In addition to our regular CRI Activities Update, this month’s Research Focus highlights collaborative work from the team led by Joseph Muenzer, MD, PhD, Professor of Pediatric and Genetics.

Activities Update: This past month we have been busy with research grants. We had a Creativity Hub submission to the UNC Office of the Vice Chancellor for Research, and although we did not receive funding, we did receive positive feedback and are exploring ways to move forward with a multi-disciplinary team across the UNC campus, focused on Child Environmental Health and Development. Also, the Carolina For The Kids (CFTK) submissions were reviewed this past month. We are waiting on the final sign off from CFTK to make the announcement for the awardees.

Our Pediatric Patient Registry Working Group continues to move forward, looking at ways to leverage existing infrastructure to gather pediatric population data. We are exploring the kinds of data we can obtain from I2B2. We are also building processes and developing objectives to access more detailed data from the Carolina Data Warehouse. In addition, we are pursuing potential cross campus collaborations to access banked samples (eg, dried blood spots), identifying processes to tap into, and assessing feasibility and necessary requirements.

This month we held our first Pediatric Scholars Program (PSP) meeting of 2018. After meeting monthly in the fall, we used our January meeting to discuss ways to reformat this program to meet the needs of our Junior Faculty. Going forward, for those with a publication history, we will be holding one-on-one meetings to develop an individual development plan. The aim is to assist junior research faculty in identifying career, peer, and research mentors, examining how they have progressed, and determining next steps. The PSP will meet as a group as requested to provide feedback on specific research projects (eg, on specific aims, manuscripts, biosketches).

Reminder: Joseph Muenzer, MD, PhD is presenting at our next CRI monthly luncheon seminar series, on Tuesday, January 16, 2018 at 12:15 pm in the Bioinformatics Auditorium (room 1131). Please mark your calendars. We look forward to seeing you there.

Research Focus of the Month: To inform each other of the research interactions in pediatrics, and in the spirit of CRI’s mission to promote collaboration, each CRI update will continue to highlight different investigators’ collaborative efforts. Below is a summary on the collaborative research from the team led by Joseph Muenzer, MD, PhD.

Joseph Muenzer, MD, PhD

Most rare diseases begin in childhood; these diseases are primarily innate or congenital. Despite the numerous challenges of studying rare diseases (eg, few and scattered patients, difficult to diagnose and code, complex treatment and care, funding), Dr. Muenzer has dedicated his career to studying one such disease, Mucopolysaccharidoses (MPS). MPS are a group of rare genetic disorders characterized by the lysosomal storage of glycosaminoglycans. Each MPS disorder is caused by the deficiency in the activity of a single, specific lysosomal enzyme required for glycosaminoglycans degradation. Glycosaminoglycans, historically known as mucopolysaccharides, are a heterogeneous group of complex linear polysaccharides that are involved in a variety of biological functions, including lubricating joints, hydrating tissues, and absorbing shock. However, without functioning lysosomal enzymes, glycosaminoglycans accumulate abnormally in the lysosomes of most cells, leading to progressive damage throughout the body. This includes the heart, bones, joints, respiratory system and central nervous system. This results in a high degree of morbidity, including short stature, developmental delays, chronic airway issues, cardiac involvement, loss of mobility and premature death. MPS affects about 2,000 people across the United States, with 7 distinct clinical types as well as multiple subtypes. MPS remains incurable and approved treatments are limited for specific MPS types. However, through the research and work of physician scientists like Dr. Muenzer, new treatments are being developed to not only treat symptoms, but halt disease progression.

Dr. Muenzer began his research interest in MPS as a fellow at the National Institutes of Health (NIH) and his research career in MPS has spanned from bench to bedside. Upon his arrival at UNC in 1993 from the University of Michigan, he developed a MPS II mouse model. The mouse model for MPS II (Hunter syndrome) allowed him to begin his interest in developing gene therapy as a treatment for MPS disorder. The MPS II mouse was also instrumental in the development of intravenous enzyme replacement therapy for Hunter syndrome. He became the lead investigator for developing intravenous enzyme replacement therapy for Hunter Syndrome, sponsored by Shire, translating preclinical basic science findings into humans with a phase I/II and a phase II/III multinational pivotal clinical trials. This resulted in approval by the FDA of idursulfase (recombinant iduronate-2-sulfatase) in 2006.

