# Combining new gene therapy with non-invasive spinal roots stimulation to improve synaptic plasticity at spino-muscular circuitry after spinal cord injury

> **NIH VA I01** · NORTHPORT VA MEDICAL CENTER · 2020 · —

## Abstract

Impaired ability of voluntary walking and bladder dysfunction is an acute problem among veterans with
spinal cord injuries (SCI). Results of recent studies, including our own, revealed that there are at least three
major factors known to limit recovery from SCI: (1) decreased neuronal excitability, (2) presence of axonal
growth/regeneration inhibitors, and (3) lack of neurotrophin support. Using animal models, we have recently
demonstrated that degradation of scar-related inhibitory Chondroitin Sulfate Proteoglycans (CSPGs) with the
enzyme Chondroitinase-ABC (ChABC), combined with AAV-based delivery of neurotrophin NT3, induced
partial improvements following mild contusion SCI. A potential disadvantage to the use of ChABC is that it is
not specific, i.e. degrades all CSPGs, including those that are important components of the extracellular matrix.
 In our search for more specific targets, we have recently demonstrated that one CSPG molecule, NG2,
known as a major obstacle to axonal regeneration following brain and spinal cord injury, blocks axonal
conduction, but other CSPGs tested did not. Acute administration of monoclonal NG2 function neutralizing
antibody (NG2-Ab; designed initially to prevent inhibitory effects of NG2 on axonal growth) prevents the
conduction block induced by acute injections of NG2 into the spinal cord. Intrathecal infusion of NG2-Ab, via
osmotic mini-pump for 2 weeks, however, induced only limited and transient improvements of motor function
following SCI. In an attempt to design an approach for safe, prolonged and clinically feasible delivery of NG2-
Ab, we have successfully created a new AAV-10 vector-based gene therapy tool for prolonged and clinically-
relevant delivery of a recombinant single chain variable fragment (scFv) anti-NG2 antibody: AAV-NG2Ab.
Results of preliminary experiments revealed that combined administration of AAV-NG2Ab and AAV-NT3
induced greater improvements, compared to ChABC/AAV-NT3, following mild (150 kDyn) contusions. Effects
of this novel gene therapy (AAV-NG2Ab/AAV-NT3) tool on motor recovery were, however, still limited in rats
with mild contusion and less obvious in rats with severe contusion SCI.
 In attempts to further improve the beneficial effects of AAV-NG2Ab/AAV-NT3 and expand improvements to
severe SCI models, we now propose to add a third treatment component, i.e. non-invasive repetitive electro-
magnetic stimulation over spinal vertebrae (rSEMS). We recently found that rSEMS strengthens transmission
and improves function of NMDA receptor at motoneuron synaptic inputs, which is required to initiate effects of
NT-3 at these inputs. Thus, in the proposed project we have designed a new additive treatment comprised of
AAV10-NG2Ab, AAV10-NT3 and rSEMS. In addition to a mild contusion model of injury, we propose to use
severe mid-thoracic contusions which are known to induce major deficits of motor function and bladder activity
in rat and human SCI. An important and novel aspect of this r...

## Key facts

- **NIH application ID:** 9898249
- **Project number:** 5I01BX004198-03
- **Recipient organization:** NORTHPORT VA MEDICAL CENTER
- **Principal Investigator:** Victor L Arvanian
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898249

## Citation

> US National Institutes of Health, RePORTER application 9898249, Combining new gene therapy with non-invasive spinal roots stimulation to improve synaptic plasticity at spino-muscular circuitry after spinal cord injury (5I01BX004198-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898249. Licensed CC0.

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