Is VEGF a good candidate to promote peripheral axonogenesis by gene therapy?

Since peripheral axons have the inherent capacity to regenerate, in theory, complete structural and functional nerve recovery following injury appears possible. However, our poor knowledge of the molecular and cellular mechanisms involved in nerve repair still limits the therapeutic application of this intrinsic property, and the main treatment options currently available aim simply at surgically reconnecting severed nerve ends. Various experimental strategies have been developed, aimed at providing an extra neurotrophic support for the proper re-establishment of functional circuits. The first gene therapy strategies mainly focused on neuroprotection, which may help to optimise axonal re-growth and nerve repair. More recently, novel emerging concepts, derived from a better understanding of the cellular and molecular events involved in axonal degeneration and regeneration, have led to the definition of novel targets for intervention. In particular, VEGF, traditionally considered the main angiogenic growth factor, is emerging as a promising therapeutic molecule for neurodegenerative disorders. We have exploited the unique properties of vectors based on the Adeno-Associated Virus (AAV) to transduce bio-engineered muscle scaffolds in a rat model of peripheral nerve lesion, with the aim of manipulating the VEGF and NRG1 trophic loops. Whereas manipulation of the NRG1-ErbB system provides a significant therapeutic benefit in term of axonal density and motor function, contrary to our expectations overexpression of VEGF does not improve axonogenesis. The VEGF anti-atrophic and anti-apoptotic effect on the muscle tissue appears to impair the process of muscle degeneration within the graft, resulting in a mechanical obstacle for fiber regeneration and growth. The nerve fibers exposed to high levels of VEGF show an increased axonal diameter, but no change in the myelin layer thickness. Altogether, these results show that AAV-transduced muscle scaffolds are an valuable tool for influencing peripheral nerve fiber regeneration. Grant support: Compagnia di San Paolo and Regione Piemonte.