As many of you are by now aware, I need to start the New Year with the sad news that Dr. Lane Rutledge, who has taken care of NF patients and their families for decades, passed away suddenly just as the New Year was dawning.  Dr. Rutledge was beloved by patients, family members, health providers, and staff, not to mention her family and the larger community.  This was very evident at her memorial service, in which a large church was filled to capacity.  It has also been evident in communications I have had from colleagues around the country.  My sincere condolences go out to her family and close friends.  I would also like to reassure her patients that we have been working so that clinical care will proceed seamlessly.  I am taking care of immediate clinical needs, such as follow-up of imaging studies or urgent clinical problems.  I am doing this together with Ms. Tammi Skelton, a nurse practitioner who works with me in NF Clinic and also had worked with Dr. Rutledge in clinic, so she knows many of Dr. Rutledge’s former patients.  We are also expanding our NF Clinic capacity, working with Dr. Katie Metrock of pediatric oncology, who will follow children with NF who have brain tumors, optic gliomas, and complex plexiform neurofibromas.  We cannot replace Dr. Rutledge but can honor her legacy by continuing to provide the highest quality of care possible for individuals with NF.

On a happier note, I’m pleased to share the recently announced news that several UAB investigators have received significant grants for NF-related preclinical research focused on restoring function to the mutated NF1 gene or its protein product. The multi-year research grants were awarded by the Gilbert Family Foundation, a private foundation established by Jennifer and Dan Gilbert of Detroit, MI, for the purpose of developing effective therapies that address the underlying genetic abnormalities in NF1. The foundation’s recent genomic therapy initiative awarded $12 million in multi-year research grants to several multi-disciplinary research teams identified through a rigorous, peer-reviewed process. UAB was awarded grants for four separate projects, which represents the largest number of grants awarded to any single institution. Other institutions with research teams receiving grants from the genome therapy initiative include: Duke University; Paris Descartes University; the University of California at Berkley; the University of California at San Diego; the University of Massachusetts; and Yale University.

A Focus on the Development of Genome-Guided Therapies 

The majority of therapeutic approaches for NF1 have focused on blocking the Ras/MAPK signaling pathway that is hyperactive in cells that have lost NF1 function due to gene mutation.  The NF1 gene encodes for a protein called neurofibromin, which regulates the activity of the Ras/MAPK cellular signaling pathway that helps to control cell growth and division.  The development of therapies that target Ras signaling has been an important approach in developing NF treatments, with the discovery of the effectiveness of MEK inhibitors such as selumetinib in reducing the size of plexiform neurofibromas being the most exciting advance.  Not all plexiform neurofibromas respond to MEK inhibitors, however, and none of the tumors completely disappears on treatment.  We therefore have been seeking additional therapies, and the primary focus of the UAB NF Research Program has been to explore methods of restoring function to the mutated NF1 gene or gene product. Our research team at UAB introduced this area of NF research, which has now gained increased attention and focus from the NF scientific community. The four UAB projects that have received funding from this initiative represent preclinical research efforts that will help to accelerate the development of therapies that could restore full or partial function to the mutated NF1 gene or gene protein.

• The first project focuses on the identification of drug compounds capable of reading through a type of truncating mutation called a premature stop, or nonsense mutation, which affects 20% of individuals with NF1. This type of mutation inserts a signal that tells the protein production machinery in the cell to stop production of neurofibromin before the complete protein is made, resulting in a truncated and nonfunctioning  protein. Drug compounds have been identified that have shown promise in overcoming the effects of premature stop mutations. The concept for this type of research was first developed by David Bedwell, Ph.D., chair of the UAB Department of Biochemistry and Molecular Genetics, who will serve as the principal investigator for the project.  The focus will be on identifying and testing drug compounds capable of reading through premature stop mutations in the NF1 gene, with the goal of allowing cells to produce a full-length, functional neurofibromin protein. 

• The next project, conducted by UAB investigator Bob Kesterson, Ph.D., in conjunction with researchers at Yale University, will utilize the CRISPR/Cas9 gene editing system to perform gene editing in NF1 animal models with mutations found in human patients. Dr. Kesterson’s previous research has used the CRISPR/Cas9 system to introduce human NF mutations into animal model systems. As part of the current project, the CRISPR/Cas9 will be used to directly correct the mutations that cause NF1 in a model system for the purpose of generating preclinical data that could serve as the foundation for clinical trials of genomic therapeutics that utilize gene editing.

• The third project, conducted by UAB investigator Deeann Wallis, Ph.D., in conjunction with researchers from the Royal Holloway University of London, focuses on correcting NF mutations in model systems using a technique called exon skipping, which causes cells to skip over mutations in the genetic code while still producing a functional protein. A gene is encoded in segments, called exons, which code for the amino acids of a protein, separated by introns, which are intervening sequences. The purpose of this project is to identify exons within the NF1 gene mutation that can be skipped while still maintaining function of the gene, allowing these mutations to be bypassed.

• The fourth project, led by UAB investigator Andre Leier, Ph.D., in conjunction with researchers from the University of California, San Diego, uses ribozyme therapy in NF1 mouse models with patient-specific mutations. Ribozymes are molecules that can be used to edit messenger RNA, allowing investigators to remove one end of the messenger RNA containing the faulty gene in order to correct the mutation.

We are excited by the opportunity pursue these projects and grateful for the support of the Gilbert Family Foundation.  I hope to have the opportunity to provide updates in the months and years to come on the progress of these and other research projects underway in the UAB NF Program.