AAV1-LPLS447X gene therapy reduces hypertriglyceridemia in apoE2 knock in mice
Abstract
Unlabelled Intramuscular (IM) application of adeno-associated virus serotype 1 (AAV1) for the delivery of human lipoprotein lipase (hLPL) was previously shown efficacious in mice with chylomicronemia. The current study addresses whether AAV1-LPL(S447X) can reduce elevated triglyceride (TG) levels in mice with attenuated clearance of TG-rich remnant particles.Methods Female mice, expressing human apoE2 but deficient for endogenous apoE (apoE2KI) received IM injections of AAV1-LPL(S447X) (n=6; 8 x 10(12) gc/kg; 4-sites) or PBS (n=5). Following lipid monitoring, the mice were challenged with intravenous Intralipid injections, and sacrificed 3 months after treatment.Results In the mice that received LPL gene therapy, a marked increase of post-heparin hLPL protein levels (averaging 517+/-277 ng/mL vs. 4+/-3 ng/mL in apoE2KI-untreated) induced 20% reductions of fasting plasma TG levels (p<0.05). This was accompanied by two-fold increased TG clearance rates after Intralipid administration at 6 weeks after treatment (p<0.05). Post-mortem analyses revealed increased levels of TG (2-fold, p<0.005) and cholesterol (1.7-fold, p<0.001) in the treated muscles.Conclusions IM application of AAV1-LPL(S447X) is effective in reducing TG levels in a mouse model for type III dyslipidemia. Thus, hypertriglyceridemia caused by attenuated uptake of TG-rich lipoproteins can be alleviated by increasing lipolytic function of the skeletal muscle tissue.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
After alipogene tiparvovec, TG drifted back to baseline levels within 6 months, although a few exceptional cases experienced sustained benefits.
“Unfortunately, TG drifted back to baseline levels within 6 months, although a few exceptional cases experienced sustained benefits.84–87”
From Clinical review on triglycerides (2020) · cites this paper as [86]
Spinal anaesthesia was needed for intramuscular injections of the adeno-associated virus subtype 1 vector carrying hyperfunctional LPL p.S447X; TG normalized within 12 weeks.
“Spinal anaesthesia was needed for intramuscular injections of the adeno-associated virus subtype 1 vector carrying hyperfunctional LPL p.S447X; TG normalized within 12 weeks.84–86”
From Clinical review on triglycerides (2020) · cites this paper as [86]
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · see citing works
Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis
Goldberg, I. J. (1996) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37569-6 · Cited by 1,009 · see citing works
Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34954-8 · Cited by 673 · see citing works
Beisiegel†, U., Weber, W., & Bengtsson-Olivecrona, G. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.19.8342 · Cited by 626 · see citing works
Weinstock, P. H., Bisgaier, C. L., Aalto‐Setälä, K., Radner, H., Ramakrishnan, R., Levak‐Frank, S., Essenburg, A. D., Zechner, R., & Breslow, J. L. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118319 · Cited by 299 · see citing works
Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome.
Brunzell, J. (1989) · Medical Entomology and Zoology · Cited by 285 · see citing works
The biochemical, clinical, and genetic features of type III hyperlipoproteinemia.
MORGANROTH, J., LEVY, R. I., & FREDRICKSON, D. S. (1975) · Annals of Internal Medicine · doi:10.7326/0003-4819-82-2-158 · Cited by 260 · see citing works
Sullivan, P. M., Mezdour, H., Quarfordt, S. H., & Maeda, N. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2673 · Cited by 254 · see citing works
Distribution and Kinetics of Lipoprotein-Bound Endotoxin
Levels, J. H. M., Abraham, P. R., van den Ende, A., & van Deventer, S. J. H. (2001) · Infection and Immunity · doi:10.1128/iai.69.5.2821-2828.2001 · Cited by 234 · see citing works
Levak‐Frank, S., Radner, H., Walsh, A., Stollberger, R., Knipping, G., Höefler, G., Sattler, W., Weinstock, P. H., Breslow, J. L., & Zechner, R. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118145 · Cited by 218 · see citing works
Lipoproteins in Health and Diseases
Betteridge, J. D., Illingworth, D. R., & Shepherd, J. (1999) · Oxford University Press eBooks · Cited by 123 · see citing works
