In addition to our regular CRI Activities Update, this month’s Research Focus highlights the research and work of Haiyan FU, PhD, Research Associate Professor of Pediatrics in the division of Genetics and Metabolism.

Activities Update:

We are excited to welcome James Hagood, MD to UNC! Dr. Hagood comes from Rady Children’s in University of California San Diego. Here at UNC he will serve as the Director of the Center for Rare and Interstitial Lung Disease, UNC Marsico Lung Institute and Children’s Research Institute. He is an expert in Childhood Interstitial Lung Disease, working on triggers/regulators of alveolar development, response to lung injury, and development of fibrosis. In this capacity he examines the epigenetic regulation of airway remodeling and normal lung development. His goal is to not only arrest but reverse fibrosis, a process once thought to be irreversible. Please join us in giving Dr. Hagood a warm welcome!

Our new chair, Dr. Davis, had the pleasure of presenting at the School of Medicine, Office of Research annual retreat. She highlighted our many pediatric research activities, and goals to continue to build strong programs in clinical, translational, and basic research.

The CRI is excited to announce that we will be cosponsoring a symposium focused on research in children’s environmental health with the Center for Environmental Health and Susceptibility at the Gillings School of Global Public Health. “Kids Matter! Research to Action in Children’s Environmental Health” will be held at the Sonja Hayes Stone Center for Black Culture and History on Friday, October 12, 2018 from 9:00am-4:30pm. The symposium will bring together scientists, clinicians, public health professionals and community advocates interested in emerging research in the field to stimulate scientific collaboration within and across disciplines. Details and registration information will be out soon.

Reminder: Haiyan Fu, PhD, will be presenting “Cross Blood-Brain Barrier Gene Delivery for Treating Neuropathic Lysosomal Storage Diseases” at our next CRI luncheon seminar series. This event will be held on Tuesday, September 11 from 12:15-1:30pm in the Bioinformatics Auditorium (room 1131). Please mark your calendars. We look forward to seeing you there.

Research Focus of the Month:

Haiyan Fu, PhD

The Department of Pediatrics is also pleased to welcome Haiyan Fu, PhD, to the UNC School of Medicine. Dr. Fu comes from The Research Institute at Nationwide Children’s Hospital, Center for Gene Therapy. She has a long-standing interest in the development of gene therapy to treat neuropathic mucopolysaccharidosis (MPS) disorders, and collaborates with Joseph Muenzer, MD, PhD, in this arena. There are 11 types of MPS, all of which are inherited disorders where the body’s enzymes cannot break down glycosaminoglycans. This buildup can lead to neurological impairment, stunted growth, and multisystem manifestations. Physical symptoms of MPS are managed through bone marrow transplants and enzyme replacement therapy. However, neurological manifestations of the disease are difficult to ameliorate because current therapeutics cannot cross the blood-brain barrier (BBB). In developing experimental treatments for MPS, Dr. Fu’s research has focused on strategies to overcome the BBB to deliver genes to the Central Nervous System. To this end, Dr. Fu’s team has developed novel gene therapy products that target the root cause of the disease, using adeno-associated virus (AAV) vectors that can cross the BBB to replace the defective gene with a correct gene, treating both the neurological and somatic manifestations of several MPS diseases via a single systemic administration. In collaboration with Dr. Muenzer, their MPS gene therapy research projects have led to 3 IND approvals from the FDA for phase 1/2 clinical trials of systemic AAV9 gene delivery in pediatric patients with MPS IIIA, MPS IIIB and MPS II.

Dr. Fu also studies the pathology and pathophysiology of MPS disorders, in order to better understand the disease mechanisms and identify alternative therapeutic targets. In recent years, her research team has expanded efforts to overcome the major challenges in translation of AAV gene therapy to clinical application in humans. Her team has been exploring potential biomarkers, especially neuro-specific biomarkers of MPS disease progression, which could be used as surrogate outcome measures in clinical trials for MPS and possibly other lysosomal storage diseases. For effective translation of AAV gene therapy, the team has also been working on developing approaches for effective depletion of the pre-existing antibodies against AAV, which is widespread in humans. Ongoing efforts in Fu lab also include developing strategies facilitating cross-BBB gene and drug delivery for the treatment of the CNS neurological diseases.

For further information:

Fu H, Zaraspe K, Murakami N, Meadows AS, Pineda RJ, McCarty DM, Muenzer J (2018) Targeting the root cause by a systemic scAAV9-hIDSgene delivery: functional correction and reversal of severe MPS II in mice. Mol Ther Methods Clin Dev. 2018 (in press)

Fu, H, Meadows, AS, Pineda, RJ, Mohney, RP, Stirdivant, S, and McCarty. Serum global metabolomics profiling reveals profound metabolic impairments in patients with MPS IIIA and MPS IIIB. Metabolic brain disease. DOI: 10.1007/s11011-017-0009-1 Metab Brain Dis. 2017 Oct;32(5):1403-1415. doi: 10.1007/s11011-017-0009-1. Epub 2017 Apr 5. PMID: 28382573

Fu, H., et al. (2017). “Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy.” Hum Gene Ther Clin Dev 2017:28(4): 187-196.

Velazquez VM, Meadows AS, Pineda RJ, Camboni M, McCarty DM, Fu H. Effective Depletion of Pre-existing anti-AAV Antibodies Requires Broad Immune Targeting. Mol Ther Clin Methods Dev. 2017 Mar 17; 4: 159–16. PMID: 28345001.

Fu H, Meadows AS, Ware T, Mohney RP,3 McCarty DM. Near complete correction of profound metabolomic impairments corresponding to functional benefit in MPS IIIB mice after IV rAAV9-hNAGLU gene delivery. Mol Ther. DIO: 10.1016/j.ymthe.2016.12. Mol Ther. 2017 Mar 1;25(3):792-802. doi: 10.1016/j.ymthe.2016.12.025. Epub 2017 Jan 28. PMID: 28143737

Fu, H., et al. “Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery.” Mol Ther Methods Clin Dev 2016: 3: 16036.

Duncan, F. J., et al. “Broad functional correction of molecular impairments by systemic delivery of scAAVrh74-hSGSH gene delivery in MPS IIIA mice.” Mol Ther 2015: 23(4): 638-647.

Meadows, A. S., et al. (2015). “A GLP-Compliant Toxicology and Biodistribution Study: Systemic Delivery of an rAAV9 Vector for the Treatment of Mucopolysaccharidosis IIIB.” Hum Gene Ther Clin Dev 26(4): 228-242.

Naughton, B. J., et al. (2015). “Blood genome-wide transcriptional profiles reflect broad molecular impairments and strong blood-brain links in Alzheimer’s disease.” J Alzheimers Dis 2015: 43(1): 93-108.

Fu, H., et al. (2011). “Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery.” Mol Ther 2011:19(6): 1025-1033.