Precision Medicine & Oncology

Emerging evidence from our laboratory using NF1 patient induced pluripotent stem cells (iPSCs) has revealed potential genotype-phenotype correlations. In these studies, some germline NF1 gene mutations resulted in profound reductions in NF1 protein (neurofibromin) expression and function, while others had more subtle effects. Based on these findings, we have generated numerous genetically-engineered mouse strains harboring actual NF1 patient germline NF1 gene mutations. The use of these strains has revealed striking differences in neurofibromin function and differential effects on glioma formation and growth. We are currently using these “precision medicine” mice to determine how the germline NF1 gene mutation creates such phenotypic diversity. We are also deploying these mice for more accurate preclinical drug studies that most closely parallel those performed in human clinical trials.

Current projects in the Gutmann research laboratory are focused on utilizing these and other approaches to create a more diverse collection of preclinical mouse strains that truly reflect the diversity of gliomas that arise in children with NF1. These projects also employ these mouse models to discover and evaluate promising treatments targeted to a given child’s tumor (precision oncology). Similar approaches are being taken using human iPSCs and derivative cells (neurons) to understand behavioral deficits and autism.

Generation of patient-specific neurons from NF1 patient skin samples. Fibroblasts migrating out of NF1 patient skin biopsies (1) are reprogrammed into induced pluripotent stem cells (iPSCs) (2-5). Mature iPSC colonies are induced into forming embryoid bodies (6-7) and subsequently neural rosettes (8-9). Rosettes have the capacity to generate neural progenitor cells (10-11) and terminally differentiated neurons (12), thus allowing us to directly test the effect of patient-specific NF1 mutations on neuronal formation and development.

Generation of patient-specific neurons from NF1 patient skin samples. Fibroblasts migrating out of NF1 patient skin biopsies (1) are reprogrammed into induced pluripotent stem cells (iPSCs) (2-5). Mature iPSC colonies are induced into forming embryoid bodies (6-7) and subsequently neural rosettes (8-9). Rosettes have the capacity to generate neural progenitor cells (10-11) and terminally differentiated neurons (12), thus allowing us to directly test the effect of patient-specific NF1 mutations on neuronal formation and development.