Gene therapy for ALS by specifically overexpressing a pleiotropic chronokine, secreted α-Klotho (s-KL), in skeletal muscles
S Verdés(1,2,5) M Herrando-Grabulosa(1,3,4) R Guerrero-Yagüe(1,2,5) M Leal-Julià(1,2) A Onieva(1,2,5) J Roig-Soriano(1,2,5) N Gaja-Capdevila(1,3,4) M Chillon(1,2,5,6) X Navarro(1,3,4) A Bosch(1,2,4,5)
1:Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB); 2:Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona (UAB); 3:Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona (UAB); 4:Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III; 5:Unitat Mixta UAB-VHIR, Vall d’Hebron Institut de Recerca (VHIR); 6:Institut Català de Recerca i Estudis Avançats (ICREA)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of cortical and spinal motoneurons (MNs). Denervation of endplates and axonal retraction is thought to lead, in a “dying-back” pattern, to the death of MNs and subsequent muscle atrophy. ALS neuropathology is mainly associated with oxidative stress, inflammation, excitotoxicity, and mitochondrial dysfunction while chronokines like α-Klotho (α-KL) may counteract some of these pathways.
In the SOD1ᴳ⁹³ᴬ mouse model we have found decreased mRNA levels of α-KL in skeletal muscles, motor cortex and lumbar spinal cord. Furthermore, in rat spinal cord organotypic cultures, the overexpression of α-KL protects spinal MNs from glutamate-induced excitotoxicity.
Given the pleiotropic beneficial properties of α-KL, we hypothesized that boosting the expression in skeletal muscles through a gene therapy treatment would protect muscles from atrophy and prevent neuronal loss in SOD1ᴳ⁹³ᴬ mice. Our results show that the overexpression of secreted α-KL in muscles enhances motor function and delays disease onset as evidenced by rotarod and grip strength tests. Improvement of the functional outcome is corraborated by increased compound muscle action potential amplitudes of the tibialis anterior and the plantar interossei muscles compared to non-treated controls. Increased amplitude of motor evoked potentials also reflects the preservation of central connectivity between upper and lower MNs. All this correlates with a preservation of motoneurons, a higher number of innervated neuromuscular junctions and a heavier gastrocnemius muscle. These findings indicate that increasing the secretion of α-Klotho by muscles is a promising approach for promoting functional improvement in ALS.