2024-03-15 08:16:51
Our muscles are controlled by motor neurons (motoneurons) located in the spinal cord, which receive and integrate excitatory and inhibitory signals from the central nervous system, to ensure the fine coordination of our movements. After a spinal cord injury, a progressive disruption of motor neuron activity generates the emergence of spasticity symptoms. It is characterized by involuntary muscle contractions (spasms), co-contractions of functionally opposite muscles and hyperexcitability of reflexes (hyperreflexia).
Calpains, directly linked to the development of spasticity
The intrinsic factors responsible for this functional disruption have been the subject of several studies. Among the key players in these disturbances are calpains, enzymes whose activity increases significantly and inappropriately following spinal cord injury. Thus, these enzymes inappropriately cleave sodium channels (Nav1.6), impairing their inactivation and promoting hyperexcitability of motor neurons.
Furthermore, on the surface of motor neurons, calpains will also cleave membrane proteins KCC2 which will no longer be able to fulfill their role in the expulsion of chloride ions from the cell. An essential process for maintaining the inhibitory functions of motor neurons. The alteration of these mechanisms by calpains is therefore directly linked to the development of spasticity.
Viral vectors to improve the quality of life of patients suffering from spasticity
In this article published in the journal Molecular Therapy, the scientists reduced the levels of calpain in the motor neurons impacted by the lesion, while preserving the physiological functions of calpain in the other neurons of the spinal cord. To this end, they adopted an innovative gene therapy approach, using viral vectors recognized for their safety, and specially designed to specifically reduce the expression of calpain1 in motor neurons. Thanks to this targeted treatment, they reduced the expression of calpain1 in the treated motor neurons, leading to a notable restoration of KCC2 levels. This restoration validates the effectiveness of the treatment in limiting the deleterious activity of calpain1 following spinal cord injury. In addition, there is a significant reduction in spasticity symptoms. These results show that inhibition of calpain1 in motor neurons via gene therapy, using non-pathogenic AAV vectors, represents an innovative and promising approach to improve the quality of life of patients suffering from spasticity.
© Frederic Brocard
Figure : Two groups of spino-injured rats (1) received intrathecal injections (2) of a control solution or of viral vectors carrying RNA reducing the expression of the calpain1 gene. In control animals we observe a drop in KCC2 levels in transfected motor neurons (3) and the emergence of spasticity which results in an increase in muscle spasms, co-contractions of antagonistic muscles (4) and hyperreflexia. In animals that received the viral vectors, inactivation of calpain1 restores KCC2 levels (5) in transfected motor neurons and spasticity is significantly reduced (6).
Learn more:
Kerzonkuf M, Verneuil J, Brocard C, Dingu N, Trouplin V, Ramirez Franco JJ, Bartoli M, Brocard F, Bras H. Knockdown of calpain1 in lumbar motoneurons reduces spasticity following spinal cord injury in adult rats. Mol Ther. 2024 Jan 29. doi: 10.1016/j.ymthe.2024.01.029.
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#Gene #therapy #muscular #disorders #linked #spinal #cord #trauma
