CRISPR/Cas9 May Be Better Than Gene Therapy at Increasing FIX Activity - Hemophilia News Today

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The gene-editing tool CRISPR/Cas9 may be superior to conventional gene therapy at increasing the activity of artificial factor IX (FIX), the blood-clotting protein missing in people with hemophilia B, according to a study in primates by Intellia Therapeutics.

Using a mouse model of liver regeneration, Intellia investigators also showed that when CRISPR/Cas9 is used to insert the human version of F9 — the gene that encodes FIX — inside liver cells, its activity levels remain stable, even as these cells proliferate to restore lost tissue.

The data were presented by Anthony Forget, PhD, senior director of genome editing at Intellia, during a talk titled, “A Modular CRISPR/Cas9 Genome Editing Platform for Durable Therapeutic Knockout and Targeted Gene Insertion Applications,” at the 16^th Annual Meeting of the Oligonucleotide Therapeutics Society. The 2020 Virtual Conference was held online Sept. 27-30.

CRISPR/Cas9 is a gene-editing tool that can be used to remove, add, or change a portion of the DNA sequence of a gene of interest. It is based on a “cut-and-paste” mechanism, in which the enzyme Cas9 is guided toward a specific DNA region with the help of a small guide RNA molecule. RNA and DNA are both nucleic acids, with RNA being produced from DNA.

This technology is currently being used by Intellia and Regeneron Pharmaceuticals to develop new treatments for different types of hemophilia. The companies recently expanded their original six-year collaboration agreement, originally launched in 2016 to develop, license, and commercialize these potential therapies.

In earlier studies, the companies reported their scientists had successfully used CRISPR/Cas9 to insert the F9 gene into the liver of non-human primates. The modified gene also increased the production and activity of FIX.

Now, Intellia presented new data from a six-week study that demonstrated a successful increase in FIX activity, to normal or even beyond normal limits, in the blood of non-human primates. According to the company, FIX activity levels may be fine-tuned by adjusting several parameters, such as the doses of CRISPR machinery components.

The investigators also showed that gene insertion mediated by CRISPR/Cas9 can lead to greater FIX activity levels over time compared with conventional gene therapy that uses adeno-associated virus vectors (AAV) to deliver modified genes to cells.

In a mouse model of liver regeneration, the companies’ scientists demonstrated that unlike conventional gene therapy, CRISPR/Cas9 can allow gene constructs to remain active inside liver cells even as they divide and expand in order to restore the tissue that was lost.

In this study, the researchers removed a portion of the animals’ liver to induce tissue regeneration. Within a period of 14 days after the animals had part of their liver removed, the activity levels of artificial F9 dropped by 85% with the gene delivered using standard gene therapy. In contrast, when CRISPR/Cas9 was used, F9 activity levels remained stable over at least 45 days.

“The persistence of these edits and durable effects further support our technology’s ability to develop potentially curative single-course therapies, and provide clear differentiation from chronic treatments and traditional AAV gene therapy,” Laura Sepp-Lorenzino, PhD, chief scientific officer at Intellia, said in a press release.

The team saw a similar gene-editing persistence following liver regeneration when using CRISPR/Cas9 to inactivate a gene called TTR, which encodes a protein that when misfolded causes hereditary ATTR amyloidosis. This is the mechanism of action of NTLA-2001, one of the company’s lead therapeutic candidates.

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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.

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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.

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