Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.This work was supported by grants from The Progeria Research Foundation (PRF 2016-65) and the Spanish MINECO (PID2019-106279RB-I00, PID2019-108489RBI00). The authors thank Fundación La Caixa (A.G.), CEI Moncloa (N.I.M.-R.), MINECO (F.J.O.-N. and M.B.) and Ministerio de Ciencia, Innovación y Universidades (N.K.-F.) for predoctoral fellowships. The authors thank C. López-Otín for kindly donating LmnaG609G/G609G progeroid and their corresponding wild-type fibroblasts and UCM’s CAIs Cytometry and Fluorescence Microscopy, Genomics, NMR, and Mass Spectrometry, for their assistance. The CNIC is supported by the Ministerio de Ciencia e Innovación, the Instituto de Salud Carlos III, and the pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant SEV-2015- 0505). The generation of the antiprogerin antibody was funded by the Wellcome Trust (098291/Z/12/Z to S.N.).S

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice

Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCIassociated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 μM, KD = 1.3 nM; inactive at LPA1,3−6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI

Validación del receptor LPA2 como nueva diana terapéutica para el tratamiento del daño medular

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 22-04-2022Spinal cord injury (SCI) involves a permanent damage to the spinal cord which can lead into permanent neurological impairments that have an enormous impact in the quality of life of affected people. The pathology of SCI is multifaceted, complex, and yet to be fully understood. Once produced the primary injury responsible of the SCI, normally related with a traumatic impact or with the appearance of a tumor, infections or degenerative processes, the only pharmacological option is to treat the secondary damage and to limit the disruption of spinal connectivity. However, there is no effective clinical treatment for SCI, since current therapies are limited to surgical decompression and the administration of anti-inflammatory drugs. Hence, it is clear that new pharmacological approaches are needed to improve SCI patient condition. In this regard, inhibition of the type 2 lysophosphatidic acid (LPA2) receptor signaling has recently emerged as a new therapeutic option to limit the SCI associated damage. However, the validation of this approach has been limited by the lack of antagonists of the LPA2 receptor. In this regard, only one compound (Cpd35, Figure 1) has been characterized as a potent (IC50 value at LPA2 of 0.017 μM) and selective LPA2 antagonist (IC50 values >50 μM at LPA1 and LPA3 receptors)...El daño medular implica una lesión permanente en la médula espinal que puede dar lugar a deficiencias neurológicas permanentes, con un gran impacto en la calidad de vida de las personas que la padecen. La patología del daño medular es polifacética, compleja, y aún no se ha llegado a conocer por completo. Una vez producida la lesión primaria responsable del daño, normalmente asociada a un traumatismo o a la aparición de un tumor, infecciones o procesos degenerativos, la única opción farmacológica es tratar el daño secundario y limitar el bloqueo de la conectividad medular. Sin embargo, no existe un tratamiento clínico eficaz para el daño medular, ya que las terapias actuales se limitan a la descompresión quirúrgica y a la administración de fármacos antiinflamatorios. Por lo tanto, es necesario buscar nuevos enfoques farmacológicos para mejorar el estado de los pacientes con lesión medular. En este sentido, la inhibición de la señalización del receptor de ácido lisofosfatídico tipo 2 (LPA2) ha surgido recientemente como una nueva opción terapéutica para limitar el daño asociado a la lesión medular. Sin embargo, la validación de esta aproximación se ha visto condicionada por la escasez de antagonistas del receptor LPA2. En este sentido, sólo un compuesto (Cpd35, Figura 1) ha sido caracterizado como un antagonista potente (CI50=0.017 μM) y selectivo del receptor LPA2 (CI50 >50 μM en los receptores LPA1 y LPA3)...Fac. de Ciencias QuímicasTRUEunpu

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration.

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 μM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP