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Light and Organic Nanotechnology for Cardiovascular Disease

Periodic Reporting for period 2 - LION-HEARTED (Light and Organic Nanotechnology for Cardiovascular Disease)

Reporting period: 2020-05-01 to 2021-10-31

Cardiovascular (CV) disease is the leading cause of mortality and morbidity worldwide, with an increasing incidence in the aging population and a huge socio-economic impact. Heart failure (HF), the common end point of virtually all CV disorders, displays the greatest negative impact on quality of life, leading to the disruption of daily management and increasing dependence on care-givers. Unfortunately, an effective pharmacological treatment is currently lacking, as it is not possible to reverse disease progression; as a consequence, the long-term survival remains poor, and heart transplantation is the only possibility for end-stage HF patients. Thus, a breakthrough approach to preserve or, at least, restore CV function and to rescue systemic blood perfusion is urgently required.
LION-HEARTED will demonstrate a novel optoceutic platform, based on synergistic combination of light and organic nanotechnology, to restore cardiac function and vascularization, by modulating fate and proliferation of main cardiovascular cell types. Optical modulation will provide unprecedented spatio-temporal resolution, lower invasiveness, and higher selectivity in respect to the traditional electrical and pharmaceutical control methods. Organic semiconductors will act as efficient, highly biocompatible phototransducers, able to trigger biological pathways relevant to cardiac repair, with a minimally invasive and gene-less approach. This strategy will circumvent most of the hurdles currently limiting the efficacy of molecular therapies, by directly stimulating the reparative phenotype of resident cardiac progenitors, cardiomyocytes, and of circulating endothelial cells homing towards the heart after an ischemic insult.
The final outcome will be the realization of a proof of concept, implantable device for enhancing cardiac repair in ischemic, aneurysm and stenosis in vivo animal models.
Main results achieved in RP1 included:

- Realization of novel functional materials and devices, for use in bio-hybrid interfaces;
- Quantitative description of the chemical/physical processes occurring at the interface between the active material and the extracellular environment;
- Establishment of microscopy techniques suitable for the study of biohybrid interfaces;
- First in vitro validation of the LION-HEARTED approach in human endothelial cells.

In RP2, remarkable results were also achieved, including:
1. Realization of porous polymer, light sensitive scaffolds, with a high surface area and sizable enhancement of photoelectrochemical (PEC) reactions;
2. Synthesis and chemical/physical characterization of polymer NPs based on low band gap materials duly completed. NPs in vitro cytotoxicity, in dark and upon illumination, successfully tested. Selection of the NPs material of choice for in vivo tests;
3. Characterization of phototransduction processes occurring at the polymer/electrolyte interface successfully completed. Identification of PEC reactions as the most relevant transduction process leading to modulation of the cell activity. Identification of selection criteria of most effective materials for LH targets. Conjugated polymer and photoexcitation protocols for the next RP agreed within LH consortium;
4. Kinetic Monte Carlo model of the biohybrid interface validated;
5. Machine learning tools developed and available to LH partners;
6. In vitro validation of the LION-HEARTED approach, in the case of the two main targeted cell models, namely human endothelial colony forming cells (ECFCs) and human induced pluripotent stem cells cardiomyocytes (hiPSC-CMs).
7. LED light sources optimized and ready for implantation in mice. First in vivo implantation successful trials;
8. Light sensitive NPs delivery in mice models and optimization of stimulation protocols in safe conditions.

Overall, all targeted objectives for the first 30 months activity have been successfully attained, and represent a solid foundation for the next reporting period and progress towards the LION-HEARTED final goal.
Optoceutics is per se a new research field, well beyond long-established pharmaceutics and even the more recent electroceutic methods. Organic nanotechnology has never been proposed in the field of regenerative medicine for cardiac cells, such as cardiomyocytes and endothelial progenitor cells. Thus, LION-HEARTED goes well beyond the current state of the art, since it exploits for the first time the synergistic combination of optical stimulation with organic nanotechnologies, and it will allow for addressing cardiovascular (CV) diseases under a completely different perspective, without the need for viral transfer or gene therapies.
The results achieved in the first year of LION-HEARTED activities represent distinct advancements respect to the current state-of-the-art, and confirm the huge potential impact of LION-HEARTED in CV diseases.
The improved life expectancy in industrialized countries will result in elderly population with increased perspective incidence of heart failure (HF). HF is regarded as a major public health issue, with a prevalence of >6.5 million patients in EU and >23 million worldwide, which is dramatically rising over the next few decades. Accordingly, there is a lifetime risk of one in five of developing this syndrome. Life expectancy after HF diagnosis ranges from 50% at 5 years to 10% at 10 years. As a consequence, HF displays the greatest negative impact on quality of life leading to the disruption of daily management and increasing dependence on care-givers. HF accounts for ≈1-2% of European hospital admissions, with 24% of patients rehospitalized within the 30-day post discharge period, and accounts for 2% of the total healthcare expenditure in western countries. Despite technological and pharmacological advances fostering early diagnosis and aggressive therapeutic interventions for CV disorders, no new effective drug has been launched on the market to prevent or cure the lethal effects of HF in the last twenty years. An innovative approach to preserve or, at least, restore the efficiency of cardiac contractility and rescue systemic blood perfusion is, therefore, required. Other than heart transplantation for end-stage HF, there are no effective therapies to treat this syndrome.
On top, the recent health emergency due to COVID-19 further strengthened the potential therapeutic impact of LION-HEARTED. Indeed, although this is a respiratory disease, COVID-19 patients also suffer from extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and stroke. Furthermore, patients with existing cardiovascular comorbidities, such as HF, have a worse clinical outcome following contraction of the viral illness. The infection, indeed, severely affects both vascular endothelial cells and cardiac myocytes, thereby compromising cardiovascular homeostasis.
The present pandemic, therefore, further boosted the quest for alternative strategies to effectively treat coronary artery disease and heart failure in non COVID-19 patients, on the one hand, and to treat the coronary events which may arise in COVID-19 patients, on the other hand.

Overall, LION-HEARTED addresses hitherto unmet therapeutic needs by envisaging an unexplored, yet technologically feasible approach. Providing the proof-of-concept for a new technology to induce cardiac repair will certainly exert a profound social and economic impact for EU population.
Light and organic nanotechnology enhance tubulogenesis processes in endothelial precursors