Inducible Constitutively Active AKT as a Gene Therapy to Restore Function in Chronic Spinal Cord Injury

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Description

Abstract Recent advances in spinal cord injury (SCI) medicine have revealed the potential for neuromodulation to target spared spinal tracts to elicit a restoration of function in chronic stages of SCI. Leveraging growth and intrinsic properties of spared axons can therefore be an effective approach to recover function in chronic SCI. Our group has optimized the use of retrogradely transported AAVs (AAVrg) to target spared axons in chronic SCI and demonstrated that augmenting the mTOR pathway via PTEN-knockout using AAVrg''s can improve locomotor abilities in mice with chronic injuries. Several outstanding questions remain regarding the mechanisms and long-term effects of sustained mTOR pathway hyperactivity in neurons including: 1) are locomotor improvements contingent upon sustained hyperactivity in the mTOR pathway (i.e. do locomotor improvements manifest from changes to intrinsic properties that would reverse upon removal of mTOR pathway stimulation, or are they a manifestation of structural axon growth); and 2) what are the long-term effects of sustained mTOR pathway hyperactivity on neuronal health and metabolism? To address these outstanding questions, we have developed an AKT InducibleVector- Expression system (AKTIVE) to temporally control the intensity and duration of mTOR pathway hyperactivity. We will use our AKTIVE system to toggle on/off increased activity in the mTOR pathway by expressing a constitutively active AKT (myrAKT) in a doxycycline-inducible manner in spared spinal tracts and determine the effects on locomotor recovery, axon growth and sprouting, as well as elucidate the effects of sustained vs transient myrAKT expression on neuronal health and metabolism. We hypothesize that a transient expression of myrAKT will result in sustained locomotor improvements, increased axon growth below the lesion, and that limiting the expression of myrAKT to a few weeks will restore normal metrics of metabolism in neurons (autophagy, mitophagy, and mitochondrial function) relative to permanent and sustained myrAKT expression. Results from our experiment will provide invaluable insights into the role of the mTOR pathway in ongoing neuronal functions in chronic SCI, as well as demonstrate the ability for transient AKT hyperactivity to affect locomotor abilities through spared axon tracts. Further, we will have demonstrated the safety and feasibility of combining inducible gene-therapy approaches for use in chronic SCI in a manner applicable to any mammalian species. Our collective efforts will set the foundations for future studies aimed at testing and optimizing our AKTIVE genetherapy approach in larger animal models.
StatusActive
Effective start/end date2/1/241/31/27

Funding

  • KY Spinal Cord and Head Injury Research Trust: $100,000.00

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