Next Generation Gene Therapy for the Treatment of Chronic Myocardial Ischemia and Heart Failure

Project Information

HeartGenes

Grant agreement ID: 884382

DOI

10.3030/884382

EC signature date 9 June 2020

Start date 1 May 2021

End date 31 January 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

ITA-SUOMEN YLIOPISTO
Finland

Periodic Reporting for period 3 - HeartGenes (Next Generation Gene Therapy for the Treatment of Chronic Myocardial Ischemia and Heart Failure)

Reporting period: 2024-05-01 to 2025-10-31

Summary of the context and overall objectives of the project

HeartGenes develops new gene therapy-based treatments for ishaemic heart disease and heart failure. These are major health problems world-wide and cause tremendous suffering, mortality, morbidity and costs to the society. The overall objective is to improve current therapy of these diseases.
https://www.uef.fi/en/unit/ai-virtanen-institute-for-molecular-sciences

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have explored therapeutic angiogenesis and several factors affecting blood vessel growth and functional blood flow in the heart using our mouse and pig models. In pig bottle-neck stent model developed in our group, we have shown that VEGF-B splice variants have different properties in the heart. Some splice variants of VEGF-B are very useful for the stimulation of angiogenesis and cardiac blood flow as measured with ultrasound, MRI and radiowater PET perfusion (1). However, there is still an urgent need to better understand the properties of various proteolytic fragments of VEGF-B in order to develop optimal therapy for ischemic and failing heart muscle. Also, some immunological problems have been observed with AAV2 vectors which have been solved by using other AAV serotypes (2).
Signaling mechanisms related to angiogenesis have been analyzed in endothelial cells, cardiomyocytes, pericytes and in heart and blood vessels in vivo. We have explored signaling properties of different VEGF-B variants and shown that one of the useful properties of VEGF-B is that it can recruit progenitor cells into the myocardium thus having an important regenerative activity in addition to the angiogenic activity (3). In addition, various non-coding RNAs associated with the activation of VEGF gene expression have been explored.
Electrophysiological mapping using NOGA catheter superimposed on PET radiowater perfusion images were found to be very accurate in the analysis of the effects of intracardiac gene transfers and therefore we have published a detailed description of our large animal ischemia model (4) where we have also developed a new, very efficient retrograde gene delivery method via coronary veins. Also, several modified and regulated vectors have been tested with concomitant perspectives and avenues for future vector development (5), including an I-Ppo homing endonuclease-reverse transcriptase fusion protein containing lentivirus that allows targeted integration to genomic safe harbors (6). Also, new nanotherapy delivery methods have been reported (7)
During the grant period four reviews about the potential use of non-coding RNAs and RNAi as drugs for vascular diseases and atherosclerosis have been published (8-11).
I sincerely thank the ERC for the very significant support for our research program.

References:
1. Korpela H, Hätinen O-P, Nieminen T, Mallick R, Toivanen P, Airaksinen J, Valli K, Hakulinen M, Poutiainen P, Nurro J, Yla-Herttuala S. Adenoviral VEGF-B186R127S gene transfer induces angiogenesis and improves perfusion in ischemic heart, iScience 24, 103533, 2021 (https://doi.org/10.1016/j.isci.2021.103533).
2. Korpela H, Lampela J, Airaksinen J, Järveläinen N, Siimes S, Valli K, Nieminen T, Turunen M, Grönman M, Saraste A, Knuuti J, Hakulinen M, Poutiainen P, Kärjä V, Nurro J, Ylä-Herttuala S, AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses. Gene Ther 29:643-652, 2022: (doi:10.1038/s41434-022-00322-9).
3. Mallick R, Gurzeler E, Toivanen PI, Nieminen T, Yla-Herttuala S. Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells. Front. Bioeng. Biotechnol. 10:1-14, 2022
(doi.org/10.3389/fbioe.2022.907538).
4. Korpela H, Siimes S, Yla-Herttuala S. Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart. J Vis Exp 175:e62833, 2021 (doi:10.3791/62833).
5. Suoranta T, Laham-Karam N and Ylä-Herttuala S. Strategies to improve safety profile of AAV vectors. Front. Mol. Med. 2:1054069, 2022 (doi: 10.3389/fmmed.2022.1054069).
6. Nousiainen A; Schenkwein D; Ylä-Herttuala S. Characterization of a new IN-I-PpoI fusion protein and a homology-arm containing transgene cassette that improve transgene expression persistence and 28S rRNA gene-targeted insertion of lentiviral vectors PlosOne 18:e0280894, 2023 (doi.org/10.1371/ journal.pone.0280894).
7. Babu M, Devi D, Mäkinen P, Örd T, Aavik E, Kaikkonen M, Ylä-Herttuala S. ApoA-I Nanotherapy Rescues Postischemic Vascular Maladaptation by Modulating Endothelial Cell and Macrophage Phenotypes in Type 2 Diabetic Mice. Arterioscl. Thromb. Vasc. Biol. 43: 2023 (doi:10.1161/ATVBAHA.122.318196).
8. Ruotsalainen A-K, Mäkinen P, Ylä-Hertuala S. Novel RNAi-based therapies for atherosclerosis. Curr Atheroscler Reports 23:45-50, 2021 (doi: 10.1007/s11883-021-00938-z).
9. Kettunen S, Ruotsalainen A-K, Yla-Herttuala S. RNA interference-based therapies for the control of atherosclerosis risk factors. Curr Opin Cardiol 37: 364-371, 2022 (doi:10.1097/HCO.0000000000000972).
10. Khachigian LM, Varcoe RL, Suoranta T, Laham-Karam N, Ylä-Herttuala S. Gene Therapeutic Strategies for Peripheral Artery Disease and New Opportunities Provided by Adeno-Associated Virus Vectors. Arterioscl. Thromb. Vasc. Biol. 43: 836-851, 2023 (doi: 10.1161/ATVBAHA.122.318902).
11. Laham-Karam N, Mushimiyimana I, Hokkanen K, Ylä-Herttuala S. Role of non-coding RNAs in physiological and pathological angiogenesis. Curr Opin Physiology 2023, 35:100690 (doi.org/10.1016/j.cophys.2023.100690).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Several new breakthroughs have been achieved (new VEGF-B designer mutants, new retrograde delivery methods to human heart, new vector backbones, and discovery of late-state immunological reactions with AAV vectors in the heart muscle). We expect to optimize our novel gene therapy-based treatments and perform required translational large animal experiments to be able to take these new treatments to the clinical testing.

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