The San Raffaele-Telethon Institute in Milan has been a leading player in gene therapy for many years. Nowadays, Angelo Lombardo, Luigi Naldini, and colleagues are making news with epigenetic editing. Their 2016 paper in Cell on hit-and-run epigenetic editing is considered seminal work. The company they co-founded, Chroma Medicine, received substantial financing, as recently reported by Nature Biotechnology. Last but not least, the presentation given in May at the annual meeting of the American Society of Gene and Cell Therapy inspired a Science news entitled “Better than CRISPR? Another way to fix gene problems may be safer and more versatile.” In brief, they injected mice to silence the expression of the PCSK9 gene, lowering “bad” cholesterol levels for months
From the base-editing idea first sketched out via email in 2013, to the invention of prime-editing in 2019. From the progeria mutation fixed in mice in 2021 to the upcoming clinical trial for coronary heart disease. The updated story of the most advanced CRISPR tools told by Harvard’s David Liu is not to be missed (here’s the link to the Life Itself conference organized by CNN).
The epigenetic way to editing is hot these days. Here are our suggested readings to keep pace:
1) the basics of the tools CRISPRoff and CRISPRon are explained on the website of the Innovative Genomics Institute
2) Nature Biotechnology news on Chroma Medicine, a company pioneering epigenetic editors
3) The Scientist on resetting the DNA of rats to reverse alcohol damage (see also the paper by Bohnsack et al. in Science Advances)
4) the review discussing translational issues in epigenetic editing published by Huerne et al. in The CRISPR Journal.
“Your mission is to make the red bar match the yellow bar”, urges a slide shown by Francis Collins at the annual meeting of the American Society of Gene & Cell Therapy held in Washington. There are almost 7,000 genetic diseases, but only about 500 with therapy. Most are not viable targets in a for-profit setting and won’t be managed by current gene-editing procedures. Hence the call to find something that is scalable. “We need a transformative approach.” Please read Kevin Davies’s account of the inspirational lecture given by the geneticist that led the Human Genome Project, then was appointed director of the NIH, and currently is Joe Biden’s scientific advisor.
The paper “Evolutionary Biology and Gene Editing of Cat Allergen Fel d 1” is a proof of principle but this is only the first step. About 15% of humans have allergic reactions to cats and the major allergen may be nonessential for those animals, given the apparent lack of evolutionary conservation. According to the bioinformatics analysis just published by Nicole Brackett et al. from the US company InBio “Fel d 1 is both a rational and viable candidate for gene deletion, which may profoundly benefit cat allergy sufferers by removing the major allergen at the source”.
Twenty-one years after genome 1.0, the Telomere-to-Telomere Consortium gives us a new assembly (T2T-CHM13) generated by long-read sequencing. It adds approximately 200 megabases of accurate genetic information, roughly equivalent to a whole chromosome. As Deanna Church writes in a perspective it is “an important step to assembly models that represent all humans, which will better support personalized medicine, population genome analysis, and genome editing”. Dont’s miss this Science issue!
Engineering lymphocytes to recognize cancer cells is a strategy that has already produced convincing clinical results thanks to CAR-T therapy. But this is not the only approach on the horizon. An emerging alternative is TCR-engineered lymphocytes, where TCR stands for T-cell receptors.Continue reading
Doug Olson was treated with engineered T cells (CAR-T) for incurable leukemia in 2010, well before CRISPR was born. Over a decade later, he still is cancer-free (see the paper in Nature), and the pioneer of the approach, Carl June, is reported to have said the C-word: cured. As immunotherapy and genome editing are crossing paths, hopefully, we expect further good news from the CAR-T frontier in the future.
The first Investigational New Drug (IND) application for base-editing technology has been cleared by the Food and Drug Administration. BEAM-101, developed by Beam Therapeutics, is an ex vivo base-editing product candidate, meaning that it uses a modified form of CRISPR capable of making single base changes without double-stranded DNA cleavage.Continue reading
“Imagine CRISPR cures” is the title of the keynote by Fyodor Urnov at the World CRISPR Day conference on October 20. The talk was far from a celebration: “The fact that editing represents an approach to the majority of monogenic diseases in principle doesn’t mean that some biotech will take on disease number 823 in practice, and there are over 5,000 monogenic conditions on OMIM. Three years to IND in the best case scenario and cost scale of more than $6m per disease, that’s incompatible with either the promise of CRISPR to edit any given mutation which it can do or the unmet medical needs”. Don’t miss the on-demand video to learn more about the challenge of N=1 trials and Urnov’s call to arm against ultra-rare diseases.