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.

In early November, several colleagues from the UAB NF Program attended the 2018 NF Conference in Paris. The annual NF Conference is an international meeting of NF scientists and clinicians that is usually held in the U.S. and is organized by the Children’s Tumor Foundation. This year CTF partnered, for the first time, with colleagues in Europe to further promote international scientific collaboration. As a result, the meeting attracted a larger international audience and was possibly the largest NF research meeting in history. Estimated attendance was approximately 900, which is far larger than the usual NF Conference attendance. The large attendance in part reflects the growing recognition of the importance of NF to our understanding of fundamental biological processes, particularly the initiation and progression of cancer, as well as the maturity of the techniques that are now available to investigate NF.

Regional Highlights

The most prestigious national award presented annually by CTF is the Friedrich von Recklinghausen Award, named for the German physician who first described ‘von Recklinghausen’s disease,’ now known as neurofibromatosis type 1. We extend our most sincere congratulations to Director of the UAB Medical Genomics Laboratory Ludwine Messiaen, Ph.D., named the 2018 recipient of the Friedrich von Recklinghausen Award, presented to individuals in the professional neurofibromatosis community who have made significant and lifelong contributions to neurofibromatosis research or clinical care. 

Dr. Messiaen’s recognition with this award can be attributed to the numerous contributions she has made to the field of NF research. She became the first scientist to establish a practical, reproducible, and valid mutation testing method for the routine molecular diagnosis of NF1. Under Dr. Messiaen’s direction, the UAB Medical Genomics Laboratory is viewed in the medical and scientific communities as the gold standard and world leader of genetic testing for all forms of NF and has identified upwards of 3,000 distinct pathogenic NF1 mutations. Using this vast catalogue of variants, Dr. Messiaen has published numerous studies of genotype/phenotype correlations, providing information about the expected course of NF1 with a specific type of NF1 mutation. This information is helpful for both clinicians and patients in gaining a better understanding of the symptoms that are likely to be most prominent with a specific type of NF1 mutation. While this is not possible for every mutation, for some it is possible.

In addition to these achievements, Dr. Messiaen discovered a new genetic cause of schwannomatosis, specifically mutations in a gene designated LZTR1. This discovery has opened the way toward diagnostic testing and new approaches to study the biology of schwannomatosis. Most importantly, the UAB Medical Genomics Laboratory under Dr. Messiaen’s leadership has maintained an unparalleled commitment to serving clinicians and patients, always going the extra mile to assist clinicians and provide whatever support and help is needed regarding the process of mutation testing and validation.

Scientific Perspective

Several reports were provided during the conference regarding various clinical trials. Physicians from the National Cancer Institute (NCI) reported the results of a clinical trial indicating that selumetinib has continued to show efficacy in reducing the size of plexiform neurofibromas. The NCI clinical trial, which included a larger group of patients than previously studied, indicated that selumetinib was effective in reducing the size of plexiform neurofibromas in approximately 70% of patients with NF1. A trial of another type of drug called cabozantinib is also showing success in reducing the size of plexiform neurofibromas, through a mechanism different from selumetinib. There is now evidence that various approaches to treatment are gaining traction in treating plexiform neurofibromas, which was not the case a short time ago.

After four days of meetings, there was an interesting closing session of the conference entitled “NF: Past, Present, and Future,” providing reflections on how NF research has grown over the years. I’ve been engaged in the field for 35 years now, and those of us who began our work more than three decades ago could never have imagined where it would take us. We have been privileged to experience a remarkable evolution in the field of NF research during that timespan, and the ground that has been covered in the field is staggering. It was encouraging to see many young investigators present at the meeting and to know that the opportunities they face are very different from when the field was in its infancy 35 or more years ago. The work these young investigators are doing gives us great hope that that the pace of discovery for new and promising NF treatments will continue to accelerate.

