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After marketing authorisation, the development of a medicinal product often continues with studies investigating new therapeutic indications. Positive results can potentially lead to changes to the terms of the marketing authorisation, such as an extension of therapeutic indication(s). These studies can be initiated and sponsored by the marketing authorisation holder (MAH) or by others. When results from an investigator-initiated trial suggest that an authorised medicinal product is safe and effective for a new therapeutic indication, physicians may want to treat their patients with this medicinal product. In such a situation, it is desirable to extend the therapeutic indication(s) via the regulatory approval process, as this can facilitate patient access within the European Union. There may however be challenges when the MAH did not conduct the study and might not have access to the data. In this perspective, we focus on the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product based on results from investigator-initiated trials. We address: (1) the advantages of an extension of indication; (2) the regulatory requirements for a variation application; (3) investigator-initiated trials as a basis for regulatory approval; (4) the role of the MAH in extending the indication. With this article, we want to emphasize the importance of a collaborative approach and dialogue between stakeholders with the aim to facilitate access to effective medicinal products.

MicroRNA-103/107 regulate systemic glucose metabolism and insulin sensitivity. For this reason, inhibitory strategies for these microRNAs are currently being tested in clinical trials. Given the high metabolic demands of the heart and the abundant cardiac expression of miR-103/107, we questioned whether antagomiR-mediated inhibition of miR-103/107 in C57BL/6J mice impacts on cardiac function. Notably, fractional shortening decreased after 6 weeks of antagomiR-103 and -107 treatment. This was paralleled by a prolonged systolic radial and circumferential time to peak and by a decreased global strain rate. Histology and electron microscopy showed reduced cardiomyocyte area and decreased mitochondrial volume and mitochondrial cristae density following antagomiR-103 and -107. In line, antagomiR-103 and -107 treatment decreased mitochondrial OXPHOS complexes’ protein levels compared to scrambled, as assessed by mass spectrometry-based label-free quantitative proteomics. MiR-103/107 inhibition in primary cardiomyocytes did not affect glycolysis rates, but it decreased mitochondrial reserve capacity, reduced mitochondrial membrane potential, and altered mitochondrial network morphology, as assessed by live-cell imaging. Our data indicate that antagomiR-103 and -107 decrease cardiac function, cardiomyocyte size, and mitochondrial oxidative capacity in the absence of pathological stimuli. These data raise concern about the possible cardiac implications of the systemic use of antagomiR-103 and -107 in the clinical setting, and careful cardiac phenotyping within ongoing trials is highly recommended. Keywords: Cardiomyocyte, cardiac, microRNA, miR-103, miR-107, antagomiR, mitochondria, metabolism, mass spectrometry, electron microscopy

The adult mammalian heart is incapable of regeneration following cardiac injury, leading to a decline in function and eventually heart failure. One of the most evident barriers limiting cardiac regeneration is the inability of cardiomyocytes to divide. It has recently become clear that the mammalian heart undergoes limited cardiomyocyte self-renewal throughout life and is even capable of modest regeneration early after birth. These exciting findings have awakened the goal to promote cardiomyogenesis of the human heart to repair cardiac injury or treat heart failure. We are still far from understanding why adult mammalian cardiomyocytes possess only a limited capacity to proliferate. Identifying the key regulators may help to progress towards such revolutionary therapy. Specific noncoding RNAs control cardiomyocyte division, including well explored microRNAs and more recently emerged long noncoding RNAs. Elucidating their function and molecular mechanisms during cardiomyogenesis is a prerequisite to advance towards therapeutic options for cardiac regeneration. In this review, we present an overview of the molecular basis of cardiac regeneration and describe current evidence implicating microRNAs and long noncoding RNAs in this process. Current limitations and future opportunities regarding how these regulatory mechanisms can be harnessed to study myocardial regeneration will be addressed.