NF1, Neurofibromin and Gene Therapy: Prospects of Next-Generation Therapy.

Neurofibromatosis type 1 [NF1] is an autosomal dominant genetic disorder affecting multiple organs. NF1 is well known for its various clinical manifestations, including café-au-late macules, Lisch nodules, bone deformity and neurofibromas. However, there is no effective therapy for NF1. Current therapies are aimed at alleviating NF1 clinical symptoms but not curing the disease. By altering pathogenic genes, gene therapy regulates cell activities at the nucleotide level. In this review, we described the structure and functions of neurofibromin domains, including GAP-related domain [GRD], cysteine-serine rich domain [CSRD], leucine-rich domain [LRD] and C-terminal domain [CTD], which respectively alter downstream pathways. By transfecting isolated sequences of these domains, researchers can partially restore normal cell functions in neurofibroma cell lines. Furthermore, recombinant transgene sequences may be designed to encode truncated proteins, which is functional and easy to be packaged into viral vectors. In addition, the treatment effect of gene therapy is also determined by various factors such as the vectors selection, transgene packaging strategies and drug administration. We summarized multiple NF1 gene therapy strategies and discussed their feasibility from multiple angles. Different protein domains alter the function and downstream pathways of neurofibromin.

[The neurobiology of learning difficulties: neurofibromatosis type 1 as a model for researching and treating learning disorders]. / Neurobiología de los trastornos del aprendizaje: neurofibromatosis de tipo 1 como modelo para investigar y tratar los trastornos del aprendizaje.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, with a prevalence of around 1:3500. The most important concern for patients and their families is the increased risk of developing benign and malignant tumours in the central and peripheral nervous systems. Up to 80% of patients, however, experience difficulties in learning processes. Symptoms compatible with attention deficit hyperactivity disorder are present in as many as 60% of patients. Learning difficulties are the chief cause of morbidity throughout their lives. DEVELOPMENT: Some recent studies have made it possible to offer a better description of the cognitive and developmental phenotype in patients with NF1. Similarly, advances in our understanding of the underlying molecular and cellular processes in cognitive impairment and access to sophisticated molecular genetics techniques have allowed a number of scientific disciplines to work together in the search for an understanding and potential solution to the cognitive disorders in this population. CONCLUSIONS: Preclinical studies show the enormous potential of certain pharmacological interventions. Transferring the results obtained in the treatment of learning difficulties in animal models of NF1 to the treatment of patients is a step that is currently under development. If it were effective, it would open the door to numerous areas of research that would rapidly increase our knowledge and the possibilities of intervention in this and many other learning disorders.