Viral therapy strategies for treating cognitive deficits of neurofibromatosis type 1

COTELLA, EVELIN M.; SALAZAR, ROSA; CHESTNUT, BRENDAN; GONZALEZ, L. SOFIA; RENEAU, KASSIDY; FISHER, AUSTEN A.; ROBINSON, J. ELLIOTT

Philadelphia

Congreso; NF conference; 2022

Children Tumour Foundation

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 haploinsufficiency 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, hyperpigmented macules, and cognitive deficits. The 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.Despite the high impact of NF1 on patients’ quality of life, there are few effective treatments for the management of cognitive symptoms.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 designing viral vectors that can be utilized to recapitulate neurofibromin function and/or correct amplified MAPK signaling, with the goal of reversing behavioral effects observed in a rodent model of NF1 (Nf1+/- C57Bl/6J:129sv/J mouse). Here, we will present progress 1) identifying new adeno-associated viral vectors (AAVs) that can cell target populations of interest in the central nervous system after intravenous injection in NF1 mouse models; 2) screening AAV-encodable transgenes capable of therapeutically modulating RAS-MAPK signaling in NF1 haploinsufficient cells in vitro and in vivo, and 3) assessing the ability of novel AAV-based treatments to correct behavioral and cellular phenotypes in NF1 model mice. If successful, this work will provide important initial preclinical evidence for the utility of AAV-based gene therapies in the treatment of NF1.