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Current Cardiology Reports
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Open Access 07-08-2024 | Heart Failure | Heart Failure (HJ Eisen, Section Editor)

Precision Genetic Therapies: Balancing Risk and Benefit in Patients with Heart Failure

Authors: Jamie R. Johnston, Eric D. Adler

Published in: Current Cardiology Reports | Issue 9/2024

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Abstract

Purpose of Review

Precision genetic medicine is evolving at a rapid pace and bears significant implications for clinical cardiology. Herein, we discuss the latest advancements and emerging strategies in gene therapy for cardiomyopathy and heart failure.

Recent Findings

Elucidating the genetic architecture of heart failure has paved the way for precision therapies in cardiovascular medicine. Recent preclinical studies and early-phase clinical trials have demonstrated encouraging results that support the development of gene therapies for heart failure arising from a variety of etiologies. In addition to the discovery of new therapeutic targets, innovative delivery platforms are being leveraged to improve the safety and efficacy of cardiac gene therapies.

Summary

Precision genetic therapy represents a potentially safe and effective approach for improving outcomes in patients with heart failure. It holds promise for radically transforming the treatment paradigm for heart failure by directly targeting the underlying etiology. As this new generation of cardiovascular medicines progress to the clinic, it is especially important to carefully evaluate the benefits and risks for patients.
Literature
1.
Tsao CW, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. 2022;145(8):e153–639.PubMedCrossRef
2.
Savarese G, et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023;118(17):3272–87.PubMedCrossRef
3.
4.
Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895–1032.PubMed
5.
6.
Lucas T, Bonauer A, Dimmeler S. RNA Therapeutics in Cardiovascular Disease. Circ Res. 2018;123(2):205–20.PubMedCrossRef
7.
8.
9.
10.
Cahill TJ, Ashrafian H, Watkins H. Genetic cardiomyopathies causing heart failure. Circ Res. 2013;113(6):660–75.PubMedCrossRef
11.
Helms AS, Thompson AD, Day SM. Translation of New and Emerging Therapies for Genetic Cardiomyopathies. JACC Basic Transl Sci. 2022;7(1):70–83.PubMedCrossRef
12.
Wang JY, Doudna JA. CRISPR technology: A decade of genome editing is only the beginning. Science. 2023;379(6629):eadd864.CrossRef
13.
Wright AV, Nunez JK, Doudna JA. Biology and Applications of CRISPR Systems: Harnessing Nature’s Toolbox for Genome Engineering. Cell. 2016;164(1–2):29–44.PubMedCrossRef
14.
Yeh CD, Richardson CD, Corn JE. Advances in genome editing through control of DNA repair pathways. Nat Cell Biol. 2019;21(12):1468–78.PubMedCrossRef
15.
16.
17.
18.
Ewaisha R, Anderson KS. Immunogenicity of CRISPR therapeutics-Critical considerations for clinical translation. Front Bioeng Biotechnol. 2023;11:1138596.PubMedPubMedCentralCrossRef
19.
20.
Hakim CH, et al. Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models. Nat Commun. 2021;12(1):6769.PubMedPubMedCentralCrossRef
21.
22.
23.
24.
25.
Hilton IB, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33(5):510–7.PubMedPubMedCentralCrossRef
26.
27.
28.
29.
Anttila V, et al. Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting. Mol Ther. 2023;31(3):866–74.PubMedCrossRef
30.
31.
Cannata A, et al. Gene Therapy for the Heart Lessons Learned and Future Perspectives. Circ Res. 2020;126(10):1394–414.PubMedCrossRef
32.
Rincon MY, VandenDriessche T, Chuah MK. Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation. Cardiovasc Res. 2015;108(1):4–20.PubMedPubMedCentralCrossRef
33.
Schiedner G, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet. 1998;18(2):180–3.PubMedCrossRef
34.
Raper SE, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80(1–2):148–58.PubMedCrossRef
35.
36.
37.
38.
Mendell JR, et al. Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations. Mol Ther Methods Clin Dev. 2022;25:74–83.PubMedPubMedCentralCrossRef
39.
40.
Tabebordbar M, et al. Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell. 2021;184(19):4919-4938 e22.PubMedPubMedCentralCrossRef
41.
Weinmann J, et al. Identification of a myotropic AAV by massively parallel in vivo evaluation of barcoded capsid variants. Nat Commun. 2020;11(1):5432.PubMedPubMedCentralCrossRef
42.
43.
44.
Papayannakos C, Daniel R. Understanding lentiviral vector chromatin targeting: working to reduce insertional mutagenic potential for gene therapy. Gene Ther. 2013;20(6):581–8.PubMedCrossRef
45.
46.
47.
48.
49.
50.
Wei T, et al. Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing. Nat Commun. 2020;11(1):3232.PubMedPubMedCentralCrossRef
51.
52.
53.
54.
Greenwell AA, et al. Barth syndrome-related cardiomyopathy is associated with a reduction in myocardial glucose oxidation. Am J Physiol Heart Circ Physiol. 2021;320(6):H2255–69.PubMedCrossRef
55.
Thompson R, et al. Current and future treatment approaches for Barth syndrome. J Inherit Metab Dis. 2022;45(1):17–28.PubMedCrossRef
56.
57.
58.
59.
