ORLANDO, Fla. – “The Wright brothers showed that you could fly a plane, but it wasn’t very far and it wasn’t very safe,” Wendell Lim told his audience at the 61st American Society of Hematology (ASH) annual meeting this weekend. “That’s where cell therapy is now.”

At a scientific session on gene editing, Lim, who is professor and chair of cellular and molecular pharmacology at the University of California, San Francisco, and the co-founder of Cell Design Labs, discussed his laboratory’s work to use gene editing to improve cell therapies, in particular CAR T cells.

To fully capitalize on their strengths, he said, cell therapies will need to be both safer and more powerful – a combination that is inherently challenging.

Lim’s synNotch technology addresses that challenge by editing cells to contain multiple sensors, whose combined input controls the “common currency” of gene expression output.

The combinatorial possibilities result in a CAR T cell that reacts to its target antigen only when it senses that it is in a tumor microenvironment, which could eliminate off-target activity.

Lim identified several “buckets” that cell therapy challenges could be sorted into, including making tumor recognition multifactorial, overcoming inhibitory signals from the tumor microenvironment, and the addition of control and safety systems.

At the same session, CRISPR pioneer Feng Zhang gave an overview of methods that can edit single genes, or even single base pairs.

While such editing is unlikely to lead to clinically meaningful effects in complex diseases, Zhang pointed out that there are more than 6,000 monogenic diseases whose causative gene is known, including sickle cell disease.

Methods like CRISPR, base editing, and prime editing could provide solutions for some of those diseases. At the meeting, Beam Therapeutics Inc. and Editas Medicine Inc., both of which were co-founded by Zhang, as well as Sangamo Therapeutics Inc. and Bluebird Bio Inc., are reporting on their gene editing efforts in sickle cell disease.

Gene repair via DNA editing is “especially attractive” for monogenic diseases that can potentially be cured in that manner. But newer forms of CRISPR can also edit RNA, which expands the technology’s potential reach.

RNA editing can edit cells regardless of whether they are dividing or not.

It is also reversible, because edited RNA will degrade after a certain period of time. That allows it to be used as an alternative to small molecules and biologics for temporarily activating or down-regulating specific pathways to trigger cellular processes. Up-regulating the protein beta-catenin, which normally plays multiple roles in development, can help with wound repair. But its long-term activation is tumorigenic, Zheng said: “It’s not something you want to keep on forever.”

Sunday’s plenary session, too, featured a presentation on gene editing. Shuquan Rao, a postdoctoral fellow at Boston Children's Hospital, discussed how gene editing the gene for neutrophil elastase (ELANE) in hematopoietic stem cells revealeddisease mechanisms and therapeutic strategies for severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a life-threatening autosomal dominant immune disorder which leaves patients both vulnerable to recurrent infections and at high risk of developing myelodysplastic syndromes and acute myeloid leukemia (AML).

Almost half of all SCN patients have mutations in ELANE. However, mutations can occur at many different spots. That makes repairing ELANE with gene editing a challenging proposition, as individualized guide RNAs would be necessary to repair each patient’s specific mutation.

In their work, Rao and his colleagues took advantage of the fact that having no neutrophil elastase is less of a problem than having a misfolded version.

While the presence of a misfolded neutrophil elastase sets off a stress response that ultimately kills cells, “neutrophils without neutrophil elastase retain essential functions,” Rao told the audience at the plenary session.

Rather than trying to repair the gene, he and his colleagues engineered additional mutations that either repressed translation of the mutated gene altogether, or allowed cells to recognize the mRNA as faulty and destroy it, also preventing protein expression.

Editing cells from three separate patients could rescue neutrophils in each case. NIH distinguished investigator Cynthia Dunbar, who introduced Rao’s presentation at the plenary session, concluded that the approach “has potential to move forward as a gene therapy for this and other autosomal dominant diseases” such as beta-thalassemia.

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