UAB genetic scientists are engaged in robust preclinical research initiatives focused on testing the effectiveness of potential new drug therapies for NF1. These efforts utilize two primary approaches to evaluate potential new drugs in the laboratory – the first is the development of animal models with patient-specific mutations and the second involves the use of specialized types of cells derived from people with the NF1 gene mutation.

Targeting Mutations Subsets in Animal Models to Test Therapeutics

Animal models are useful in allowing scientists to study the process of specific diseases and the effectiveness of new drug treatments. These models often serve as an important foundation of drug research before clinical trials can begin in humans. UAB genetic scientists Bob Kesterson, Ph.D., and Deeann Wallis, Ph.D., have developed animal models with patient-specific NF1 mutations for understanding both the structure and function of the NF1 gene and how each specific mutation might be optimally targeted for potential new drug therapies.

A mutation of the NF1 gene leads to the production of a nonfunctional neurofibromin protein that is unable to regulate cell growth and division, resulting in the growth of neurofibromas. 

There are thousands of distinct mutations in different patients with NF1, and these mutations are distributed across the gene with no specific mutation predominating. However, it is possible to identify mutation subsets through genetic testing that can allow scientists to develop distinct approaches to restore function to specific types of mutated genes.

In this way, rather than the need to develop thousands of drugs, one for each mutation, it may be possible to develop a few, each of which targets a specific type of mutation.  The animal models with patient-specific NF mutations are valuable for testing the effectiveness of various drug compounds in overcoming the effects of specific mutations, with the hope of allowing the development of a functional neurofibromin protein.

Testing Potential Drug Therapies Using Induced Pluripotent Stem (iPS) Cells

To test the effectiveness of potential new drug therapies for NF1, UAB genetic scientists are also using specialized types of cells derived from people with the NF1 gene mutation. Induced pluripotent stem (iPS) cells are a type of cell that has been reprogrammed from an adult cell and can develop into virtually any type of cell in the body. This new approach to creating disease-specific stem cells from adult tissue – first pioneered in 2007 by Nobel Prize-winning scientist Shinya Yamanaka – holds great promise in providing medical researchers with a supply of disease-specific cells that can be used to test drug effectiveness and safety. Induced pluripotent stem cells are different from embryonic cells because they are derived from adult tissue rather than embryos. Also, these types of cells are distinct from adult stem cells, which occur naturally in small numbers in the human body.

Using cells from a biopsy taken from either skin or a neurofibroma of a patient with NF1, scientists can create iPS cells by treating them with specific genes that cause them to behave like undifferentiated stem cells. As a result, researchers have access to patient-specific cell lines that can be studied and used to test the effectiveness of potential new drug therapies for NF1. Instead of using animal models or other organisms such as yeast, iPS cell technology allows human stem cells to be created from people with specific genetic mutations. Because the iPS cells contain a complete set of the genes that resulted in the disease, they represent a highly advanced model for studying NF1 and testing new drugs and treatments.

For more information, please contact the UAB Neurofibromatosis Program at 205-934-4983.