His international collaborations across Brazil (Roberto Giugliani, MD, PhD, MSc, of the Federal University of Rio Grande do Sul and National Institute on Population Medical Genetics), Germany (Michael Beck, MD, of the Johannes Gutenberg University Mainz), Italy (Maurizio Scarpa, MD, PhD of Helios Dr. Horst Schdmit Clinic and the University of Padova), and Switzerland (Virginie Jego, MSc, of Cytel, Inc), revealed that treatment of Hunter syndrome with intravenous recombinant iduronate-2-sulfatase enzyme replacement therapy had a positive effect on glycosaminoglycan levels, walking tests, left ventricle mass index, lung function, and hepatosplenomegaly after 1, 2 and 3 years of treatment.

Although intravenous enzyme replacement therapy for Hunter syndrome has been successful in helping the physical disease, it does not help the central nervous system involvement since intravenous administered enzyme does not cross the blood-brain barrier. Since 2009, Dr. Muenzer has focused his clinical research on developing treatment for the brain disease in the severe form of Hunter syndrome, administering intrathecal enzyme replacement therapy via an intrathecal drug delivery device (IDDD). Implantation of the IDDD and its use is complicated due abnormal tissue and anatomy, as well as the airway issues and developmental delay seen in the severe form of Hunter syndrome. Collaboration with the UNC Pediatric Pain and Sedation Consult Service led to the development of sedation procedures required to safely administer intrathecal enzyme. The complex intrathecal enzyme replacement clinical trials has required collaboration across multiple fields, including: Zheng (Jane) Fan, MD, Associate Professor, Child Neurology, Sleep Medicine and Clinical Genetics; Scott Elton, MD, Clinical Professor, Division Chief and Director Pediatric Neurosurgery; Margot Stein, PhD, Clinical Associate Professor, Dental Ecology, School of Dentistry and the entirety of the pediatric sedation and anesthesia team.

His long-term collaboration with Nationwide Children’s Hospital’s Center for Gene Therapy, led to the development of human gene therapy for MPS IIIA (Sanfilippo Syndrome) using adeno-associated viral vectors. A phase I/II human gene therapy clinical trial started in 2016 at Nationwide. Additional preclinical gene therapy research collaboration has led to further developmental research in MPS II. In December 2017, the FDA approved an Investigational New Drug (IND) application to proceed with gene therapy clinical trials in Hunter Syndrome patients.

Funding for rare diseases remains a challenge, with families and parent organizations often coming together to fund research. Dr. Muenzer and the Division of Genetics and Metabolism, Department of Pediatrics, were recently the recipients of a $1,000,000 gift from Catherine and Wayne Bardsley of McLean, VA, in honor of their late son, Jeffrey David Bardsley. Jeff, who died of cancer unrelated to his MPS II diagnosis in 2016, was enrolled in one of Dr. Muenzer’s first clinical trials at UNC. Half of the Bardsley’s gift will fund a fellowship within the Division of Genetics and Metabolism to develop the next generation of genetic physician scientists, while the other half will support the ongoing research of Dr. Muenzer. You can read more about the Bardsley family and their experiences here. Also, Nancy and Vaughn Bryson are funding an endowed chair in the Department of Pediatrics to support future MPS patient care and research at UNC.

Links for more information about Dr. Muenzer, and a selection of publications, are listed below.

http://news.unchealthcare.org/uncchildrens/news/2017/may/heritable

https://clinicaltrials.gov/ct2/show/NCT03041324?recrs=ab&cond=mps&cntry1=NA%3AUS&state1=NA%3AUS%3ANC&rank=2

Muenzer J, Jones SA, Tylki-Szymańska A, Harmatz P, Mendelsohn NJ, Guffon N, Giugliani R, Burton BK, Scarpa M, Beck M, Jangelind Y, Hernberg-Stahl E, Larsen MP, Pulles, Whiteman DAH. Orphanet J Rare Dis. 2017 May 2;12(1):82
https://www.ncbi.nlm.nih.gov/pubmed/28464912

Muenzer J, Giugliani R, Scarpa M, Tylki-Szymańska A, Jego V, Beck M. Orphanet J Rare Dis. 2017 Oct 3;12(1)
https://www.ncbi.nlm.nih.gov/pubmed/28974237

Muenzer, J. Molecular Genetics and Metabolism 111 (2014) 63–72
https://www.ncbi.nlm.nih.gov/pubmed/24388732

Fu H, DiRosario J, Kang L, Muenzer J, McCarty DM. J Gene Med. 2010 Jul;12(7):624-33.
https://www.ncbi.nlm.nih.gov/pubmed/20603889

Project Alive: Rare Disease Foundation Contract Gene Therapy for Hunter Syndrome Clinical Trial
http://etradewire.com/news/rare-disease-foundation-signs-1-4-million-contract-to-produce-gene-therapy-vector-for-hunter-syndrome-clinical-trial