Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials.

Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.

Potential endpoints for assessment of bone health in persons with neurofibromatosis type 1.

Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.