Rare diseases are those for which there are less than 5 sufferers for every 10,000 inhabitants. It is estimated that there are about 7,000 rare diseases that affect around 7% of the world population. One of them is CDKL5 deficiency disorder (CDD), a condition that was first documented less than 20 years ago and that causes seizures within the first few months of life, severe intellectual disability and motor impairment. CDD is a rare, untreatable, and difficult to diagnose disease, manifesting itself in one in 45,000 births worldwide. 90% of those affected by CDD are women.
The main limitation in the search for treatments against this rare disease is that mouse animal models do not develop epilepsy, one of the main symptoms of CDD, thus making it difficult to identify possible therapeutic strategies. Now, a study published on the cover of the prestigious journal Science Translational Medicine, led by Prof. Di Giovanni’s laboratory at Imperial College London, in which the Institute for Bioengineering of Catalonia (IBEC) participated, has identified that, in patients with CDD, there is an alteration in the perception of pain—more than 50% of caregivers report that their patients present a defective perception of pain—and that the CDKL5 protein is related to this process.
This new and previously unknown function associated with CDKL5 has also been observed in mice. According to expert Arnau Hervera from IBEC’s Molecular and Cellular Neurobiotechnology group and associate researcher at the Faculty of Biology at UB and at the Institute of Neurosciences (UBNeuro), who was also involved in the study: “We are very satisfied with the results obtained as it opens up a unique opportunity to test treatments for CDD in mouse models in preclinical settings prior to trials with real patients.”
The mechanism of pain and CDD
CDD disease is caused by the mutation of the CDKL5 gene, located on the X chromosome, and is strongly expressed in the central nervous system (CNS). This alteration causes the defective production of the CDKL5 protein, involved in neuronal development and synapse formation, affecting cognitive processes as important as learning and memory.
The present study has shown, for the first time, that the CDKL5 gene is also expressed in the Peripheral Nervous System (PNS). Specifically, in neurons related to pain perception, also called nociceptive neurons, located in the spinal ganglia. This behavior has been identified in both mice and human induced pluripotent stem cell nociceptors. “This unprecedented regulatory mechanism, dependent on the CDKL5 protein for pain perception, allows us to use sensitivity to nociceptive stimuli as an indicator of success in therapeutic trials based on mouse models,” says Arnau Hervera, who is also a member of CIBERNED. Indeed, this finding opens up an important route in the detection and monitoring of treatments against CDD: the use of mouse models.
The work has also shown that the deficiency of the CDKL5 protein also translates into defective innervation of the skin, which probably results in the deterioration of pain perception, as occurs in patients with CDD. “This discovery reveals that both gene therapy and other interventions aimed at restoring pain perception in patients with CDKL5 deficiency should target not only the brain but also the spinal ganglia and, therefore, the peripheral nervous system,” concludes Arnau Hervera.
Reference article: P. L. Montanara, A. Hervera, L. L. Baltussen, Th. H. Hutson, I. Palmisano, F. De Virgiliis, G. Kong, J. Chadwick, Y. Gao, K. Bartus, Q. A. Majid, N. Gorgoraptis, K. Wong, J. Downs, T. Pizzorusso, S. K. Ultanir, H. Leonard, H. Yu, D. S. Millar, N. Istvan, N. D. Mazarakis, S. Di Giovanni. Cyclin-dependent–like kinase 5 is required for pain signaling in human sensory neurons and mouse models. Science Translational Medicine, 2020.
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