Randy Chandler, Ph.D., M.B.

Dr. Chandler has specific expertise and research interest in developing and testing various gene therapy approaches, such as AAV gene delivery, genome editing, and mRNA therapy, to cure rare genetic disorders. The primary focus of his research has been to develop gene therapies for two severe inherited organic acidemias, MMA and PA, for which more effective treatments are needed than those that currently exist. Dr. Chandler was the first to establish long-term efficacy for AAV-mediated gene delivery for MMA and PA. In addition, his research has shown that mRNA therapy and gene editing approaches could also be potentially beneficial for MMA patients. Importantly, Dr. Chandler’s research relating to the in vivo gene editing in murine models of MMA has shown that the corrected MMA hepatocytes have a growth advantage, which allows corrected hepatocytes to outcompete uncorrected hepatocytes and to repopulate MMA-diseased livers. The gene therapy approaches and methods he has developed have also been applied by the OAR Section to treat murine models of related organic acidemias. Dr. Chandler regularly collaborates with other NHGRI labs, NIH Institutes,and biotechnology companies in designing gene therapy vectors and preparing FDA Interact, IND and ODD submissions for gene therapy applications. In collaboration with Dr. William Pavan’s (NHGRI) and Dr. Denny Porter’s (NICHD) labs, he led efforts to develop AAV gene therapy to treat Niemann-Pick Disease, Type C1 disease, a rare and lethal inherited neurological disorder. This breakthrough has resulted in continued efforts to advance gene therapy as a treatment for this disease.

In addition to developing gene therapy approaches for genetic diseases, Dr. Chandler’s research focuses on the potential toxicities associated with gene therapies. He has demonstrated that AAV vectors can cause insertional mutagenesis in mice treated as neonates and that this toxicity is dose-dependent. His research has also demonstrated that enhancer elements in the AAV vectors are likely the cause of upregulation of oncogenes and tumorigenesis in mice treated with AAV. Importantly, his AAV integration studies revealed that transcriptionally active genes in the murine liver, such as albumin, may be an integration hotspot for AAV.

Lastly, Dr. Chandler's research has involved the use of gene editing and transgenic constructs to create murine models of human genetic diseases both to test gene therapies and to understand pathophysiology. He was the first to demonstrate that mice and patients with MMA both have a tissue-specific mitochondrial dysmorphology and impaired mitochondrial function. In addition, these murine models have been used to establish biomarkers, to develop assays that can be used to monitor the effects of gene therapy, and to establish efficacy data to support human clinical translation.