LPA disruption with AAV-CRISPR potently lowers plasma apo(a) in transgenic mouse model: A proof-of-concept study

Doerfler, Alexandria M.; Assini, Julia M.; Youssef, Amer; Saxena, Lavanya; Yaseen, Adam B.; Giorgi, M. De; Chuecos, Marcel; Hurley, Ayrea; Li, Ang; Marcovina, Santica M.; Bao, Gang; Boffa, Michael B.; Koschinsky, Marlys L.; Lagor, William R.

doi:10.1016/j.omtm.2022.10.009

Cited by 11 publications

(5 citation statements)

References 55 publications

(62 reference statements)

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“…Authors demonstrated that AAV-CRISPR/Cas9 nearly completely eliminated apo(a) from circulation within a week. This proof-of-concept study establishes the feasibility of using CRISPR-Cas9 to disrupt LPA in vivo [ 77 ]. This is the first study performed in an LPA transgenic mouse model expressing apo(a) demonstrating a successful in vivo editing of LPA and suggests that one-time treatment with a gene-editing nuclease could provide permanent removal of Lp(a) in patients at high residual CVD risk attributed to Lp(a).…”

Section: Methodsmentioning

confidence: 68%

“…Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a) levels. To address this hypothesis an LPA transgenic mouse model expressing apo(a) of physiologically relevant size was generated [ 77 ]. Adeno-associated virus (AAV) vector delivery of CRISPR/Cas9 was used to disrupt the LPA transgene in the liver [ 77 ].…”

Section: Methodsmentioning

confidence: 99%

“…To address this hypothesis an LPA transgenic mouse model expressing apo(a) of physiologically relevant size was generated [ 77 ]. Adeno-associated virus (AAV) vector delivery of CRISPR/Cas9 was used to disrupt the LPA transgene in the liver [ 77 ]. Authors demonstrated that AAV-CRISPR/Cas9 nearly completely eliminated apo(a) from circulation within a week.…”

Section: Methodsmentioning

confidence: 99%

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Treatment of Lp(a): Is It the Future or Are We Ready Today?

Tselepis

2023

Curr Atheroscler Rep

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Purpose of Review The goal of this review is to present the pharmacodynamic effectiveness as well as the clinical efficacy and safety of investigational antisense oligonucleotides (ASOs) and small interference RNAs (siRNAs) drugs that specifically target lipoprotein(a) (Lp(a)). The review will discuss whether the existing lipid-lowering therapies are adequate to treat high Lp(a) levels or whether it is necessary to use the emerging new therapeutic approaches which are based on the current RNA technologies. Recent Findings Lipoprotein(a) (Lp(a)) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD), independent of other conventional risk factors. High Lp(a) levels are also independently associated with an increased risk of aortic stenosis progression rate. Plasma Lp(a) levels are primarily genetically determined by variation in the LPA gene coding for apo(a). All secondary prevention trials have demonstrated that the existing hypolipidemic therapies are not adequate to reduce Lp(a) levels to such an extent that could lead to a substantial reduction of ASCVD risk. This has led to the development of new drugs that target the mRNA transcript of LPA and efficiently inhibit Lp(a) synthesis leading to potent Lp(a) reduction. These new drugs are the ASO pelacarsen and the siRNAs olpasiran and SLN360. Recent pharmacodynamic studies showed that all these drugs potently reduce Lp(a) up to 98%, in a dose-dependent manner. Ongoing clinical trials will determine the Lp(a)-lowering efficacy, tolerability, and safety of these drugs as well as their potential effectiveness in reducing the ASCVD risk attributed to high plasma Lp(a) levels. Summary We are not ready today to significantly reduce plasma Lp(a). Emerging therapies potently decrease Lp(a) and ongoing clinical trials will determine their effectiveness in reducing ASCVD risk in subjects with high Lp(a) levels.

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Section: Methodsmentioning

confidence: 68%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Treatment of Lp(a): Is It the Future or Are We Ready Today?

Tselepis

2023

Curr Atheroscler Rep

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“…In this experimental model, the AAV-CRISPR complex effectively reduced plasma concentrations of apo(a) to almost undetectable levels within a week of administration. This reduction in apo(a) persisted for at least four weeks of observation, with over 99% elimination in male mice and over 96% elimination in female mice [ 254 ]. Although of high importance, further research is needed to evaluate the safety, feasibility, and long-term efficacy of this approach in human subjects.…”

Section: Molecular Lp(a)-targeting Therapies: In the Heart Of The Pro...mentioning

confidence: 99%

“…As a result, inhibition of the Lp(a) formation is observed ( D ). AAV facilitates the transfer of CRISPR in the liver, where CRISPR disrupts the LPA gene, resulting in the removal of Lp(a) particles from the plasma [ 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 ]. Abbreviations: AAV: adeno-associated virus; apo(a): apolipoprotein(a); ApoB100: apolipoproteinB100; ASGPR, Asialoglycoprotein receptor; ASO: antisense oligonucleotide; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeat; GalNAc: N-Acetylgalactosamine; KIV: kringle IV; Lp(a): lipoprotein(a); mRNA, messenger RNA; RISC: RNA-induced silencing complex; RNAase: ribonuclease; siRNA: small-interfering RNA.…”

Section: Figurementioning

confidence: 99%

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?

Tsioulos,

Kounatidis,

Vallianou

et al. 2024

IJMS

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Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Lp(a) plasma levels are considered to be 70–90% genetically determined through the codominant expression of the LPA gene. Therefore, Lp(a) levels are almost stable during an individual’s lifetime. This lifelong stability, together with the difficulties in measuring Lp(a) levels in a standardized manner, may account for the scarcity of available drugs targeting Lp(a). In this review, we synopsize the latest data regarding the structure, metabolism, and factors affecting circulating levels of Lp(a), as well as the laboratory determination measurement of Lp(a), its role in the pathogenesis of ASCVD and thrombosis, and the potential use of various therapeutic agents targeting Lp(a). In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed.

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