Finding new strategies to treat behavioral deficits associated to neurofibromatosis type 1

COTELLA, EVELIN M.; SALAZAR, ROSA; GONZALEZ, L. SOFIA; RENEAU, KASSIDY; FISHER, AUSTEN A.; RAUT, NAMRATA G.R. ; JANKOWSKI, MICAHEL P. ; ROBINSON, J. ELLIOTT

San Diego

Congreso; Society for Neuroscience; 2022

Rasopathies are a family of genetic conditions characterized by aberrant amplification of the Ras/mitogen activated protein kinase (MAPK) signaling cascade. Neurofibromatosis type 1 (NF1) is an autosomal dominant Rasopathy caused by haploinsufiency of the NF1 gene, which codes for neurofibromin – a negative regulator of activated Ras. Symptoms of NF1 include increased risk for benign or malignant tumorigenesis, musculoskeletal abnormalities, hyper-pigmented macules, and cognitive deficits. Often, patients also present pain hypersensitivity. Cognitive symptoms of NF1 include impaired executive functioning, autistic features, speech and language delays, attention deficits, hyperactivity, and impulsivity. Based on work in rodent and fly models, the pathophysiology of behavioral and cognitive symptomatology may involve Ras-evoked excitation/inhibition (E/I) imbalance, as well as perturbations in neural circuits that release dopamine. Targeted gene therapies are a promising approach to treating these sequelae, as the expression of therapeutic proteins may be restricted to neural or glial populations of interest using unique gene regulatory elements or cell type-specific promoters/enhancer elements. Our lab has focused on identifying behavioral abnormalities in a mouse model of NF1 (Nf1+/- C57Bl/6J:129sv/J mouse) with the ultimate goal of designing viral vectors that can be administered systemically to reverse these effects. Using new adeno-associated viral vectors (AAVs) that can target populations of interest in the central and peripheral nervous system after intravenous injection, we screened AAV-encodable transgenes capable of therapeutically modulating Ras-MAPK signaling in NF1 haploinsufficient cells in vitro and in vivo, to correct behavioral and cellular phenotypes in NF1 model mice. These phenotype include alterations in cellular morphology in primary culture of embryonic hippocampal neurons and behavioral alterations such as fragmented grooming behavior, reduced psychomotor activity under bright light, and increased pain sensitivity assessed in the mechanical conflict-avoidance test. This work will provide important initial preclinical evidence for the utility of AAV-based gene therapies in the treatment of NF1 in non-oncological related symptoms.