Barcelona, Spain, September 8, 2022 – Accure Therapeutics, a private translational R&D engine at clinical stage in the Central Nervous System (CNS) field, today announces the publication of a preclinical efficacy study in the special issue of “Role of Matrix Metalloproteinases in disease” of the peer-reviewed journal Biomedicines. The paper, “The Gelatinase Inhibitor ACT-03 Reduces Gliosis in the Rapid Kindling Rat Model of Epilepsy, and Attenuates Inflammation and Loss of Barrier Integrity In Vitro” is focused on determining the drug’s mechanism that lead to the reduction of symptoms, namely seizure activity, cognitive decline and neuronal loss, in preclinical animals models of epilepsy.
In a previous publication entitled “The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects”, Accure Therapeutics (ATX) and its collaborators investigated the disease modifying capacity of ACT-03 in two preclinical animal models of epilepsy, observing a clear and long-lasting decrease of seizure activity after an initial brain insult and amelioration of the cognitive decline and neuronal lost related to the epileptogenesis process. The observed efficacy was linked to inhibition of MMP9 and MMP2 according to Western blot analysis.
In the publication ATX is announcing today, the pathological processes that are modulated by ACT-03 treatment have been investigated to provide more insight in the potential uses of ACT-03. For this purpose, ATX together with their collaborators at Amsterdam UMC and University of Amsterdam, has studied the effects of ACT-03 treatment on astrogliosis and microgliosis in the brain of kindled rats, and further investigated the cellular and molecular alterations in vitro using astrocytes and brain endothelial cultures, with a focus on neuroinflammatory markers and endothelial barrier integrity.
Results indicate that ACT-03 attenuates, in a significant manner, seizure-induced astro- and microgliosis in brain tissue of kindled rats. In vitro, under neuroinflammatory conditions, ACT-03 has been found to reduce the expression of various pro-inflammatory factors and transcriptional regulators related to neuroinflammatory processes such IL-1β, IL-6, TGFβ-R1, TGFβ-R2, COX2, TGFβ, ICAM1, MMP3 and cFOS.
In regards the effect of ACT-03-treatment on the integrity of the blood-brain barrier (BBB), albumin immunohistochemistry did not show extravasation of the blood-borne protein albumin into the parenchyma in the rapid kindling rat model, suggesting a protective of ACT-03 at BBB level. This finding has been confirmed in an in vitro cellular model of the BBB, where the treatment of the cell co-culture with ACT-03 under proinflammatory conditions preserves the integrity of the barrier and prevents leakage.
Overall, published results show that ACT-03 reduces astro- and microgliosis in the rapid kindling model, and attenuates inflammation and loss of BBB integrity. These data mechanistically support the antiseizure and antiepileptogenic effects previously reported in two rodent models of temporal lobe epilepsy. Therefore, ACT-03 is of interest for further clinical evaluation as a novel therapeutic treatment for epilepsies with brain inflammation and/or BBB dysfunction.
Accure Therapeutics owns an international ‘composition of matter’ patent that covers the use of ACT-03 and its derivatives, which is granted in all the major pharmaceutical markets.
Accure Therapeutics’ next aim is to complete the necessary preclinical pharmacodynamics, safety, pharmacology and toxicology studies required to enable testing of ACT-03 in clinical trials.
MMPs are extracellular zinc-dependent endopeptidases crucial involve in the maintenance of the extracellular matrix homeostasis and regulation of several biological processes during normal physiological conditions, such as cell migration and synaptic plasticity. However, in pathological conditions MMP activation represents the response to an injury and amplifies brain damage. MMPs contribute to the aberrant synaptic plasticity, blood-brain barrier dysfunction, the reorganization of the extracellular matrix, the formation of the epileptic circuitry and neuronal death – all observed in epilepsy. Past use of MMP broad-spectrum inhibitors produced severe side effects due to their lack of selectivity. Over the last few years, emerging evidence has suggested that MMP type 9 (MMP9), and to a lesser extent MMP type-2 (MMP2), play a prominent role in epiletogenesis when dysregulated. This indicates that highly selective MMP9 and MMP2 are novel therapeutic targets in the treatment of epilepsy.
