CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a § 371 national stage of PCT International Application No. PCT/EP2015/081048, filed Dec. 22, 2015, claiming priority of Australian Patent Application No. AU2014905240, filed Dec. 23, 2014, the contents of each of which are hereby incorporated by reference into the application.

TECHNICAL FIELD

The present disclosure relates to methods for preventing progressive heart failure in subjects with persistent left ventricular (LV) dysfunction. Such methods may also be used for treating or preventing progressive heart failure in subjects with a proximal left anterior descending (LAD) lesion and persistent left ventricular dysfunction.

BACKGROUND

Myocardial infarction (MI) is still one of the main causes of mortality and morbidity in developed countries. A recent update of US Medicare records was published that evaluated data involving 350,509 acute MI hospitalization in patients >65 years who were discharged alive after their event (Schuster et al. (2004) Physiol Heart Circa Physiol., 287(2):525-32). Within the first year post the index event, 25.9% of the MI patients died with 50.5% re-hospitalized. In the month after a MI, the likelihood of death was 21 times higher and the likelihood of hospitalization and was 12 times higher than among the general Medicare-age population.

Patients who have larger infarcts post MI and more post-infarct LV dysfunction are at significantly increased risk of experiencing mid-to-long term cardiac events and death. Specifically, subjects having anterior wall infarcts, larger infarcts, and more LV dysfunction in the post-infarct period are at significantly increased risk of experiencing mid-to-long term cardiac events and death (Eitel et al. (2010) J Am Coll Cardiol., 55:2470-9).

An infarct due to proximal LAD occlusion continues to be a major risk factor for progressive LV dilatation, remodelling, and symptomatic progressive heart failure. In the post-angioplasty era, 3-year mortality post MI is still the highest for proximal LAD lesions (10% vs 3% for distal LAD) (Elsman et al. (2006) Am J Cardiol., 97(8):1137-41) and this is most likely due to the 40% greater infarct size associated with this anatomical lesion (Elsman et al. (2006) Am J Cardiol., 97(8):1137-41). Since infarct size >18.5% has been shown prospectively to result in a 30% incidence of Heart Failure-related Major Adverse Cardiac Events (HF-MACE, defined as heart failure hospitalization or death) over 2 years (Wu et al. (2008) Heart, 94:730-736), this suggests that a population of MI patients with proximal LAD lesions, low ejection fraction and large infarcts is at the highest risk of subsequent HF-MACE.

Clearly, there is a need in the art for treating or preventing progressive heart failure.

SUMMARY

The present disclosure is based on the unexpected identification of a population of myocardial infarction (MI) subjects that respond well to stem cell therapy.

A large number of MI subjects with elevated troponin or CK-MB (>4× upper limits of normal (ULN)), a regional heart wall abnormality and, depressed global left ventricular systolic function (less than or equal 45% and greater than or equal to 20%) as determined on screening cardiac imaging performed within approximately 24 hours of the MI, were administered stem cell or placebo therapy shortly after MI.

The present inventors found that global left ventricular systolic function recovered to normal levels in a majority of these subjects approximately 5 days post MI. Administration of stem cell therapy provided no therapeutic improvement over placebo therapy in these subjects.

Surprisingly, administration of stem cell therapy provided a pronounced therapeutic improvement over placebo therapy in subjects who had proximal left anterior descending (LAD) arterial lesions. These results indicate that stem cell therapy may be useful for treating or preventing progressive heart failure in a sub-population of MI subjects, in particular, MI subjects with proximal LAD lesions.

Accordingly, in one example, the present disclosure provides a method of treating or preventing progressive heart failure in a myocardial infarction subject, the method comprising administering to the subject a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom, wherein the subject has a proximal left anterior descending (LAD) lesion.

In another example, the method comprises the steps of: i) selecting a subject having a proximal left anterior descending (LAD) lesion, and ii) administering to the subject a population of mesenchymal lineage stem or precursor cells and/or progeny thereof and/or soluble factors derived therefrom.

The present inventors also identified that the subjects with proximal LAD lesions that responded well to stem cell therapy also had persistent low ejection fraction approximately 5 days post MI. These results indicate that the methods of the present disclosure may also be useful for treating or preventing progressive heart failure in subjects with proximal LAD lesions and persistent low ejection fraction.

Accordingly, in another example, the present disclosure provides a method of treating progressive heart failure in a myocardial infarction subject, the method comprising administering to the subject a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom, wherein the subject has a proximal left anterior descending (LAD) lesion and has persistent left ventricular dysfunction.

In one example, the subject also has an elevated left ventricular end systolic volume (LVESV) of greater than 70 mL. In one example, the LVESV is greater than 80 mL, greater than 90 mL, greater than 100 mL, greater than 110 mL or greater than 120 mL. In another example, the LVESV is greater than 80 mL/m2, greater than 90 mL/m2, greater than 100 mL/m2, greater than 110 mL/m2, or greater than 120 mL/m2.

In an example, the subject has a left ventricular ejection fraction (LVEF) of less than about 55%. In another example, the subject has a LVEF of less than about 45%. In another example, the subject has a LVEF of less than about 40%. In an example, the LVEF is measured via cardiovascular magnetic resonance imaging (cMR).

The present inventors have also identified that the timing of administration post MI may also benefit subjects. Thus, in an example, the mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom are administered between about 1 and 7 days post-myocardial infarction. In an example, the mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom are administered between about 2 and 7 days post-myocardial infarction. In another example, the mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom are administered between about 3 and 5 days post-myocardial infarction.

