Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease

Abstract

CRISPR-Cas9 gene editing is emerging as a prospective therapy for genomic mutations. However, current editing approaches are directed primarily toward relatively small cohorts of patients with specific mutations. Here, we describe a cardioprotective strategy potentially applicable to a broad range of patients with heart disease. We used base editing to ablate the oxidative activation sites of CaMKIIδ, a primary driver of cardiac disease. We show in cardiomyocytes derived from human induced pluripotent stem cells that editing the CaMKIIδ gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKIIδ editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKIIδ gene editing may thus represent a permanent and advanced strategy for heart disease therapy.

The mitochondrial regulation of smooth muscle cell proliferation in type 2 diabetes

“…However, significant neurologic side effects, including seizure activity, were reported after administration of Ru265 in vivo 56 and the in vivo efficacy of other inhibitors remains to be determined. As an attractive alternative, Crispr/Cas9 technology has been recently deployed to selectively ablate activated CaMKII 57 . Given that mitochondrial Ca 2+ entry is ubiquitous, effective use of any of these nascent tools for prevention of neointima formation would require the development of delivery strategies that are selective for VSMCs.…”

Nuclear Calcium in Cardiac (Patho)Physiology: Small Compartment, Big Impact

“…Similarly, gene therapy approaches to restore physiological SR Ca 2+ reuptake, although promising in preclinical models [ 93 ], have failed to produce results in HF patients [ 94 , 95 ]. Encouraging results, however, were published very recently by Lebek et al showing that CRISPR-Cas9 base editing to ablate the oxidative activation sites of CaMKIIδ was effective in protecting the heart from ischemia-reperfusion damage in mouse models [ 96 ].…”

CRISPR Editing Takes Aim at Ischemia/Reperfusion Injury

“…Examination of patient samples from these trials revealed poor viral infection of myocardium. In contrast to the CUPID trials, Lebek and colleagues opted for intramyocardial injection delivery, which is considered to lead to higher retention of injectate . However, intracardiac delivery has been mired with proarrhythmic adverse effects in human and primate trials exploring stem cell therapy, and importantly, these adverse effects were underappreciated in small animal models .…”

“…Altogether, Lebek and colleagues provide an elegant strategy for preventing CaMKII-dependent injury in ischemia/reperfusion. Their study further cements CaMKII as a pivotal cardiac therapeutic target and provides valuable insight into the feasibility of CaMKII inhibition postinjury.…”

“…Although Ca 2+ / calmodulin-dependent protein kinase II (CaMKII) is one of the most extensively validated cardiovascular targets, including in ischemic heart injury, CaMKII antagonists have not yet reached human use. Lebek et al 1 describe a promising clustered regularly interspaced short palindromic repeats (CRISPR)-based approach to abrogate oxidation-mediated CaMKII hyperactivity and rescue cardiac function after ischemia/reperfusion injury. Here, we summarize the therapeutic relevance of cardiac CaMKII, highlight the hurdles overcome and enthusiasm brought forth by the work of Lebek and colleagues, 1 and discuss the obstacles that currently hinder translation of CRISPR-based modulation of CaMKII into patients.…”