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‘We use gene therapy to restore injured connections in the brain’

Interview with Joost Verhaagen

Joost VerhaagenWorldwide, there are 4 million people with a spinal cord injury, and each year sees some 130.000 new cases. After spinal cord injury, the connections between nerve cells in the brain and in the spinal cord are lost and fail to grow back. In patients this results in permanent disability, including paralysis below the level of the injury, and loss of sensorimotor, bladder and sexual function.

‘We want to find ways to promote axonal regeneration following brain and spinal cord injury’, says Joost Verhaagen, ‘and therefore we need to understand the neuron-intrinsic and extrinsic molecular mechanisms that frustrate repair’.

We are investigating whether we can reprogram injured neurons into a regenerative state’

Nerve cells in the brain and spinal cord do not turn on the molecular machinery required for vigorous regrowth of their injured axons. In contrast, peripheral nerve cells do regenerate successfully because they have a kind of ‘switch’ which turns on a robust regenerative machinery. ‘We have identified key molecular components (transcription factors) of this “switch”. We use these to activate the regeneration program in CNS neurons after a spinal cord lesion. In other words: we are investigating whether we can reprogram injured neurons into a regenerative state’.

The ‘switch’ proteins are delivered to injured neurons by gene therapy. Gene delivery with viral vectors has resolved the ‘delivery’ problem for neuroactive therapeutic genes. Viral vectors efficiently target injured neurons and delivery of the ‘switch’ genes occurs with high precision.

Regeneration also fails because inhibitory proteins around injured axons prevent long distance axon regeneration. ‘The chemorepulsive axon guidance protein Semaphorin3A is induced in injured spinal cord tissue. Interestingly, we have discovered that Semaphorin3A is also a component of perineuronal nets’, explains Verhaagen. Perineuronal nets are specialized extracellular matrix structures around neurons which stabilize the synapses embedded in the nets. Perineuronal nets have now taken center stage because they regulate axonal growth and synaptic plasticity, and therefore play a key role in neurological and psychiatric disease states.

Semaphorin 3ASemaphorin 3A  

Immunohistochemical staining of Semaphorin3A (red) in a perineuronal net which enwraps a par-valbumine (green) positive interneuron in the rat cortex

Verhaagen expects that neuronal reprogramming and modification of the extracellular matrix can be the basis for potential gene therapeutic approaches to promote axon regeneration, and he predicts that ‘in the future, the study of perineuronal nets during normal physiological processes, for instance learning and memory, and in brain diseases may result in entirely unexpected disease modifying treatments’.