Periodic Reporting for period 1 - ReDHeaD (Repurposing a known drug to treat heart diseases)
Berichtszeitraum: 2020-09-01 bis 2022-02-28
Despite a constant decline in mortality rates of patients with acute myocardial infarction (MI) due to improvements in medical care, the incidence of patients that develop ischemic heart failure (HF) is increasing. At present, disease management is directed in large part toward lifestyle and metabolic changes that help in slowing down disease progression. The lack of a real therapeutic success among the intensive clinical efforts highlights the need for novel therapeutic approaches to cure heart failure.
Glatiramer-acetate (GA) is a synthetic random copolymer currently used as the first line of treatment for multiple sclerosis (MS). The therapeutic activity of GA is attributed to its immunomodulatory effect at different levels of the innate and adaptive immune response, which are essential players in the repair processes of various tissues, including the heart. For these reasons, we have studied the potential application of GA for improving heart function using murine models of heart injuries.
We tested the therapeutic efficacy of GA in improving heart function in a mouse model of acute MI. Transient treatment with GA, 14 days from the day of injury, resulted in improved cardiac function and reduced scar area measured 35 dpmi. Interestingly, delayed administration of 24-48hrs also resulted in improved cardiac functions. This suggests that GA has a wide temporal window of therapeutic effect and could therefore be used to treat late-arrival, ST-elevation MI patients that need medical intervention. Examination of GA mode-of-action revealed that it induced a protective effect, inhibiting the ischemia-induced death of cardiomyocytes. GA modulated the repertoire of pro-inflammatory cytokines and enhanced reparative inflammation. In addition to its known immunomodulation function, GA treatment exhibited additional beneficial effects, including reduced fibrosis and enhanced angiogenesis. Our results in the acute MI mouse model show that GA can elicit multiple reparative pathways. Therefore, we proceeded to determine whether treatment with GA could have beneficial effects in our heart failure rat model of permanent LAD ligation, allowing 4 weeks post-MI remodeling before treating the animals with GA. The improved systolic parameters were accompanied by reduced scar area in GA-treated rats. These results suggest that transient GA treatment induces a stable improvement in functional parameters and prevents further deterioration associated with pathological remodeling of the left ventricle. Moreover, our results indicate that healing can be obtained with a new regimen of treatment. Overall, we show pleiotropic beneficial effects of GA treatment on the injured heart as manifested by functional improvement and scar reduction in rodent models of cardiac ischemia, which support drug repurposing of GA for the treatment of heart diseases.
Encouraged by our preclinical results, we designed a Phase 2a clinical trial of 20 patients to determine whether GA treatment may be safe and beneficial for HF patients. This trial focuses on acute decompensated HF patients with reduced EF, aiming to assess the anti-inflammatory effects of short-term GA treatment on patients hospitalized due to a sudden worsening of HF symptoms. The trial is currently ongoing and will first enable the determination of GA safety in these patients and second, establish a proof-of-concept for efficacy as determined by measuring the levels of various cytokines and cardiac injury biomarkers. The trial is currently ongoing and has already yielded promising preliminary results. The regimen we used for the trial is based on our observations in animal models, highlighting the relevance of the animal studies to the clinical stage. The benefits of repurposing a known drug, which may help to prevent deterioration of the failing heart, are enormous and could influence millions worldwide.
A patent application for the use of GA to treat heart diseases is granted.
Glatiramer-acetate (GA) is a synthetic random copolymer currently used as the first line of treatment for multiple sclerosis (MS). The therapeutic activity of GA is attributed to its immunomodulatory effect at different levels of the innate and adaptive immune response, which are essential players in the repair processes of various tissues, including the heart. For these reasons, we have studied the potential application of GA for improving heart function using murine models of heart injuries.
We tested the therapeutic efficacy of GA in improving heart function in a mouse model of acute MI. Transient treatment with GA, 14 days from the day of injury, resulted in improved cardiac function and reduced scar area measured 35 dpmi. Interestingly, delayed administration of 24-48hrs also resulted in improved cardiac functions. This suggests that GA has a wide temporal window of therapeutic effect and could therefore be used to treat late-arrival, ST-elevation MI patients that need medical intervention. Examination of GA mode-of-action revealed that it induced a protective effect, inhibiting the ischemia-induced death of cardiomyocytes. GA modulated the repertoire of pro-inflammatory cytokines and enhanced reparative inflammation. In addition to its known immunomodulation function, GA treatment exhibited additional beneficial effects, including reduced fibrosis and enhanced angiogenesis. Our results in the acute MI mouse model show that GA can elicit multiple reparative pathways. Therefore, we proceeded to determine whether treatment with GA could have beneficial effects in our heart failure rat model of permanent LAD ligation, allowing 4 weeks post-MI remodeling before treating the animals with GA. The improved systolic parameters were accompanied by reduced scar area in GA-treated rats. These results suggest that transient GA treatment induces a stable improvement in functional parameters and prevents further deterioration associated with pathological remodeling of the left ventricle. Moreover, our results indicate that healing can be obtained with a new regimen of treatment. Overall, we show pleiotropic beneficial effects of GA treatment on the injured heart as manifested by functional improvement and scar reduction in rodent models of cardiac ischemia, which support drug repurposing of GA for the treatment of heart diseases.
Encouraged by our preclinical results, we designed a Phase 2a clinical trial of 20 patients to determine whether GA treatment may be safe and beneficial for HF patients. This trial focuses on acute decompensated HF patients with reduced EF, aiming to assess the anti-inflammatory effects of short-term GA treatment on patients hospitalized due to a sudden worsening of HF symptoms. The trial is currently ongoing and will first enable the determination of GA safety in these patients and second, establish a proof-of-concept for efficacy as determined by measuring the levels of various cytokines and cardiac injury biomarkers. The trial is currently ongoing and has already yielded promising preliminary results. The regimen we used for the trial is based on our observations in animal models, highlighting the relevance of the animal studies to the clinical stage. The benefits of repurposing a known drug, which may help to prevent deterioration of the failing heart, are enormous and could influence millions worldwide.
A patent application for the use of GA to treat heart diseases is granted.