Biomedical subjects

M Cecilia Ljungberg

Publications and source records attributed to M Cecilia Ljungberg.

3 recordsLinked to original sources

PubMed2025

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene.

Homology-directed repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, fumarylacetoacetate hydrolase (Fah), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, human factor IX (FIX). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.

Animals↗

PubMed2006

Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia.

OBJECTIVE: The cortex of patients with cortical dysplasia contains several abnormal cell types. Among the dysplastic cells, cytomegalic neurons are known to be electrically hyperactive and may contribute to epileptic activity. In this study, we sought to identify molecular markers of cytomegalic neurons in focal or hemispheric cortical dysplasia and to determine whether the activity of the mammalian target of rapamycin (mTOR) kinase is abnormally high in these cells. METHODS: Microarray analysis of gene expression in large dysplastic cells microdissected from cortical dysplasia surgical specimens was used to identify markers of cytomegalic neurons. Immunohistochemistry and immunofluorescence analysis of cortical sections was used to validate the microarray results and to probe the activity of mTOR in cytomegalic neurons using phospho-specific antibodies directed against known mTOR targets. RESULTS: We demonstrate that the neurofilament heavy chain is a reliable marker of cytomegalic neurons and that targets of the mTOR kinase, such as the ribosomal protein S6, eIF4G, and Akt, are hyperphosphorylated in these dysplastic neurons. INTERPRETATION: We conclude that mTOR kinase hyperactivation is a molecular mechanism underlying the development of cytomegalic neurons. This finding may lead to the development of novel therapeutic approaches for childhood epilepsy associated with cortical dysplasia.

Adolescent↗

PubMed2002

Truncated apoE forms tangle-like structures in a neuronal cell line.

Apolipoprotein E is the predominant brain lipoprotein and polymorphic variation in the APOE gene the major genetic susceptibly factor for late onset Alzheimer's disease (AD). Recently it was reported that carboxyl-truncated ApoE fragments induce tangle-like structures in neurons. We confirm the finding: in mouse neuroblastoma cells truncated apoE fragments lacking the carboxyterminus induce structures that have the appearance of neurofibrillary tangles. However these tangles are not induced in non-neuronal cells even in the presence of co-expressed neurofilaments or tau. Further understanding of the basis of this cell specificity might add to understanding of the cell specificity of tangles in AD.

Alzheimer Disease↗