Preclinical models play a critical role in the drug development process. Not only are they used to generate the evidence and data necessary to advance a promising treatment to clinical trials, but they can help researchers learn more about the disease and identify new therapeutic targets. To that end, preclinical models provide a key role in developing treatments for neurofibromatosis type 1 (NF1). The Gilbert Family Foundation (GFF) not only supports projects that utilize available preclinical models, but projects that aim to expand these resources.

What are preclinical models?

Preclinical models are research tools meant to simulate some aspect of human biology. These models are then used by scientists to evaluate the mechanisms of how drugs work (mechanism of action), how well drugs work (drug efficacy), and how safe drugs are (drug toxicity).

Preclinical models can be split into two main types: in vitro models, or cells derived from animals or cell lines outside a living organism, and in vivo models, or living organisms such as mice, rats, pigs, or non-human primates. In addition, through genetic engineering or transplanting diseased tissue (i.e. tumors) into animals, sophisticated models can be created that closely recapitulate human disease.

How are preclinical models used in GFF-funded research?

GFF supports projects that use preclinical models to build knowledge of NF1 pathogenesis (i.e. learn how the disease develops). GFF also supports projects that test the efficacy of new therapies and explore biological phenomenon relevant to NF1.

For example, within GFF’s Vision Restoration Initiative (VRI), David Gutmann, MD, PhD, Director of NF Center and Donald O. Schnuck Family Professor at Washington University in St. Louis, develops and uses genetically engineered mouse models with NF1 mutations that develop optic pathway gliomas to identify disease mechanisms that could be targeted by new drugs. Dr. Gutmann uses these models to explore variables that affect optic pathway glioma development, and to investigate specific time windows for intervention where the application of therapies could disrupt tumor formation and allow for visual recovery.

Similarly, in GFF’s Gene Therapy Initiative (GTI), Adrienne Watson, PhD, Vice President of Research and Development at Recombinetics, LLC, and her team developed an NF1 pig model that replicates several of the clinical manifestations of the human disease to evaluate promising gene therapies. Starting with in vitro studies using NF1-mutant cells isolated from the NF1 pig models, Watson tests several potential therapeutic drugs for their ability to restore normal function. She then tests the best drugs in vivo to evaluate both safety and efficacy. The data generated serve as critical evidence of whether the therapies are successful enough to move to clinical trials.

Lastly, Dan Goldman, PhD, Professor of Molecular & Behavioral Neuroscience at the University of Michigan and investigator with GFF’s VRI, utilizes zebrafish as a preclinical model. Zebrafish can generate new cells in their retina and recover vision after injury, and Goldman aims to determine the factors that induce regeneration in zebrafish and translate these findings to mice and then subsequently to humans.

How is GFF involved in supporting the development and availability of preclinical models?

GFF also aims to increase accessibility to preclinical models and strategies for the NF research community at large. While GFF awardees have access to several robust models they use to develop NF1 therapies, such as those described above, GFF aims to expand the numbers and types of these resources. Having a suite of models available with different NF1 patient mutations and species types that replicate different aspects of human disease will increase confidence in potential treatments, especially when a drug candidate can demonstrate efficacy in multiple models.

Furthermore, as established models continue to be evaluated and new models developed, GFF aims to improve transparency on the uses and characteristics of existing models. Through a collaboration with Sage Bionetworks, GFF is developing a database for NF1 research tools, including NF1-associated animal models and cell lines. This database will summarize key details about each model to help researchers, pharmaceutical companies, and research funders better source and effectively utilize these tools.

Preclinical models are a fundamental resource to advance treatments for NF1. GFF is dedicated to improving their quality and proper use and ensuring their availability to the research community and putting an effective cure to NF1 within reach.