Highlights of Australia Visit

I recently returned from a visit to Melbourne, Australia, where I met with the NF team affiliated with the Royal Children’s Hospital and the Murdoch Children’s Research Institute. The NF Clinical Trials Consortium has benefitted from a long-term collaboration with the Australian NF team; during this trip, I met with the group of investigators who conducted the clinical trial evaluating the effectiveness of lovastatin in improving cognitive problems in people with NF1. Lovastatin is a widely-used cholesterol-lowering drug; in previous mouse studies, it was shown to improve learning in the mouse NF1 model, perhaps based on interference with Ras binding to the cell membrane. Based on the results of these studies, some parents of children with NF1 asked for prescriptions of lovastatin for their children. While lovastatin is a relatively safe medication, there are side effects to be considered when prescribing it, especially for children.

The clinical trial evaluating the effectiveness of lovastatin for learning problems in NF1, known as the STARS study, was conducted through the NF Clinical Trials Consortium. Serving as the lead investigators, the Australian research group had responsibility for study design, recruitment of many of the participants, and data evaluation. The STARS study showed that lovastatin was not an effective treatment for learning problems in NF1. This finding was important because it demonstrated that it’s not appropriate to expose a child with NF1 to the side effects of this medication if the goal is to improve cognitive function. During my visit, the research team also shared information about other exciting work in which they are engaged related to neurocognitive issues in NF1, as well as other areas.

Also during my visit, I was honored to speak at an event held by the Australian NF patient advocacy group, the Children’s Tumour Foundation. This organization is similar to the Children’s Tumor Foundation in the U.S., as it serves as a major source of patient advocacy for NF in adults and children in Australia. The event had robust attendance and featured numerous speakers from around the region. I was also grateful to have the opportunity to connect with Australian NF families to discuss their challenges and concerns, which are much the same as those faced by NF families in the U.S. and elsewhere in the world. My discussions with these families are a reminder that NF is an international condition that affects individuals and families in a similar way regardless of race, ethnicity, or socioeconomic status.

As I mentioned in the previous blog, the 2018 NF Conference will be held in Paris in November, which is the first time this international conference has been held outside the U.S. Our group from UAB will be well represented at the conference, with plans to provide several poster presentations and at least one platform presentation summarizing our drug discovery initiatives and progress in clinical trials. Our lab work is focused on restoring function to the mutated NF1 gene or gene product; we’ve recently obtained renewed funding to advance these projects to the next stage, and I’ll discuss these developments in a future blog.

Guidelines for Finding an Experienced NF Program

Following on the conversation I had with patients and families in Australia, a commonly asked question from individuals and families affected by NF is: How do I find an experienced NF program? Sometimes this is a challenging task, especially for people who don’t live near large cities or major academic centers. For those who do live near major academic medical centers, it’s important to know that most of these centers have practitioners who are experienced in managing NF, although they may or may not have a dedicated NF clinic.

An important resource for locating an experienced clinician or clinic is to check the “Find a Doctor” list of NF clinics that is maintained and regularly updated on the Children’s Tumor Foundation (CTF) web site (www.ctf.org/understanding-nf/find-a-doctor). To be placed on this list, clinics much submit initial information, as well as annual renewal information to remain on the list. As part of the renewal process, NF clinics are asked whether their program is engaged in clinical research, whether they see both adult and pediatric patients, and how care transitions from adult to pediatric patients are managed. Providing a continuum of care for pediatric and adult patients can be challenging if NF programs don’t have clinicians with experience in treating both children and adults. Other important questions in evaluating the quality of an NF program include:
  • How many patients are seen in the clinic?
  • Does the clinic provide access to a consistent group of clinicians?
  • What is the capacity to coordinate care with other specialties?
  • Is the NF program participating in clinical studies and publishing the results?
  • Is the NF program participating in national and international NF conferences?

These measures are indicators of a program’s commitment to providing the highest level of NF care and also serve as the hallmark of a center of excellence for an NF clinic.