diff --git a/docs/pages/blog/cutonestrand.mdx b/docs/pages/blog/cutonestrand.mdx new file mode 100644 index 0000000..28c34a6 --- /dev/null +++ b/docs/pages/blog/cutonestrand.mdx @@ -0,0 +1,80 @@ +--- +layout: minimal +authors: + - "[cbenoit](www.linkedin.com/in/clement-benoit)" +date: 2024-08-01 +--- + +# How data analysis can help to fix genetic disorders + +## Introduction + +Gene therapy as seen a major breakthrough with the development of **CRISPR-Cas9** technology. +This revolutionary tool allows scientists to precisely edit genes, offering new hope for +treating genetic disorders and diseases. **With the potential to correct genetic mutations at +the source, CRISPR-Cas9 opens up a world of possibilities for personalized medicine and targeted therapies.** +The future of gene therapy looks brighter than ever, + with the promise of improved treatments and even potential cures for a wide range of conditions. + +[Autosomal-dominant disorders](https://www.genome.gov/genetics-glossary/Autosomal-Dominant-Disorder) are among the diseases that could see gene treatments in the future. +As the name dominant implies, the presence of a single pathogenic mutated allele is sufficient for +the disease to appear, so some researchers are counting on crispr-cas9 technology to break the mutated allele. +Only the wild-type allele remains, and the disease is thus cured. +Although the effectiveness of this approach looks promising [^1] [^2] [^3], a number of issues still need +to be addressed, two of which we will try to address in this article : + +

+

+ + How can the design of these personalized medicine treatments can be effective and quick for each patient ?

+ How can we specifically target the mutated allele without breaking the functional allele or another part of + the genome ? +
+
+

+ +## Data analysis can be use to create a list of interesting genomic regions for gene therapy + +The targeted genome cleavage is achieved by targeting sequence-specific cleavage of S. pyogenes Cas9 (spCas9) +endonuclease with a gRNA. In order for the gRNA to successfully direct Cas9 cleavage, +the corresponding target DNA sequence in the genome must be found next to a PAM site, +also known as a Protospacer Adjacent Motif. The canonical PAM is associated with the spCas9 nuclease is **5'-NGG-3'**. +We are therefore going to try to draw up an exhaustive list of all the genomic regions that could be used for this +gene therapy. +1) We start by selecting all the SNPs that are frequent in the population (> 5%), for which we can +use the gnomAD database [^4]. We want the list created to be usable to treat as many +patients as possible, so we avoid SNPs that are too rare. +2) Only SNPs that induce the disappearance or appearance of the **5‘-NGG-3’** + motif will allow us to target only the mutated allele while preserving the WT. To do this, we wrote an in-house script in Python. +3) We used the [jvarkit tools suite](https://github.com/lindenb/jvarkit) to reconstitute the genomic context of these SNPs, i.e. +to add the flanking sequences to the left and right of our SNPs of interest, according to the human reference genome. +4) Finally, we used the [FlashFry](https://github.com/mckennalab/FlashFry) tool to calculate and predict efficiency and specificity +scores for each of the positions we selected. We wanted to cut the diseased gene efficiently, +without altering other regions of the genome. + +Using this method, we were able to draw up a list of genomic positions of interest in the treatment of Ryanodine receptor +type 1-related myopathies (RYR1-RM) of the ‘Autosomal-Dominant-Disorder’ type. [^5] +Thanks to next-generation sequencing, it is possible to obtain both genomic sequences of a patient +at a reasonable cost. All the positions on our list for which the patient is heterozygous are therefore +candidates for gene therapy! + +[Check out the analysis code here !](https://github.com/clbenoit/CutOneStrand) + +## Generalization + +Of course, the implementation of gene therapy has to deal with other obstacles and questions, +but this approach can be generalised to other Autosomal-Dominant-Disorders and enable carers to +screen the genome extensively in order to create a short list of regions +of interest for this type of gene therapy ! + + +[^1]: Anzalone A.V, Koblan L.W and Liu D.R . **Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors** [DOI](https://www.nature.com/articles/s41587-020-0561-9) +[^2]: F Chemello, A.C Chai, H Li, C Rodriguez-Caycedo, E Sanchez-Ortiz, A Atmanli, A.A Mireault, N Liu, + R Bassel-Duby, E.N Olson. **Precise correction of Duchenne muscular dystrophy exon + deletion mutations by base and prime editing** [DOI](https://pubmed.ncbi.nlm.nih.gov/33931459/) +[^3]: Kelly Godbout, Joël Rousseau, Jacques P Tremblay. **Successful Correction by Prime Editing of a + Mutation in the RYR1 Gene Responsible for a Myopathy** [DOI](https://www.mdpi.com/2073-4409/13/1/31) +[^4]: [The Genome Aggregation Database (gnomAD)](https://gnomad.broadinstitute.org/about) +[^5]: Mathilde Beaufils, Margaux Melka, Julie Brocard, Clement Benoit, Nagi Debbah, Kamel Mamchaoui, +Norma B. Romero, Anne Frédérique Dalmas-Laurent, Susana Quijano-Roy, Julien Fauré, John Rendu +and Isabelle Marty. **Functional benefit of CRISPR-Cas9-induced allele deletion for RYR1 dominant mutation** \ No newline at end of file diff --git a/docs/pages/blog/gsea.mdx b/docs/pages/blog/gsea.mdx index a7fc762..eec1c12 100644 --- a/docs/pages/blog/gsea.mdx +++ b/docs/pages/blog/gsea.mdx @@ -5,7 +5,7 @@ authors: date: 2024-02-15 --- -# A quick overview of GSEA analysis +# A quick overview of Gene sets enrichment analysis ## Why GSEA Analysis ? @@ -15,7 +15,8 @@ This is why reproducibility is one of the major challenges facing studies involv Finally, interpreting lists of thousands of differentially expressed genes is a tedious exercise for the biologist. -The GSEA, by dezooming from the scale of the gene to that of the pathway. Improves the reproducibility of studies, while facilitating their interpetation. +The GSEA, by dezooming from the scale of the gene to that of the pathway. Improves the reproducibility of studies, +while facilitating their interpetation. ## Principles diff --git a/docs/pages/index.mdx b/docs/pages/index.mdx index d8b144f..ad12f74 100755 --- a/docs/pages/index.mdx +++ b/docs/pages/index.mdx @@ -7,7 +7,7 @@ import { HomePage } from "vocs/components"; {/* */} -

I'm Clement BENOIT

+

Hi !

I'm Clement BENOIT


I'm a Grenoble based data engineer with a specialty in omics bioinformatics , currently working at Grenoble Alpes University Hospital (CHUGA), helping build tools to leverage health data for clinical diagnosis.