The present inventors have further characterised the population of subjects that may benefit from the methods of the present disclosure based on the level of serum biomarkers relative to the upper limits of normal (ULM). In an example, the subject has greater than about 2× upper limit of normal creatine kinase-MB and/or troponin. In another example, the subject has greater than about 4× upper limit of normal creatine kinase-MB and/or troponin and/or myoglobin.

The present inventors have further characterised the population of subjects that may benefit from the methods of the present disclosure based on infarct size. In an example, the subject has an infarct size between about 10-25% of the left ventricle. In another example, the subject has an infarct size greater than about 18.5% of the left ventricle. In an example, infarct size is measured via cMR.

In another example, the methods of the present disclosure comprise administering a population of mesenchymal lineage precursor or stem cells enriched for STRO-1+cells and/or progeny thereof and/or soluble factors derived therefrom.

In another example, the methods of the present disclosure comprise administering a population of mesenchymal lineage precursor or stem cells enriched for STRO-1brightcells and/or progeny thereof and/or soluble factors derived therefrom.

In an example, the population of mesenchymal lineage precursor or stem cells express tissue non-specific alkaline phosphatase (TNAP) and/or the progeny cells and/or soluble factors are derived from mesenchymal lineage precursor or stem cells that express TNAP.

In an example, the population of mesenchymal lineage precursor or stem cells express angiopoietin-1 (Ang1) in an amount of at least 0.1 μg/106cells and/or the progeny cells and/or soluble factors are derived from mesenchymal lineage precursor or stem cells that express Ang1 in an amount of at least 0.1 μg/106cells. In an example, the population of mesenchymal lineage precursor or stem cells express Ang1 in an amount of at least 0.5 μg/106cells. In an example, the population of mesenchymal lineage precursor or stem cells express Ang1 in an amount of at least 0.7 μg/106cells. In an example, the population of mesenchymal lineage precursor or stem cells express Ang1 in an amount of at least 1 μg/106cells.

In an example, the population of mesenchymal lineage precursor or stem cells express Vascular Endothelial Growth Factor (VEGF) in an amount less than about 0.05 μg/106cells and/or the progeny cells and/or soluble factors are derived from mesenchymal lineage precursor or stem cells that express VEGF in an amount less than about 0.05 μg/106cells and/or the progeny cells. In an example, the population of mesenchymal lineage precursor or stem cells express VEGF in an amount less than about 0.03 μg/106cells.

In an example, the population of mesenchymal lineage precursor or stem cells express Ang1:VEGF at a ratio of at least about 2:1 and/or the progeny cells and/or soluble factors are derived from mesenchymal lineage precursor or stem cells that express Ang1:VEGF at a ratio of at least about 2:1. In an example, the population of mesenchymal lineage precursor or stem cells express Ang1:VEGF at a ratio of at least about 10:1. In an example, the population of mesenchymal lineage precursor or stem cells express Ang1:VEGF at a ratio of at least about 20:1. In an example, the population of mesenchymal lineage precursor or stem cells express Ang1:VEGF at a ratio of at least about 30:1.

In an example, the population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom are administered systemically. In an example, the population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom are administered intravenously, intramuscularly or intranasally. For example, the population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom can be administered intravenously.

In an example, multiple doses of the population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom are administered.

In an example, the methods of the present disclosure comprise administering between 1×106to 8×108cells. In an example, the methods of the present disclosure comprise administering between 1.2×108to 4×108cells. In an example, the methods of the present disclosure comprise administering at least about 1.5×108cells.

In an example, the population of cells and/or progeny cells are autogeneic or allogeneic and/or the soluble factors are derived from autogeneic or allogeneic cells.

In an example, the population of cells and/or progeny thereof have been culture expanded prior to administration and/or prior to obtaining the soluble factors.

In an example, the mesenchymal lineage precursor or stem cells and/or progeny cells thereof and/or soluble factors derived therefrom are administered in the form of a composition comprising the mesenchymal lineage precursor or stem cells and/or progeny cells thereof and/or soluble factors derived therefrom and a carrier and/or excipient. For example, the composition may comprise a cryopreservative.

Thus, in an example, the present disclosure relates to a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom for use in the treatment or prevention of progressive heart failure in a myocardial infarction (MI) subject, wherein the subject has a proximal left anterior descending (LAD) arterial lesion. In another example, the present disclosure relates to a use of a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom in the manufacture of a medicament for treating or preventing progressive heart failure in a myocardial infarction (MI) subject, wherein the subject has a proximal left anterior descending (LAD) arterial lesion. In these examples, the subject can have persistent left ventricular dysfunction. For example, the subject can have a LVEF of less than about 55%. In another example, the subject has a LVEF of less than about 45%. In another example, the subject has a LVEF of less than about 40%. In these examples, the mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom can be administered between about 1 and 7 days post-myocardial infarction. For example, the mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom are administered between about 3 and 5 days post-myocardial infarction. In these examples, the subject can ha greater than about 2× upper limit of normal creatine kinase-MB and/or troponin. In another example, the subject has greater than about 4× upper limit of normal creatine kinase-MB and/or troponin and/or myoglobin. In these examples, the subject can have an infarct size between about 10-25% of the left ventricle. In another example, the subject may have an infarct size greater than about 18.5% of the left ventricle. In these examples, the LVEF or infarct size may be measured via cMR.

