Targeting TDP-43 splicing repression for ALS-FTD: mechanism-based gene therapy and fluid biomarker

Recent human studies strongly support the view that loss of TDP-43 splicing repression underlies the pathogenesis of ALS-FTD, a disorder spectrum currently without disease modifying therapy. To address this unmet need, we employ an AAV gene therapy approach to complement the loss of TDP-43 by delivering a novel splicing repressor (AAV.PHP.eB-CTR) to adult brain or spinal cord neurons, respectively, in a mouse model lacking TDP-43 either in forebrain or spinal motor neurons. We report that such a mechanism-based therapy when delivered during early symptomatic stage of disease prevents inclusion of cryptic exons and attenuates neuron loss. No overt phenotype is observed in aged control mice transduced with AAV.PHP.eB-CTR. These results validate a gene therapy to complement the loss of TDP-43 splicing repression. With our mechanism-based fluid biomarker to monitor loss of TDP-43 function, we are poised to provide for ALS-FTD an unprecedented opportunity clinical testing of this mechanism-based gene therapy.