Women Researchers in NF – Adrienne L. Watson

The Value of Large Animal Models in Neurofibromatosis Research
Adrienne L. Watson, PhD, Therillume Inc.

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I began my research in the Neurofibromatosis field in 2009, as a graduate student in Dr. David Largaespada’s laboratory at the University of Minnesota. At this time, many novel preclinical models of Neurofibromatosis Type 1 (NF1) and Neurofibromatosis Type 2 (NF2) were coming out of some of the best laboratories in the world. This was the decade of mouse models of NF, including models that came out of the laboratories of Dr. David Gutmann, Dr, Nancy Ratner, Dr. Wade Clapp, and Dr. Luis Parada. In 2011, I was given the honor of a Young Investigator Award from the Children’s Tumor Foundation. This award kicked off my career in studying NF, and my passion for better understanding this complex disease and finding ways to improve the lives of patients. My work has been dedicated to developing novel preclinical animal models to study NF, and led to the creation of several mouse models, identification of critical signaling pathways that can be targeted to treat NF, and most impactfully, the first large animal models of both NF1 and NF2.

My journey to success is owed to the guidance of exceptional mentors.  Dr. David Largaespada was my graduate research advisor and has become a career-long collaborator and friend. Dr. Largaespada has brought new technologies like Sleeping Beauty and CRISPR/Cas9 to rare diseases like NF1 to develop better models and to understand the molecular pathways that impact disease progression. From the clinical perspective, Dr. Chris Moertel has been my guiding light, giving me the opportunity to interact with patients and families with NF, and allowing me to understand the importance of our work in helping his patients. Dr. David Gutman has also been a superfan of mine and has provided me with guidance and perspective in my research and my career. Finally, Dr. Nancy Ratner has been a friend and collaborator who has taught me the importance of working with the right team and going to the ends of the earth to find the scientific answers you seek.

The use of preclinical models in NF research has evolved significantly over the last 2 decades, driven by advancements in technology, increased understanding of the disease, and the need for more clinically relevant models. Here are some key ways in which animal research has evolved in neurofibromatosis research:

1. Use of Genetically Engineered Animal Models: The development of genetically engineered animal models, including mice and other organisms, has been a major advancement in NF research. The ability to knock out Nf1 and Nf2 in specific cell types at specific times has led to the development of critical preclinical models of various features of the disease. Animal models also have allowed researchers to study the effects of specific gene mutations on disease development and progression, providing valuable insights into genotype-specific effects.
2. Focus on Tumor Microenvironment: NF is characterized by the formation of tumors in various tissues. Animal research has evolved to include a greater emphasis on studying the tumor microenvironment, including the interactions between tumor cells, immune cells, and the surrounding tissue. This focus on the tumor microenvironment has provided insights into the factors, including the heterozygous field, that contribute to tumor growth and progression in NF.
3. Integration of Imaging Techniques: Advances in imaging techniques have revolutionized NF research by enabling non-invasive monitoring of disease progression and treatment response in animal models. Techniques such as volumetric magnetic resonance imaging (MRI) allow researchers to visualize and quantify tumor growth and evaluate the efficacy of therapeutic interventions.
4. Development of Preclinical Therapeutic Trials: Animal research in NF has evolved to include the development of preclinical therapeutic trials. These trials involve testing potential therapies in animal models to assess their safety, efficacy, and optimal dosing regimens. The use of animal models in preclinical trials helps identify promising therapeutic candidates and provides valuable data for designing and optimizing clinical trials in humans. Notably, the success of MEK inhibitors for plexiform neurofibromas was predicted by mouse models.
5. Integration of Translational Approaches: There is a growing emphasis on translational research in NF, aiming to bridge the gap between preclinical studies and clinical applications. Animal research has evolved to incorporate more translational approaches, such as the use of patient-derived xenograft models, where tumor cells from NF patients are implanted into animal models. These models allow researchers to study the response of patient-specific tumors to different treatments, facilitating personalized medicine approaches.

Overall, animal research in neurofibromatosis has evolved to encompass a broader range of models, techniques, and approaches. This evolution has enabled researchers to gain a deeper understanding of the disease, evaluate potential therapies more accurately, and accelerate the translation of preclinical findings into clinical practice. My contribution to the NF field is the development of the first large animal models of NF1 and NF2. While small animal models, such as mice, had been widely used in NF research, there was a growing recognition of the limitations of these models in fully recapitulating the disease phenotypes observed in humans. To overcome these limitations and augment the preclinical models that were being used, my team developed minipigs that harbored patient specific NF1 or NF2 mutations that led to phenotypes that recapitulated the disease phenotypes seen in human patients and have gained prominence in NF research.

The minipig models of NF1 and NF2 offer a closer resemblance to human physiology and allow for more accurate evaluation of potential therapies. Large animal models, particularly pigs, share many physiological and anatomical similarities with humans. This similarity allows researchers to study the disease in a more relevant context, as the responses and outcomes observed in these models are more likely to translate to human patients. Large animals have similar organ systems, immune responses, and metabolic processes, making them valuable tools for studying the complex mechanisms underlying NF. Our NF1 minipigs better recapitulated certain disease phenotypes such as optic pathway glioma, cutaneous neurofibromas, spontaneous loss of heterozygosity, and café au lait macules better than many of the models that came before them. Further, the size of the minipig is quite similar to an adult human, which enables researchers to perform surgical and interventional studies that are not feasible in smaller animals. For instance, pigs can undergo surgical procedures to implant devices or deliver therapies directly to affected tissues, allowing researchers to assess the efficacy and safety of these potential treatment types. These studies provide valuable insights into the feasibility and potential outcomes of interventions in human patients. Our work shed light on the advantages of large animal models in pharmacokinetic and safety studies. The larger body size of these animals allows for more accurate dosing and monitoring of drug levels, providing valuable data on drug distribution, metabolism, and elimination. The model was also very useful for pharmacodynamic studies not possible in human patients. Additionally, large animal models can help identify potential toxicities and adverse effects of therapeutic interventions, aiding in the development of safer and more effective treatments.  The ultimate goal of NF research is to develop therapies that can be translated into clinical practice. Large animal models play a crucial role in bridging the gap between preclinical studies and human trials. The data obtained from large animal models can provide critical evidence of safety, efficacy, and dosing regimens, helping to inform the design and optimization of clinical trials. This translational approach accelerates the development of potential treatments for NF patients.

It is my wish to see all NF patients cured of their disease. To make this dream a reality, scientists and clinicians throughout the world will have to continue to build collaborations, utilize novel technologies to study the disease, and rely on multiple preclinical models to safely bring effective therapies to patients. This will also take the support of foundations like the Children’s Tumor Foundation and the Gilbert Family Foundation, who continue to show support of the research and clinical trials for NF. I am very fortunate to have been a part of the story of NF and continue to watch this field closely for the next major developments!