Taylor MRG, et al. Danon disease presenting with dilated cardiomyopathy and a complex phenotype. J Hum Genet. 2007;52(10):830–5.PubMedCrossRef
60.
Yang Z, et al. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation. 2005;112(11):1612–7.PubMedCrossRef
61.
62.
63.
64.
Keyt LK, et al. Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics. Front Cardiovasc Med. 2022;9:972301.PubMedPubMedCentralCrossRef
65.
66.
67.
Mearini G, et al. Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice. Nat Commun. 2014;5:5515.PubMedCrossRef
68.
69.
70.
Martin TG, et al. Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover. Nat Commun. 2021;12(1):2942.PubMedPubMedCentralCrossRef
71.
Qu HQ, Feldman AM, Hakonarson H. Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies. J Am Heart Assoc. 2022;11(23):e027373.PubMedPubMedCentralCrossRef
72.
73.
Knezevic T, et al. Adeno-associated Virus Serotype 9 - Driven Expression of BAG3 Improves Left Ventricular Function in Murine Hearts with Left Ventricular Dysfunction Secondary to a Myocardial Infarction. JACC Basic Transl Sci. 2016;1(7):647–56.PubMedPubMedCentralCrossRef
74.
Myers VD, et al. Cardiac Transduction in Mini-Pigs After Low-Dose Retrograde Coronary Sinus Infusion of AAV9-BAG3: A Pilot Study. JACC Basic Transl Sci. 2022;7(9):951–3.PubMedPubMedCentralCrossRef
75.
76.
Venugopal V, Pavlakis S. Duchenne muscular dystrophy. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
77.
78.
79.
Mullard A. FDA approves first gene therapy for Duchenne muscular dystrophy, despite internal objections. Nat Rev Drug Discov. 2023;22(8):610.PubMedCrossRef
80.
81.
82.
83.
84.
Bokhari SRA, Zulfiqar H, Hariz A. Fabry disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
85.
Monda E, et al. Cardiovascular Involvement in Fabry’s Disease: New Advances in Diagnostic Strategies, Outcome Prediction and Management. Card Fail Rev. 2023;9:e12.PubMedPubMedCentralCrossRef
86.
Pieroni M, et al. Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week. J Am Coll Cardiol. 2021;77(7):922–36.PubMedCrossRef
87.
Deng M, et al. Systematic gene therapy derived from an investigative study of AAV2/8 vector gene therapy for Fabry disease. Orphanet J Rare Dis. 2023;18(1):275.PubMedPubMedCentralCrossRef
88.
Jain A, Zahra F. Transthyretin amyloid cardiomyopathy (ATTR-CM). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
89.
Kittleson MM, et al. Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. Circulation. 2020;142(1):e7–22.PubMedCrossRef
90.
Aimo A, et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol. 2022;19(10):655–67.PubMedCrossRef
91.
Finn JD, et al. A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing. Cell Rep. 2018;22(9):2227–35.PubMedCrossRef
92.
Gillmore JD, et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. 2021;385(6):493–502.PubMedCrossRef
93.
94.
95.
Silvestri NJ, et al. Cardiac involvement in the muscular dystrophies. Muscle Nerve. 2018;57(5):707–15.PubMedCrossRef
96.
97.
Hermann H, Wuebbles RD, Burkin DJ. A gene therapy approach for the treatment of limb-girdle muscular dystrophy 2C/R5. Mol Ther Methods Clin Dev. 2023;29:160–1.PubMedPubMedCentralCrossRef
98.
Seo YE, et al. Systemic gamma-sarcoglycan AAV gene transfer results in dose-dependent correction of muscle deficits in the LGMD 2C/R5 mouse model. Mol Ther Methods Clin Dev. 2023;28:284–99.PubMedPubMedCentralCrossRef
99.
Sakuru R. Bollu PC. Hurler syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
100.
101.
102.
103.
Salik I, Rawla P. Marfan syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
104.
105.
Zeng Y, et al. Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos. Mol Ther. 2018;26(11):2631–7.PubMedPubMedCentralCrossRef
106.
Sickles CK, Gross GP. Progeria. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
107.
108.
Williams CT, De Jesus O. Friedreich Ataxia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
109.
Lynch DR, Farmer G. Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions. Neuronal Signal. 2021;5(2):NS20200093.PubMedPubMedCentralCrossRef
110.
Perdomini M, et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. Nat Med. 2014;20(5):542–7.PubMedCrossRef
111.
Salami CO, et al. Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich’s Ataxia Corrected by AAV-mediated Gene Therapy. Hum Gene Ther. 2020;31(15–16):819–27.PubMedCrossRef
112.
113.
Rajkumar V, Dumpa V. Lysosomal storage disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
114.
Stevens D, Milani-Nejad S, Mozaffar T. Pompe Disease: a Clinical, Diagnostic, and Therapeutic Overview. Curr Treat Options Neurol. 2022;24(11):573–88.PubMedPubMedCentralCrossRef
115.
Eggers M, et al. Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. EMBO Mol Med. 2022;14(1):e13968.PubMedCrossRef
116.
117.
118.
Argiro A, Ding J, Adler E. Gene therapy for heart failure and cardiomyopathies. Rev Esp Cardiol (Engl Ed). 2023;76(12):1042–1054
119.
Metadata
Title
Precision Genetic Therapies: Balancing Risk and Benefit in Patients with Heart Failure
Authors
Jamie R. Johnston
Eric D. Adler
Publication date
07-08-2024
Publisher
Springer US
Published in
Current Cardiology Reports / Issue 9/2024
Print ISSN: 1523-3782
Electronic ISSN: 1534-3170
DOI
https://doi.org/10.1007/s11886-024-02096-5

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