Gene Therapy for Hypertension, Atherosclerosis, and Familial Hypercholesterolemia: The Old Concepts and the New Era
Abstract
:1. Introduction
2. Materials and Methods
3. Gene Therapy for EH
3.1. Targeting the RAAS
3.2. Targeting the β1-Rs
3.3. Targeting Kallikrein
3.4. Targeting Nitric Oxide Synthetase (NOS)
3.5. Targeting Atrial Natriuretic Peptide (ANP)
3.6. Targeting Brain Natriuretic Peptide (BNP)
3.7. Targeting Adrenomedullin (ADM)
3.8. Clinical Trials Developed Evaluating the Pharmacological Correspondence and Clinical Characteristics Based on the Personal Gene Polymorphisms
4. Gene Therapy for Atherosclerosis
4.1. Targeting Lipoprotein Metabolism
4.2. Targeting Inflammation
5. Gene Therapy for FH
5.1. Animal Models for FH Gene Therapy
5.2. FH Gene Therapy Studies in Humans
6. Limitations of the Clinical Implications of Gene Therapy
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AAV | Adeno-associated virus |
ACE | Angiotensin-converting enzyme |
AdeNOS | Ad-encoding endothelial nitric oxide synthase |
ADM | Adrenomedullin |
AmiRNA | Artificial microribonucleic acid |
AngI | Angiotensin I |
AngII | Angiotensin II |
ANP | Atrial natriuretic peptide |
AOGEN | Precursor hormone angiotensinogen gene |
AP | Arterial pressure |
ApoA-I | Apolipoprotein AI |
ApoA-IM | Apolipoprotein A-I Milano |
APOA-V | Apolipoprotein A-V |
ApoB | Apolipoprotein B |
APOC3 | Apolipoprotein C3 |
ApoE | Apolipoprotein E |
AS-ODNs | Antisense synthetic oligodeoxynucleotides |
AT1R | Angiotensin II type 1 receptor |
AT2R | Angiotensin II type 2 receptor |
BNP | Brain natriuretic peptide |
Cdna | Complementary deoxyribonucleic acid |
CMV | Cytomegalovirus |
CVD | Cardiovascular disease |
DBP | Diastolic blood pressure |
DOCA-HR | Deoxycorticosterone acetate-salt hypertensive rats |
EH | Essential hypertension |
eNOS | Endothelial nitric oxide synthase |
FH | Familial hypercholesterolemia |
HDL | High-density lipoprotein |
He | Heterozygous |
HMG-CoA | Β-Hydroxy Β-Methylglutaryl-CoA |
Ho | Homozygous |
IL-10 | Intereukin-10 |
JGCs | Juxtaglomerular cells |
LDL | Low-Density lipoprotein |
LDLR | Low-Density lipoprotein receptor |
Lp(a) | Lipoprotein a |
LPL | Lipoprotein lipase |
LVH | Left ventricular hypertrophy |
MESH | Medical subject headings |
MR | Mineralocorticoid receptor |
mRNA | Messenger ribonucleic acid |
nNOS | Neuronal nitric oxide synthase |
NO | Nitric oxide |
NOS | Nitric oxide synthetase |
PCKS9 | Proprotein convertase subtilisin/kexin type 9 |
PVN | Paraventricular nucleus |
RAAS | Renin–angiotensin–aldosterone system |
RNAi | Ribonucleic acid interference |
ROS | Reactive oxygen species |
RSV | Rous sarcoma virus |
SBP | Systolic blood pressure |
SHR | Spontaneously hypertensive rats |
shRNA | Short hairpin ribonucleic acid |
siRNA | Small interfering ribonucleic acid |
STAT3 | Signal transducer and activator of transcription 3 |
TGF-β | Transforming growth factor beta |
TGs | Triglycerides |
TIMP-1 | Tissue metallopeptidase inhibitor- 1 |
TiO2 | Titanium dioxide |
VCAM-1 | Vascular cell adhesion molecule-1 |
VLDL | Very low-density lipoprotein |
β1-Rs | B-1-adrenergic receptors |
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Study | Method of Gene Administration | Outcome | Reference |
---|---|---|---|
Chao et al. | eNOS gene direct administration | Decrease in SBP and DBP | [77] |
Miller et al. | eNOS gene via AAV vector | Decrease in SBP and DBP | [78] |
Gava et al. | eNOS gene via AAV vector | Prevention of renovascular hypertension | [79] |
Zhao et al. | eNOS cDNA | Decrease in SBP and DBP in hyperglycemic rats | [80] |
Trial Number | Method of Gene Administration | Target | Effect | Reference |
---|---|---|---|---|
FH | ||||
CT-AMT-011-01 | AAV | LPL Deficiency | 40% decrease in TGs in three to 12 weeks | [110] |
NCT02651675 | AAV8 | LDLR | No clinical outcome | [140] |
NCT05043181 | AAV | LDLR | Decrease in TC, TGs, LDL-C, and HDL-C | [141] |
NCT03400800 | AAV | PCSK9 | A 50% decrease in LDL-C | [142] |
NCT03747224 | AAV | PCSK9 | A 42% decrease in LDL-C | [143] |
NCT04606602 | SiRNA | Lp(a) | Dose-dependent decrease in Lp(a) 70% (300 mg) or 80% (600 mg) | [146] |
NCT04270760 | SiRNA | Lp(a) | Lower levels of Lp(a) | [150] |
NCT03626662 | SiRNA | Lp(a) | A 76–91% decrease in Lp(a) levels | [144] |
NCT02900027 | ASO | ApoC3 | A 93% decrease in ApoC3 | [147] |
NCT03385239 | ASO | ApoC3 | Reduction in TG levels | [148] |
NCT02211209 | ASO | ApoC3 | A decrease 84% of ApoC3 | [149] |
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Evangelidis, N.; Evangelidis, P. Gene Therapy for Hypertension, Atherosclerosis, and Familial Hypercholesterolemia: The Old Concepts and the New Era. Biologics 2024, 4, 143-160. https://doi.org/10.3390/biologics4020010
Evangelidis N, Evangelidis P. Gene Therapy for Hypertension, Atherosclerosis, and Familial Hypercholesterolemia: The Old Concepts and the New Era. Biologics. 2024; 4(2):143-160. https://doi.org/10.3390/biologics4020010
Chicago/Turabian StyleEvangelidis, Nikolaos, and Paschalis Evangelidis. 2024. "Gene Therapy for Hypertension, Atherosclerosis, and Familial Hypercholesterolemia: The Old Concepts and the New Era" Biologics 4, no. 2: 143-160. https://doi.org/10.3390/biologics4020010