowship trainees, and graduate and post-graduate students.
Teaching efforts. Dr. Kishnani has served as a principal investigator, co-investigator, faculty member, and mentor for numerous grant-funded training programs, including the Duke Research Training Program for Pediatricians, Postdoctoral Training in Genomic Medicine Research, the Duke Multidisciplinary Training Program in Pediatric Lung Disease, the Pfizer/ACMG Foundation Fellowship, the UNC-Duke Collaborative Clinical Pharmacology Postdoctoral Training Program, the Institutional Training Grant in Pediatric Cardiology, the Lysosomal Disease Network Fellowship, the Clinical and Translational Science Research Program, and the Duke Medical Scientist Training Program. Her legacy as an educator also includes developing opportunities for undergraduate and high school students to expose young minds to the worlds of science and medicine.
Contributions to the Broader Scientific Community: A Peerless Expert. Dr. Kishnani and her team are considered world experts and provide consultation to more than 250 treating physicians and researchers throughout North Carolina, the USA and worldwide. Ongoing work in documenting the natural history of Pompe and other GSDs has contributed invaluable insights into the lived experience of patients and the impact of their disease sequelae. Carefully selected multifaceted longitudinal data also assess treatment outcomes and aid in the development of adjunctive treatment modalities and gene therapies. To date, documentation and analysis of this natural history has identified several long-term complications in Pompe, Gaucher and other GSDs.
Sustained impact has been recognized for over 30 years. Since joining Duke as a clinical fellow in 1991, Dr. Kishnani has been honored by both internal and external organizations, both in the US and overseas, including special recognition by University president Nannerl O. Keohane at the Duke University board of trustees 1999 annual meeting (for original research in Down syndrome); special recognition honors from the Triangle Down Syndrome Network board of directors in 2001 (for contributions professionally and personally in the lives of individuals with Down syndrome); Exceptional Parent Magazine’s 2005 Maxwell J. Schleiffer Distinguished Service Award (for passion, dedication, professionalism and inspiration to people with disabilities, particularly those with Pompe Disease); the 2008 Ruth and A. Morris Williams, Jr. Faculty Research Prize (for
intellectual vigor, dedication, and scientific ingenuity needed to make a critical impact on the future of medical research); the 2010 National Down Syndrome Congress’s Christian Pueschel Memorial Research Award (for outstanding clinical research that improves lives through greater understanding of Down syndrome); the 2016 Rare Disease Report’s Rare Disease Hero Award (for advancing the management of lysosomal diseases); the 2021 Duke Medical Alumni Association’s Distinguished Faculty Award; and was featured in the 2021 Pioneering Women in Science for Duke Health exhibit. Her international renown is also reflected in honors from Indian organizations, including the Society for Indian Academy of Medical Genetics’ 2015 Dr. S.S. Agarwal Oration Award for “Novel Therapies for Genetic Disorders”; and the Indian Society of Inborn Errors of Metabolism’s 2017 Sandor Oration Award for work in rare disease in India. She was a nominee for the Dr. K. C. Chaudhuri Life Time Achievement Award. This award is given annually to a pediatrician who has contributed significantly to the field of academics, research, and patient care in India or abroad.
Leadership in professional organizations. Dr. Kishnani serves as chair of the North American Pompe Registry and Hypophosphatasia Global Registry and of the US Scientific Advisory Board for the Association of Glycogen Storage Diseases. Among many others too numerous to list here, she sits on the medical advisory board of the National Gaucher Foundation, the International Pompe Registry Board of Advisors, the National Patient-Centered Clinical Research Network (PCORnet) task force and has served on the Councils of the National Institute of Child Health and the Human Development Council of the National Institutes of Health. She initiated and co-chaired the Rare Disease Investigator Training Course, “US Conference on Rare Diseases and Orphan Products,” a unique collaboration among the FDA, NIH, NORD and Duke University. She also served as an ad-hoc member of both open and closed FDA panel meetings addressing rare disease treatments. Another highlight of her service is her membership in the National Down Syndrome Society’s National Government Affairs Committee, in which she is actively involved to maintain the DS-Connect Down syndrome registry and the partnerships necessary for new therapy development.
Public impact. Since 2012, she and her team have hosted semi-annual family meetings for patients with GSD II (Pompe disease) and their families who travel from around the world to learn about the newest research developments and treatment options, undergo evaluations by Dr. Kishnani and her clinical team, and meet other families. Attendance at these meetings has grown year after year. Her reach extends internationally, exemplified by her commitment to supporting rare disease research and treatment in developing countries. Chief among these is the India Charitable Access program, which was initiated 10 years ago with the intent to increase knowledge and close the gaps in care for patients with genetic disorders. She travels to India three to four times a year to fulfill this commitment and has succeeded in raising awareness of the diagnosis and management of genetic disorders and inborn errors of metabolism and has saved lives in the process.
Patient advocacy. According to an extensive government-commissioned review of data from the Pompe Disease Registry and medical literature, nationwide newborn screening for
Pompe disease would save 13 lives and keep 26 infants from needing ventilators annually. An active and long-time member of the Newborn Screening Translational Research Network’s Lysosomal Storage Disease Newborn Screening Group, Dr. Kishnani has been a tireless advocate for including Pompe disease in the newborn screening panel. Pompe disease is only the third disease in ten years to receive the RUSP NBS designation, and it is the first disease to have been recommended under a newly stringent evidence-review process. This was influential in several states’ adding Pompe and other lysosomal storage disorders to their own NBS panels, a major advance in more timely diagnosis and life-saving treatment. She has also been a leading voice in the movement to include coverage for Pompe disease treatment in health insurance plans in the US and abroad, not only advocating for policy change, but also representing families in their own struggles for coverage.
In conclusion, Dr. Kishnani is uniquely qualified to receive the 2021 North Carolina Award in Science. Her revolutionary work in real-time application of basic science discoveries to clinical trials, directly improves the life of children and adults with rare genetic diseases. The impact of her work is truly astounding. Because of her passion, intellect, and focus, many babies who previously would have died in the first year of life, are alive today. For multiple decades, she has inspired mentees to pursue careers in genetic research.
This is another long-lasting legacy—a new generation of scientists and clinicians working together to bring state-of-the-art bench research to the clinic, to take clinical observations back to the bench, and to maximize complex collaborations among the clinical, scientific, academic, industrial, and regulatory communities. All this in her dedication to further advances in the diagnosis, treatment, and management of patients with rare genetic diseases. There is nobody more deserving than Dr. Kishnani for this award.
Sincerely,
Coleen K Cunningham M.D.
Professor and Chair of Pediatrics, University of California Irvine
Pediatrician in Chief, Children’s Hospital of Orange County