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. 2023 Jun 24;11(7):1807.
doi: 10.3390/biomedicines11071807.

Exploring the Therapeutic Potential of Phosphorylated Cis-Tau Antibody in a Pig Model of Traumatic Brain Injury

Samuel S Shin  1 , Vanessa M Mazandi  2 , Andrea L C Schneider  1   3 , Sarah Morton  2   4 , Jonathan P Starr  2   4 , M Katie Weeks  2   4 , Nicholas J Widmann  2   4 , David H Jang  4   5 , Shih-Han Kao  2   4 , Michael K Ahlijanian  6 , Todd J Kilbaugh  2   4
Affiliations

Exploring the Therapeutic Potential of Phosphorylated Cis-Tau Antibody in a Pig Model of Traumatic Brain Injury

Samuel S Shin et al. Biomedicines. .

Abstract

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.

Keywords: PNT001; TBI; phosphorylated tau; tau; traumatic brain injury.

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Conflict of interest statement

Michael Ahlijanian is an employee of Pinteon Therapeutics and received financial compensation.

Figures

Figure 1
Figure 1
Schematic of the study. Data from DTI database of sham pigs at 24 h and 14 days were compared to the PNT001-treated CCI group and vehicle-treated CCI group. LP = lumbar puncture, PNT = PNT001.
Figure 2
Figure 2
FA map showing difference between sham vs PNT-treated CCI group (top) and sham vs vehicle-treated CCI group (bottom) at 1 day following injury. The red–yellow regions show FA-reduced areas as compared to sham group.
Figure 3
Figure 3
DTI parameter comparison between vehicle-treated CCI group and PNT-treated pigs normalized to sham group at 1 day. Region specific changes in FA (A) and MD (B) are shown here.
Figure 4
Figure 4
FA map showing difference between sham vs PNT001-treated CCI group (top) and sham vs vehicle-treated CCI group (bottom) at 14 days. The red regions show FA-reduced areas as compared to sham group. PNT = PNT001.
Figure 5
Figure 5
DTI parameter comparison between vehicle-treated and PNT001-treated CCI groups normalized to sham group at 14 days. PNT = PNT001. * p < 0.05. Region specific changes in FA (A) and MD (B) are shown here.
Figure 6
Figure 6
Plasma levels of biomarkers over 14 days. NfL (A), GFAP (B), and UCHL-1 (C) are displayed at 1–4-day intervals during the acute-to-subacute period following TBI. The biomarker assay lacked the sensitivity to detect pig plasma tau. ** p < 0.01.
Figure 7
Figure 7
CSF levels of biomarkers over 14 days. NfL (A), GFAP (B), tau (C), and UCHL-1 (D) are displayed at two time points: 1 h and 14 days following TBI. PNT = PNT001.
See this image and copyright information in PMC

References

    1. Shin R.W., Iwaki T., Kitamoto T., Tateishi J. Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer’s disease brain tissues. Lab. Investig. 1991;64:693–702. - PubMed
    1. Cleveland D.W., Hwo S.Y., Kirschner M.W. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J. Mol. Biol. 1977;116:207–225. doi: 10.1016/0022-2836(77)90213-3. - DOI - PubMed
    1. Tagge C.A., Fisher A.M., Minaeva O.V., Gaudreau-Balderrama A., Moncaster J.A., Zhang X.L., Wojnarowicz M.W., Casey N., Lu H., Kokiko-Cochran O.N., et al. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain. 2018;141:422–458. doi: 10.1093/brain/awx350. - DOI - PMC - PubMed
    1. Kondo A., Shahpasand K., Mannix R., Qiu J., Moncaster J., Chen C.H., Yao Y., Lin Y.M., Driver J.A., Sun Y., et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature. 2015;523:431–436. doi: 10.1038/nature14658. - DOI - PMC - PubMed
    1. Mez J., Daneshvar D.H., Kiernan P.T., Abdolmohammadi B., Alvarez V.E., Huber B.R., Alosco M.L., Solomon T.M., Nowinski C.J., McHale L., et al. Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017;318:360–370. doi: 10.1001/jama.2017.8334. - DOI - PMC - PubMed