178 | Validating new strategies to treat behavioral deficits associated to neurofibromatosis type 1

Disorders of the Nervous System

Author: Evelin Cotella | Email: ecotella@immf.uncor.edu

Evelin Cotella , Rosa Salazar , Kassidy Reneau , Austen Fisher , Namrata Raut , Michael Jankowski , Elliott Robinson

1° Div. of Exp. Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
2° Dept. of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
3° Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET-UNC

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 and skin abnormalities, pain hypersensitivity and cognitive deficits. Cognitive symptoms of NF1 include impaired executive functioning, autistic features, speech and language delays, attention deficits, hyperactivity, and impulsivity. Our lab has focused on identifying behavioral abnormalities in a mouse model of NF1 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. 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.