Zhigang He, Boston Children’s Hospital, Boston, USA

Developing a safe strategy for promoting axon regeneration and functional recovery after spinal cord injury

Funded in: 2015, 2016, 2017, 2018


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Problem: Axon regeneration is limited in the CNS. PTEN deletion, a promising target, might however not be safe.

Target: Osteopontin and the addition of a growth factor might be a promising alternative target.

Goal: This might lead to the development of clinically applicable neural repair strategies.

 

PTEN deletion is an effective genetic strategy of promoting the regeneration of injured corticospinal tract (CST) axons. However, PTEN is a tumor suppressor, a gene controlling the cell cycle; Shutting down or mutating this gene might lead to tumor formation. Therefore, it might not be an ideal target for clinical intervention. Thus, it is desirable to develop a safe strategy of mimicking the effects of PTEN deletion.

Recently, the team was analyzing the mechanisms underlying optic nerve regeneration mediated by PTEN deletion. They found that the subtype of retinal ganglion cells expressing osteopontin (OPN) showed dramatically increased axon regeneration upon PTEN deletion. Strikingly, forced expression of OPN plus a growth factor, either IGF or BDNF, mimics the regeneration-promoting effects of PTEN deletion in the optic nerve injury model.

Based on the similarities between optic nerve regeneration and CST regeneration, this proposed study will examine the hypothesis that a similar combinatorial treatment might, like PTEN deletion, promote CST regeneration and functional recovery. They will focus on subacute and chronic SCI models.

First, they will assess the role of viral-assisted expression of OPN and IGF-1 on promoting CST axon regeneration and functional recovery.

Second, the experiments will be conducted to assess the effects of viral-assisted expression of OPN and IGF-1 on enhancing the regeneration of other descending axon tracts and functional recovery.

Third, we will examine the effects of systematic delivery of OPN and IGF-1 on axon regeneration and functional recovery in SCI models.

In addition to full length OPN, they will also aim towards developing OPN-based peptides for possible translational applications. The team around Zhigang He expects that this series of studies will lead to the development of clinically applicable neural repair strategies.