Radiation-primed hepatocyte transplantation in murine monogeneic dyslipidemia normalizes cholesterol and prevents atherosclerosis

Barahman, Mark; Zhang, Wei; Harris, Hillary Yaffe; Aiyer, Anita; Kabarriti, Rafi; Kinkhabwala, Milan; Roy‐Chowdhury, Namita; Beck, Amanda P.; Scanlan, Thomas S.; Roy‐Chowdhury, Jayanta; Asp, Patrik; Guha, Chandan

doi:10.1016/j.jhep.2019.01.010

Cited by 19 publications

(16 citation statements)

References 54 publications

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“…Pharmacological and temporary induction of liver regeneration may, therefore, be a viable strategy to enhance hepatocyte gene repair in a clinical setting. In fact, T3 analogs with hepatocyte specificity have been used in rodents to induce liver regeneration 29 and are in clinical trials for hyperlipidemia in humans. 30 We also investigated whether the FA DNA repair pathway 31,32 plays a role in hepatocyte gene repair.…”

Section: Discussionmentioning

confidence: 99%

Induced Liver Regeneration Enhances CRISPR/Cas9-Mediated Gene Repair in Tyrosinemia Type 1

et al. 2021

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The efficiency of gene repair by homologous recombination in the liver is enhanced by CRISP/Cas9 incision near the mutation. In this study, we explored interventions designed to further enhance in vivo hepatocyte gene repair in a model of hereditary tyrosinemia. A two-AAV system was employed: one virus carried a Staphylococcus pyogenes Cas9 (SpCas9) expression cassette and the other harbored a U6 promoter-driven sgRNA and a fragment of fumarylacetoacetate hydrolase (Fah) genomic DNA as the homologous recombination donor. In neonatal mice, a gene correction frequency of *10.8% of hepatocytes was achieved. The efficiency in adult mice was significantly lower at *1.6%. To determine whether hepatocyte replication could enhance the targeting frequency, cell division was induced with thyroid hormone T3. This more than doubled the gene correction efficiency to 3.5% (p < 0.005). To determine whether SpCas9 delivery was rate limiting, the gene repair AAV was administered to SpCas9 transgenic mice. However, this did not significantly enhance gene repair. Finally, we tested whether the Fanconi anemia (FA) DNA repair pathway was important in hepatocyte gene repair. Gene correction frequencies were significantly lower in neonatal mice lacking the FA complementation group A (Fanca) gene. Taken together, we conclude that pharmacological induction of hepatocyte replication along with manipulation of DNA repair pathways could be a useful strategy for enhancing in vivo gene correction.

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Section: Discussionmentioning

confidence: 99%

Induced Liver Regeneration Enhances CRISPR/Cas9-Mediated Gene Repair in Tyrosinemia Type 1

et al. 2021

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“… 10 , 15 Dyslipidemia is associated with an increased risk of the development of atherosclerosis. 25 Several studies have demonstrated that atherosclerosis promotes neuronal degeneration or neurotransmitter synthesis disorder, 26 , 27 which leads to a disorderly increase in lipid metabolites (such as oxidized lipids). The accumulation of oxidized lipids in the microvasculature stimulates the local release of inflammatory mediators, 28 which can directly initiate and accelerate sensitization of pain-sensing nociceptors located at functional afferent neurons.…”

Section: Discussionmentioning

confidence: 99%

Association of dyslipidemia with chronic non-malignant pain in elderly patients with femoral neck fractures treated by primary total hip arthroplasty: a retrospective study

Wang

et al. 2021

J Int Med Res

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Objective The association of chronic non-malignant pain (CNP) with dyslipidemia is unclear. This retrospective study was performed to evaluate the association between CNP and dyslipidemia in elderly patients with femoral neck fractures (FNFs) treated by primary unilateral total hip arthroplasty (THA). Methods We retrospectively identified 521 consecutive patients with FNFs (AO/OTA type 31B) who underwent primary unilateral THA from 2009 to 2021. The study population was divided into patients with and without CNP. Serum lipids were measured for each patient. The association between CNP and dyslipidemia was assessed using a multivariate binary logistic regression model. Results In total, 436 patients (220 with CNP, 216 without CNP) were eligible for analysis. In the quantile regression, the adverse effect of CNP was significantly attenuated by resilience in patients with a high high-density lipoprotein (HDL) concentration and low low-density lipoprotein (LDL) concentration. The multivariate binary logistic regression model showed that the HDL and LDL concentrations were the only variables significantly associated with the development of CNP. Conclusion Both a low HDL and high LDL concentration may result in the occurrence of CNP in elderly patients with FNFs treated by primary unilateral THA.

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“…Accordingly, irradiation of the host liver has been studied in both rats and humans showing some benefit regarding cell proliferation 45 . Even better results have been obtained by employing the combination of focal radiation with hepatic cell growth stimuli (hepatic mitogen GC-1) in mice 46 . Other approaches include gene therapy to provide a selected repopulating advantage to hepatocytes 47 or strategies to prevent immunological activation that would hamper engraftment 48 .…”

Section: Hepatocyte Transplantation (Ht) and Cell Therapiesmentioning

confidence: 99%

Regenerative hepatology: In the quest for a modern prometheus?

Papatheodoridi

Mazza

Pinzani

2020

Digestive and Liver Disease

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Radiation-primed hepatocyte transplantation in murine monogeneic dyslipidemia normalizes cholesterol and prevents atherosclerosis

Abstract: Background & Aims: Inherited abnormalities in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR) function result in early onset cardiovascular disease and death.

Cited by 19 publications

References 54 publications

Induced Liver Regeneration Enhances CRISPR/Cas9-Mediated Gene Repair in Tyrosinemia Type 1

Induced Liver Regeneration Enhances CRISPR/Cas9-Mediated Gene Repair in Tyrosinemia Type 1

Association of dyslipidemia with chronic non-malignant pain in elderly patients with femoral neck fractures treated by primary total hip arthroplasty: a retrospective study

Regenerative hepatology: In the quest for a modern prometheus?

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