Publications by authors named "Olga Krabbe"

3 Publications

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Author Correction: Predictable and precise template-free CRISPR editing of pathogenic variants.

Nature 2019 03;567(7746):E1-E2

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

In this Article, a data processing error affected Fig. 3e and Extended Data Table 2; these errors have been corrected online.
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http://dx.doi.org/10.1038/s41586-019-0938-4DOI Listing
March 2019

Predictable and precise template-free CRISPR editing of pathogenic variants.

Nature 2018 11 7;563(7733):646-651. Epub 2018 Nov 7.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Following Cas9 cleavage, DNA repair without a donor template is generally considered stochastic, heterogeneous and impractical beyond gene disruption. Here, we show that template-free Cas9 editing is predictable and capable of precise repair to a predicted genotype, enabling correction of disease-associated mutations in humans. We constructed a library of 2,000 Cas9 guide RNAs paired with DNA target sites and trained inDelphi, a machine learning model that predicts genotypes and frequencies of 1- to 60-base-pair deletions and 1-base-pair insertions with high accuracy (r = 0.87) in five human and mouse cell lines. inDelphi predicts that 5-11% of Cas9 guide RNAs targeting the human genome are 'precise-50', yielding a single genotype comprising greater than or equal to 50% of all major editing products. We experimentally confirmed precise-50 insertions and deletions in 195 human disease-relevant alleles, including correction in primary patient-derived fibroblasts of pathogenic alleles to wild-type genotype for Hermansky-Pudlak syndrome and Menkes disease. This study establishes an approach for precise, template-free genome editing.
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http://dx.doi.org/10.1038/s41586-018-0686-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517069PMC
November 2018

Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis.

Immunology 2018 02 26;153(2):179-189. Epub 2017 Oct 26.

Department of Molecular Cancer Research and Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

The global obesity epidemic and its associated co-morbidities, including type 2 diabetes, cardiovascular disease and certain types of cancers, have drawn attention to the pivotal role of adipocytes in health and disease. Besides their 'classical' function in energy storage and release, adipocytes interact with adipose-tissue-resident immune cells, among which are lipid-responsive invariant natural killer T (iNKT) cells. The iNKT cells are activated by lipid antigens presented by antigen-presenting cells as CD1d/lipid complexes. Upon activation, iNKT cells can rapidly secrete soluble mediators that either promote or oppose inflammation. In lean adipose tissue, iNKT cells elicit a predominantly anti-inflammatory immune response, whereas obesity is associated with declining iNKT cell numbers. Recent work showed that adipocytes act as non-professional antigen-presenting cells for lipid antigens. Here, we discuss endogenous lipid antigen processing and presentation by adipocytes, and speculate on how these lipid antigens, together with 'environmental factors' such as tissue/organ environment and co-stimulatory signals, are able to influence the fate of adipose-tissue-resident iNKT cells, and thereby the role of these cells in obesity and its associated pathologies.
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http://dx.doi.org/10.1111/imm.12839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765379PMC
February 2018