Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis.

TitlePreservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis.
Publication TypeJournal Article
Year of Publication2015
AuthorsJackson KL, Dayton RD, Orchard EA, Ju S, Ringe D, Petsko GA, Maquat LE, Klein RL
JournalGene Ther
Date Published2015 Jan
KeywordsAmyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Female, Forelimb, Genetic Therapy, HEK293 Cells, Humans, Male, Motor Activity, Paralysis, Rats, Sprague-Dawley, Trans-Activators

Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that requires upframeshift protein 1 (UPF1). This study demonstrates that human UPF1 exerts protective effects in a rat paralysis model based on the amyotrophic lateral sclerosis (ALS)-associated protein, TDP-43 (transactive response DNA-binding protein 43‚ÄČkDa). An adeno-associated virus vector (AAV9) was used to express TDP-43 throughout the spinal cord of rats, inducing reproducible limb paralysis, to recapitulate the paralysis in ALS. We selected UPF1 for therapeutic testing based on a genetic screen in yeast. The expression of human TDP-43 or human UPF1 in the spinal cord was titrated to less than twofold over the respective endogenous level. AAV9 human mycUPF1 clearly improved overall motor scores in rats also expressing TDP-43. The gene therapy effect of mycUPF1 was specific and reproducible compared with groups receiving either empty vector or green fluorescent protein vector controls. The gene therapy maintained forelimb motor function in rats that would otherwise become quadriplegic. This work helps validate UPF1 as a novel therapeutic for ALS and other TDP-43-related diseases and may implicate UPF1 and NMD involvement in the underlying disease mechanisms.

Alternate JournalGene Ther.
PubMed ID25354681
PubMed Central IDPMC4924570
Grant ListP30 GM092424 / GM / NIGMS NIH HHS / United States
P41 RR001646 / RR / NCRR NIH HHS / United States
R01 GM059614 / GM / NIGMS NIH HHS / United States