Exploring the Therapeutic Potential of Phosphorylated <i>Cis</i>-Tau Antibody in a Pig Model of Traumatic Brain Injury
Samuel S. Shin,
Vanessa M. Mazandi,
Andrea L. C. Schneider,
Sarah Morton,
Jonathan P. Starr,
M. Katie Weeks,
Nicholas J. Widmann,
David H. Jang,
Shih-Han Kao,
Michael K. Ahlijanian,
Todd J. Kilbaugh
Affiliations
Samuel S. Shin
Division of Neurocritical Care, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Vanessa M. Mazandi
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Andrea L. C. Schneider
Division of Neurocritical Care, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Sarah Morton
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Jonathan P. Starr
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
M. Katie Weeks
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Nicholas J. Widmann
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
David H. Jang
Resuscitation Science Center of Emphasis, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Shih-Han Kao
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Michael K. Ahlijanian
Pinteon Therapeutics, Inc., Newton, MA 02459, USA
Todd J. Kilbaugh
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Traumatic brain injury (TBI) results in the generation of tau. As hyperphosphorylated tau (p-tau) is one of the major consequences of TBI, targeting p-tau in TBI may lead to the development of new therapy. Twenty-five pigs underwent a controlled cortical impact. One hour after TBI, pigs were administered either vehicle (n = 13) or PNT001 (n = 12), a monoclonal antibody for the cis conformer of tau phosphorylated at threonine 231. Plasma biomarkers of neural injury were assessed for 14 days. Diffusion tensor imaging was performed at day 1 and 14 after injury, and these were compared to historical control animals (n = 4). The fractional anisotropy data showed significant white matter injury for groups at 1 day after injury in the corona radiata. At 14 days, the vehicle-treated pigs, but not the PNT001-treated animals, exhibited significant white matter injury compared to sham pigs in the ipsilateral corona radiata. The PNT001-treated pigs had significantly lower levels of plasma glial fibrillary acidic protein (GFAP) at day 2 and day 4. These findings demonstrate a subtle reduction in the areas of white matter injury and biomarkers of neurological injury after treatment with PNT001 following TBI. These findings support additional studies for PNT001 as well as the potential use of this agent in clinical trials in the near future.
