Tarun Sontam

Background: Spinal cord injury (SCI) is a form of traumatic and/or degenerative damage to the spinal cord that dramatically impacts quality of life and can ultimately lead to severe functional effects such as loss of mobility and/or sensation. Around the world, there are about 930,000 new cases of SCI added each year, with up to 90% of cases due to traffic accidents, violence, sports, and falls.¹ No cure exists for SCI, and almost all SCIs are currently managed with a course of steroids followed by physical/occupational therapy to control symptoms.² One reason for the poor prognosis seen in many SCI patients is that the central nervous system (CNS) has little regenerative potential and therefore limited functional recovery following injury.² Previous studies have shown that blocking phosphatase and tensin homolog (PTEN) in retinal ganglion cells increases regeneration of the optic nerve.³ These findings suggest PTEN as a possible therapeutic target for the treatment of SCI.

Objective: In this narrative review, we explored the efficacy of blocking PTEN in spinal cord neurons and the impacts it has on structural regeneration and functional recovery following spinal cord injury.

Search Methods: An online search in the PubMed database was conducted using the following keywords: “PTEN”, “SCI”, “axon regeneration”, “functional outcomes”. Papers published before 2017 were excluded from the search.

Results: Administration of a PTEN antagonistic peptide (PAP) in vitro was shown to induce significantly greater neurite outgrowth in E19 mouse cortical neurons and 8-week-old mouse dorsal root ganglion (DRG) neurons compared to a control TAT peptide (CTP).⁴ In an in vivo study using 9-week-old male mice with a 1-mm-deep dorsal transection lesion at T7 to model SCI, injection of PAP into the sensorimotor cortex induced significant corticospinal tract (CST) axon sprouting rostral to the lesion compared to CTP treatment.⁴ In another study, injection of a PTEN inhibitor tissue gene nerve in rats with a contusion at the T9-T10 level led to significantly increased bladder contraction pressure and significantly decreased bladder intercontractional interval compared to the SCI only group.⁵ Concurrent constitutive activation of rapidly accelerated fibrosarcoma kinase (B-RAF), a neuron-intrinsic molecule critical for neurotrophin-induced sensory axon outgrowth, in addition to PTEN inhibition in 6-week-old mice with crushed T10-T11 segments led to numerous DRG axons to grow from 250-2000 mm across the lesion site.⁶ Finally, concurrent PTEN interference with left forepaw training in mice with crushed left dorsal cords at C5 led to significantly lower error percentage of the left forepaw during horizontal ladder testing and showed significantly improved and more frequent left forepaw usage during the rearing test compared to the control and PTEN inhibition only groups.⁷

Conclusions: Studies have shown that inhibition of PTEN leads to improved growth of descending fibers and enhanced functional recovery following SCI.^4-7 Co-targeting other neuron intrinsic factors like B-RAF and utilizing rehabilitative training in addition to PTEN inhibition provides a synergistic effect on axon regeneration.^6-7 Future directions include looking at the role of PTEN inhibition in cancer development given its prominent role as a tumor-suppressor gene.

Works Cited:

1.  Injury GBDTB, Spinal Cord Injury C. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. Jan 2019;18(1):56-87. doi:10.1016/S1474-4422(18)30415-0
2. Eckert MJ, Martin MJ. Trauma: Spinal Cord Injury. Surg Clin North Am. Oct 2017;97(5):1031-1045. doi:10.1016/j.suc.2017.06.008
3. Huang ZR, Chen HY, Hu ZZ, Xie P, Liu QH. PTEN knockdown with the Y444F mutant AAV2 vector promotes axonal regeneration in the adult optic nerve. Neural Regen Res. Jan 2018;13(1):135-144. doi:10.4103/1673-5374.224381
4. Bhowmick S, Abdul-Muneer PM. PTEN Blocking Stimulates Corticospinal and Raphespinal Axonal Regeneration and Promotes Functional Recovery After Spinal Cord Injury. J Neuropathol Exp Neurol. Jan 20 2021;80(2):169-181. doi:10.1093/jnen/nlaa147
5. Cho YS, Kim SJ, Kim KH. Evaluation of PTEN Inhibitor Following Spinal Cord Injury on Recovery of Voiding Efficiency and Motor Function Observed by Regeneration in Spinal Cord. Int Neurourol J. Nov 2020;24(Suppl 2):104-110. doi:10.5213/inj.2040448.224
6. Noristani HN, Kim H, Pang S, Zhong J, Son YJ. Co-targeting B-RAF and PTEN Enables Sensory Axons to Regenerate Across and Beyond the Spinal Cord Injury. Front Mol Neurosci. 2022;15:891463. doi:10.3389/fnmol.2022.891463
7. Pan L, Tan B, Tang W, et al. Combining task-based rehabilitative training with PTEN inhibition promotes axon regeneration and upper extremity skilled motor function recovery after cervical spinal cord injury in adult mice. Behav Brain Res. May 7 2021;405:113197. doi:10.1016/j.bbr.2021.113197