Tag Archives: CRISPR-Cas9

A “Swell Diagnosis” (part 2)

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Recently, this blog post reviewed a case presentation of hereditary angioedema which often presents with bouts of severe abdominal pain: “A Swell Diagnosis”

Now, a study has shown how this can be effectively treated with CRISPR gene editing:

  • HJ Longhurst et al. N Engl J Med 2024; 390:432-441. CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

My take: Gene therapies have been very expensive. If this therapy is approved for hereditary angioedema it will be too. However, some of the current treatments for preventing hereditary angioedema are also quite costly.

Related blog posts:

“Our Gene-Edited Future”

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NPR: He Inherited A Devastating Disease. A CRISPR Gene-Editing Breakthrough Stopped It

Previously the CRISPR gene-editing has been used to counter genetic defects in conditions like sickle cell and thalasemia. This has involved taking cells out of the body, editing them in the lab, and infusing them back in or injecting CRISPR directly into cells that need fixing.

Now, scientists are directly injecting nanoparticles with the CRISPR gene-editing tools. Here’s an excerpt:

Doctors infused billions of microscopic structures known as nanoparticles carrying genetic instructions for the CRISPR gene-editor into four patients in London and two in New Zealand. The nanoparticles were absorbed by their livers, where they unleashed armies of CRISPR gene-editors. The CRISPR editor honed in on the target gene in the liver and sliced it, disabling production of the destructive protein.

Within weeks, the levels of protein causing the disease plummeted, especially in the volunteers who received a higher dose. Researchers reported at the Peripheral Nerve Society Annual Meeting and in a paper published in The New England Journal of Medicine.

“This is really opening a new era as we think about gene-editing where we can begin to think about accessing all kinds of different tissue in the body via systemic administration“

Related study: JD Gilmore et al. NEJM. 2021. DOI: 10.1056/NEJMoa2107454. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

My take: This type of discovery could dramatically improve the treatment of many diseases including heart disease, muscular dystrophy and brain diseases such as Alzheimer’s.

Related blog post: Genetically Modified Humans: Genome Editing 101

Genetically Modified Humans: Genome Editing 101

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In a review at last year’s NASPGHAN meeting, John Barnard gave a basic science review (Basic Science Year in Review -#NASPGHAN 2014 | gutsandgrowth) that touched on CRISPR-Cas9 for genome engineering (Cell 2014; 157: 1262-78).  Reading through a recent editorial (Lander ES. NEJM 2015; 373: 5-7), it seems that the potential for genome editing is not that far from landing into clinical use.

His points:

Genome editing holds great therapeutic promise…

  • “physicians might edit a patient’s immune cells to delete the CCR5 gene, conferring the resistance to HIV carried by the 1% of the U.S. population.”
  • “Editing blood stem cells might cure sickle cell anemia and hemophilia.”
  • Eliminate genes which increase the risk for Alzheimer’s, Huntingdon’s disease and heart attacks

Concerns:

  • “Genetically modified humans” and true “designer babies”
  • Technical issues to perform editing with precision.
  • Unanticipated effects with various edits. “We remain terrible at predicting the consequences of even simple genetic modification.”
  • Who decides?  Future generations cannot consent to their modification.
  • Is it morally right? “Would the ‘best’ genomes go to the most privileged?”

In the U.S., genome editing would not garner approval from FDA or NIH in the near future. But, given the advancing technical capabilities, it is not too early to begin the discussion about genome editing.  At the very least, this technology should spurn a couple great sci-fi movies.

Take-home point: “Authorizing scientists to make permanent changes to the DNA of our species is a decision that should require broad societal understanding and consent…We should exercise great caution before we rewrite” the human genome.

Zoo Atlanta (Kinda looks like a genetically-modified giraffe)

Zoo Atlanta (Kinda looks like a genetically-modified giraffe)

Basic Science Year in Review –#NASPGHAN 2014

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John Barnard –Basic Science Year in Review

“Emerging Trends and Provocative Findings in Basic Science”

This blog entry has abbreviated/summarized this terrific presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  To minimize these issues, I have placed a link to most of Dr. Barnard’s slides which he shared:

2014 John Barnard Slides

“Big Data” –big increase in “big data” cited in pubmed over past year.

  • Good read on this subject: Foreign Affairs: The Rise of Big Data Kenneth Cukier

Scientific fraud –more attention to this issue this past year. Two papers in Nature were retracted. One researcher committed suicide and one arrested. Scientific fraud undermines important messages & ruins credibility of other important advances.

CRISPR-Cas9: Gene editing.  CRISPRs –“RNA guides”  Cas9: “molecular scissors” (endonucleases)

“Genome editing has never been easier.”  Examples:

  • Cell Stem Cell 2013: 13: 653-58. “Functional repair of CFTR by CRISPR-Cas9”
  • Also, genome editing has been used in mouse model of tyrosinemia.

Liver regeneration in zebrafish. Implication: Liver cells will be regenerated in humans. Gastroenterol 2014; 146: 789.

Microbiome Big Data:

  • J Clin Invest 2014; 124: 3617. This was a very important and complex study.  The slides explaining this study start at slide 35.
  • Pediatric Crohn disease exhibit specific ileal transcriptome and microbiome signature.
  • RISK study (CCFA). Treatment-naïve, 28 sites.
  • 1281 ileal host genes in ileocolonic Crohn’s, 1055 in Colonic Crohn’s had ileal host genes =82% similar, 232 host genes in ulcerative colitis –18% similar to ileocolonic Crohn’s.
  • Tissue microbiomes are where changes are noted; changes are not evident in luminal microbiome.
  • Antibiotics worsen dysbiosis.
  • Microbiome at diagnosis strongly correlates with Crohn’s disease.

Microbiome –affects the entire body:

  • J Clin Invest 2014; 124: 3391. Incorporation of microbes with genetically-engineered E coli can prevent obesity in mice

Recommended Reading by Dr. Barnard: “Missing Microbes” How the overuse of antibiotics is fueling our modern plagues. Martin Blaser