Coleman, T., Seip, R. L., Gimble, J. M., Lee, D., Maeda, N., & Semenkovich, C. F. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.21.12518 · Cited by 113 · see citing works
Ross, C. J., Twisk, J., Bakker, A. C., Miao, F., Verbart, D. J., Rip, J., Godbey, T., Dijkhuizen, P. A., Hermens, W. T. J. M. C., Kastelein, J. J. P., et al. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.487 · Cited by 82 · see citing works
Self-citationGinzinger, D. G., Lewis, M. E. S., Ma, Y., Jones, B. R., Liu, G., & Jones, S. D. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118541 · Cited by 80 · see citing works
Ross, C. J., Twisk, J., Meulenberg, J. J. M., Liu, G., van den Oever, K., Moraal, E., Hermens, W. T., Rip, J., Kastelein, J. J. P., Kuivenhoven, J. A., et al. (2004) · Human Gene Therapy · doi:10.1089/hum.2004.15.906 · Cited by 78 · see citing works
Self-citationZhang, H., Reymer, P. W. A., Liu, M.-S., Forsythe, I. J., Groenemeyer, B. E., Frohlich, J. J., Brunzell, J. D., Kastelein, J. J. P., Hayden, M. R., & Ma, Y. (1995) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.15.10.1695 · Cited by 68 · see citing works
Self-citationRoss, C. J., Liu, G., Kuivenhoven, J. A., Twisk, J., Rip, J., van Dop, W. A., Excoffon, K. J. D. A., Lewis, M. E. S., Kastelein, J. J. P., & Hayden, M. R. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000176971.27302.b0 · Cited by 65 · see citing works
Self-citationGene Therapy for Lipoprotein Lipase Deficiency: Working Toward Clinical Application
Rip, J., Nierman, M. C., Sierts, J. A., Petersen, W., van den Oever, K., van Raalte, D. H., Ross, C. J., Hayden, M. R., Bakker, A. C., Dijkhuizen, P. A., et al. (2005) · Human Gene Therapy · doi:10.1089/hum.2005.16.1276 · Cited by 63 · see citing works
Self-citationZheng, C., Murdoch, S. J., Brunzell, J. D., & Sacks, F. M. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000203512.01007.3d · Cited by 48 · see citing works
Phenotypic Correction of Feline Lipoprotein Lipase Deficiency by Adenoviral Gene Transfer
Liu, G., Excoffon, K. J. D. A., Wilson, J. E., et al. (2000) · Human Gene Therapy · doi:10.1089/10430340050016120 · Cited by 42 · see citing works
Höefler, G., Noehammer, C., Levak‐Frank, S., et al. (1997) · Biochimie · doi:10.1016/s0300-9084(97)81509-x · Cited by 39 · see citing works
Bruemmer, D., Evans, D., Berg, D. V., Greten, H., Beisiegel†, U., & Mann, W. A. (1998) · Journal of Molecular Medicine · doi:10.1007/s001090050227 · Cited by 26 · see citing works
Lipoprotein lipase deficiency with pancreatitis in mink: biochemical characterization and pathology
Christophersen, B. O., Nordstoga, K., Shen, Y. H., Olivecrona, T., & Olivecrona, G. (1997) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37209-6 · Cited by 26 · see citing works
Mann, W. A., Meyer, N., Berg, D. V., Greten, H., & Beisiegel†, U. (1999) · Atherosclerosis · doi:10.1016/s0021-9150(99)00015-5 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Clinical review on triglycerides
Laufs, U., Parhofer, K. G., Ginsberg, H. N., & Hegele, R. A. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz785 · Cited by 544 · see citing works
Chylomicronaemia–current diagnosis and future therapies
Brahm, A. J., & Hegele, R. A. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.26 · Cited by 356 · see citing works
Lipid-Lowering Agents: Targets Beyond PCSK9
Hegele, R. A., & Tsimikas, S. (2019) · Circulation Research · doi:10.1161/circresaha.118.313171 · Cited by 171 · see citing works
- Authors
- Rip, J., van Dijk, K. W., Sierts, J. A., Kastelein, J. J. P., Twisk, J., & Kuivenhoven, J. A.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 1761
- Issue
- 10
- Pages
- 1163-1168
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W2037618939
- Cited by
- 11
- References
- 24
- Citations by year
- 2022: 2 · 2019: 2 · 2017: 1 · 2015: 2 · 2014: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- lipoprotein lipase, hypertriglyceridemia, triglyceride-rich lipoproteins, triglyceride clearance, intramuscular injection
- MeSH terms
- Dependovirus, Animals, Female, Genetic Vectors, Humans, Injections, Intramuscular, Lipids, Lipoprotein Lipase, Mice, Transgenic, Muscles, Triglycerides, Hypertriglyceridemia, Genetic Therapy, Mice, Apolipoprotein E2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
