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LPA disruption with AAV-CRISPR potently lowers plasma apo(a) in transgenic mouse model: A proof-of-concept study.
Doerfler, Alexandria M; Park, So Hyun; Assini, Julia M; Youssef, Amer; Saxena, Lavanya; Yaseen, Adam B; De Giorgi, Marco; Chuecos, Marcel; Hurley, Ayrea E; Li, Ang; Marcovina, Santica M; Bao, Gang; Boffa, Michael B; Koschinsky, Marlys L; Lagor, William R.
Affiliation
  • Doerfler AM; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Park SH; Department of Bioengineering, Rice University, Houston, TX 77030, USA.
  • Assini JM; Department of Biochemistry, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, ON N6A 5B7, Canada.
  • Youssef A; Robarts Research Institute, Schulich School of Medicine and Dentistry, London, ON N6G 2V4, Canada.
  • Saxena L; Department of Bioengineering, Rice University, Houston, TX 77030, USA.
  • Yaseen AB; Department of Bioengineering, Rice University, Houston, TX 77030, USA.
  • De Giorgi M; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Chuecos M; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Hurley AE; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Li A; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Marcovina SM; Department of Bioengineering, Rice University, Houston, TX 77030, USA.
  • Bao G; Medpace Reference Laboratories, Cincinnati, OH 45227, USA.
  • Boffa MB; Department of Bioengineering, Rice University, Houston, TX 77030, USA.
  • Koschinsky ML; Department of Biochemistry, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, ON N6A 5B7, Canada.
  • Lagor WR; Robarts Research Institute, Schulich School of Medicine and Dentistry, London, ON N6G 2V4, Canada.
Mol Ther Methods Clin Dev ; 27: 337-351, 2022 Dec 08.
Article in En | MEDLINE | ID: mdl-36381302
Lipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles and consists of an apolipoprotein(a) (apo(a)) molecule covalently bound to apolipoprotein B-100. The metabolism of Lp(a) particles is distinct from that of low-density lipoprotein (LDL) cholesterol, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for cardiovascular disease. Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a). We generated an LPA transgenic mouse model expressing apo(a) of physiologically relevant size. Adeno-associated virus (AAV) vector delivery of CRISPR-Cas9 was used to disrupt the LPA transgene in the liver. AAV-CRISPR nearly completely eliminated apo(a) from the circulation within a week. We performed genome-wide off-target assays to determine the specificity of CRISPR-Cas9 editing within the context of the human genome. Interestingly, we identified intrachromosomal rearrangements within the LPA cDNA in the transgenic mice as well as in the LPA gene in HEK293T cells, due to the repetitive sequences within LPA itself and neighboring pseudogenes. This proof-of-concept study establishes the feasibility of using CRISPR-Cas9 to disrupt LPA in vivo, and highlights the importance of examining the diverse consequences of CRISPR cutting within repetitive loci and in the genome globally.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: Mol Ther Methods Clin Dev Year: 2022 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: Mol Ther Methods Clin Dev Year: 2022 Document type: Article Affiliation country: Country of publication: