CRISPR/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide

Pain
Aubin MoutalRajesh Khanna

Abstract

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain. Targeted intrathecal delivery of guide RNA/Cas9 nuclease plasmid in combination with a cationic polymer was used to generate allele-specific C-terminal truncation of neurofibromin, the protein encoded by the Nf1 gene. Rats with truncation of neurofibromin, showed increases in voltage-gated calcium (specifically N-type or CaV2.2) and voltage-gated sodium (particularly tetrodotoxin-sensitive) currents in dorsal root ganglion neurons. These gains-of-function resulted in increased nociceptor excitability and behavioral hyperalgesia. The cytosolic regulatory pr...Continue Reading

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Citations

Apr 19, 2018·Expert Opinion on Therapeutic Targets·James A Walker, Meena Upadhyaya
Aug 25, 2017·Channels·Aubin MoutalRajesh Khanna
Feb 9, 2019·Biomaterials Science·Joon Eoh, Luo Gu
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May 31, 2019·Pain·Daniel BullockMichael Costigan
Mar 28, 2019·Molecular Neurobiology·Aubin MoutalRajesh Khanna
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Dec 20, 2018·Molecular Neurobiology·Jie YuRajesh Khanna
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Nov 5, 2019·Channels·Aubin MoutalRajesh Khanna
Aug 11, 2020·Pain·Kimberly GomezRajesh Khanna
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Apr 16, 2018·Neuroscience·Aubin MoutalRajesh Khanna
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