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Global Translational Medicine ABE gene therapy for CVDs

rAAV vectors . Alternatively, the recent engineering of derived from HGPS patients. After a puromycin selection
[30]
smaller Cas proteins and the more compact designs of for virus-transduced cells, the authors observed ~84%
the rAAV vector has enabled ABE delivery using a single correction of the pathogenic mutation, substantially
rAAV particle . reduced progerin expression, and the ameliorated nuclear
[31]
[30]
Another well-established tool for in vivo ABE delivery shape phenotypes .
is the LNPs, which are nanoscale semi-solid particles that Next, the same team designed a dual-AAV system to
are assembled by four types of lipids, namely, cholesterol, deliver ABEs to a transgenic HGPS mouse model that
phospholipids, ionizable lipids, and PEGylated (PEG constitutively expresses the human progerin (Figure 2A).
means polyethylene glycol) lipids. The ionizable lipid A single intravenous injection of these AAVs resulted in
can undergo a pH-dependent charge conversion and variable editing efficiencies (10 – 60%) among the heart,
allow mRNA encapsulation into LNP . On intravenous the quad, the liver, the aorta, and the bones. Strikingly,
[32]
administration, conventional LNPs deliver nucleic acids this single-dose treatment was sufficient to reduce the loss
primarily to the liver. The recent development of novel of vascular smooth muscle cells and the periadventitial
lipid formulas allows LNPs to target the lungs, the spleen, thickening of the aorta, which are key pathological
and some other organs . features of HGPS. This ABE treatment also increased the
[33]
Since the first U.S. Food and Drug Administration median lifespan of the mouse model from 215 to 510 days,
[30]
(FDA) approval of LNP drugs in 2018 , LNPs have drawn approaching the old age of healthy mice . Therefore,
[34]
tremendous attentions from both biotechnological and AAV-mediated ABE treatment might potentially be a
pharmaceutical researchers. LNPs have demonstrated a permanent cure for HGPS in the future.
great safety record largely, because the lipid components 3.2. Inherited hypertrophic cardiomyopathy
can be quickly metabolized and cleared from the body. As
the major vector for COVID-19 mRNA vaccine, the LNP In addition to HGPS, hypertrophic cardiomyopathy
technology and industry are both rapidly growing and (HCM) is another CVD that would potentially benefit from
maturing . LNPs have recently carried the first ABE drug ABE treatment. Unlike HGPS, which is a very rare disease
[32]
for CVDs into a clinical trial (NCT05398029), holding the with a prevalence of 1 in 20 million people, HCM is the
great promise to facilitate ABE-based treatment of more leading cause of cardiac sudden death in people younger
[40]
human diseases. than 35-years-old . HCM is featured by the excessive
thickening of myocardium and the hypercontractile
3. Landmark studies of ABE therapy for CVDs phenotype of cardiomyocytes . SNVs in genes coding
[41]
[42]
3.1. Hutchinson-gilford progeria syndrome sarcomere proteins, particularly MYH7 and MYBPC3 , are
the major causes of HCMs. Despite the recent development
One of the first evidence demonstrating the effectiveness of cardiac myosin inhibitors [43-45] as breakthrough drugs for
of ABE in gene therapy involves the Hutchinson-Gilford HCM, their application is usually limited to a subgroup of
Progeria Syndrome (HGPS) . HGPS is a rare disease with HCM patients, and their therapeutic effects are far from
[30]
whole-body premature aging phenotypes. Among these being satisfactory. Therefore, it is critical to develop a new
phenotypes, vascular malformation and dysfunction are approach to treat this disease.
most critical as these patients usually die of atherosclerosis
and heart attacks in their teens . Therefore, here we Dr. Feng Lan’s group performed the first proof-of-
[35]
treated HGPS as a special type of CVD. concept study to test the ability of ABE to treat HCM in
mice . They created a clinically relevant mouse model
[46]
HGPS is commonly caused by a heterozygous LMNA carrying the HCM pathogenic MYH6-R404Q/+ mutation
c.1824 C>T/p.G608G mutation. This mutation activates a (Myh6 c.1211C>T) and validated its pathogenic role in
cryptic splicing site in the gene and aberrantly produces HCM. Then, they microinjected ABEmax-NG mRNA
a splicing variant protein called progerin [36-38] . Despite and sgRNA into the mutant zygotes, allowing the embryo
much effort to reduce the toxic effects of progerin, to develop to birth, and then genotyped the animals to
particularly with the development of the FDA-approved evaluate the effect of the ABE (Figure 2B). Their results
farnesyltransferase inhibitor drugs , the patients can only demonstrated that the overall editing efficiency is 91% on
[39]
survive for another 2–3 years. the Myh6 c.1211C>T loci among the mutant embryos. The
The LMNA c.1824 C>T mutation falls into the SNV genetically corrected mice showed normal heart weight,
category that is editable by ABE. To test this idea, Dr. David less fibrosis, orderly arranged myofilaments, and normal
Liu’s team firstly used a lentiviral vector to deliver the left ventricular wall thickness, effectively preventing the
ABEmax-VRQR base editors to treat fibroblasts that are HCM phenotypes in the R404Q/+ mice.

Volume 2 Issue 1 (2023) 5 https://doi.org/10.36922/gtm.232