It may have been one long, wet week at the 2023 J.P. Morgan Healthcare Conference in San Francisco, but it would take more than an atmospheric river to dampen the spirits of Tessera Therapeutics CEO Mike Severino, M.D.
“People ask me how it went and I tell them, ‘Other than the weather, it was all good,’” said Severino, who took the helm at the Boston-based biotech last summer after a 20-year career in Big Pharma, most recently as vice-chairman and president at AbbVie.
He certainly has something to be excited about: During a session at JPM on Jan. 9, Tessera presented data from human cells, mice and nonhuman primates that validates its platform to rewrite genes, generate CAR T cells and, potentially, deliver them directly to target sites with a single IV infusion.
“We’re building a platform that has the ability to make whatever change is needed in the human genome to address disease,” he said.
Tessera’s platform aims to do what CRISPR and other gene therapies cannot: rewrite genes within the body, swapping out individual base pairs rather than simply cutting out or inserting new sequences (though the company says it can do that, too). The technique doesn’t require removing and reinfusing cells like in cell-based gene therapy, nor does it make double-stranded DNA breaks like CRISPR.
Instead, the platform leverages the same kind of machinery cells use to write genes naturally, Severino said. It's based on mobile genetic elements, segments of DNA that can move around the genome altering, inserting and removing other genes.
One arm of Tessera's platform, RNA Gene Writing, is modeled after retrotransposons, RNA-based mobile genetic elements that engineer the genome by making nicks in DNA then reverse-transcribing it. The other, DNA Gene Writing, is based on mobile genetic elements that integrate DNA sequences into the genome.
“We can make small changes, we can write genes in, we can create advanced cell therapies and we’re covering all of this with a strong focus on delivery, too,” he said. RNA Gene Writers are delivered to cells in lipid nanoparticles, as opposed to viral vectors like other gene therapies.
Demonstrating the capabilities of the RNA Gene Writers tech at JPM, Tessera presented data from primate models of phenylketonuria, or PKU. The disease is caused by a mutation in the phenylalanine hydroxylase (PAH) gene. The point mutation R408W in the PAH gene alters the production of a liver cell enzyme needed to metabolize the amino acid phenylalanine. Phenylalanine builds up in the body as a result, requiring patients to undergo cumbersome, lifelong treatments and stick to strict diet restrictions to keep it from reaching dangerous levels. While some companies have tried to tackle PKU with gene therapy, they’ve had little success so far.
Tessera’s approach appeared to have better luck, at least in the pre-clinical data revealed to date. To effectively “cure” PKU, the researchers needed to alter a single base pair in at least 10% of alleles in the animals’ liver cells. The company’s RNA Gene Writers did it in up to 35% after just one injection in nonhuman primates.
“That’s very exciting for us as we move this technology towards the clinic,” Severino said. The company is working on other indications in the liver as well, he added. Though he declined to disclose a timeline for tests in humans, Severino said he felt the technology was progressing quickly.
That means the company's sickle cell disease program, too. Sickle cell disease is an inherited condition that causes a mutation in the genes for hemoglobin production. The malformed hemoglobin that results from the mutation causes patients' red blood cells to form a "sickle" shape, which can lead to pain, vision loss, anemia, frequent infections and stroke. The only cure for the disease is a bone marrow transplant from a sibling whose blood cells are matched to the patient's.
Data from experiments on cells from human sickle cell patients showed that Tessera's RNA Gene Writers normalized the genetic mutation in the hemoglobin genes that cause cell sickling. All of the untreated cells produced mutated hemoglobin, while 98% of the treated cells produced normal hemoglobin. When the cells were cultured, they proliferated and differentiated, with the rate of the corrected cells improving over time, Severino said.
Beyond altering mutations, Tessera also demonstrated that the RNA Gene Writers can be used to engineer CAR T cells. In what he described as a “first for human genetics,” Severino explained how the company paired an mRNA sequence encoding the gene writer with a second RNA (the template) to deliver instructions into T cells. When injected into mice, those T cells were able to eliminate implanted human tumor cells.
“We can use this technology to write a CAR construct, or a CAR cassette, into T cells using all RNA composition,” Severino said.
The platform could theoretically eliminate the cumbersome process of conducting CAR T cell therapy, which includes harvesting a patients' cells, engineering them to attack their cancer, giving the patient chemotherapy to make room in the immune system for the altered cells to grow, and finally reinfusing them. Many cancer patients can't wait for or tolerate the process, Severino said.
“This opens the possibility for simple IV infusion to generate CAR Ts in vivo in a patient,” he explained. “Same-day therapy. That would be a game changer in and of itself.”
Early data in mice and primates using a reporter gene showed that lipid nanoparticles delivered the gene writers to more than 80% of T cells in mice, while efficiency in primates was around 35 to 50%.
Ideally, all the therapies would work within the bodies of patients without having to remove the cells to engineer them. To that end, the researchers are doubling down on delivery, optimizing their lipid nanoparticles to get the gene writers into as many target cells as possible.
“You can have the best gene writing or gene editing tool available to you, but if you can’t get it where it needs to go in a patient in a way that’s safe and effective, it’s not going to have the impact that you want it to have,” Severino explained. “It’s not going to help patients.”
The data from the PKU primate models shows that the tech is already capable of that. And experiments using reporter genes (but not the gene writers themselves) in nonhuman primate bone marrow hematopoietic stem cells suggested that the delivery system targeting sickle cell disease was on the right track too: The reporter genes showed up in about 30% of target cells, more than the 20% estimated to be necessary for therapeutic benefit.
“Everything we’ve talked about on the gene writing side is coupled with very strong work and internal capabilities on the delivery side,” Severino said. “When you put those two together, I think we have a tremendous opportunity in front of us.”
Editor's note: A previous version of this article stated that Severino was vice president and chairman of AbbVie. He was vice-chairman and president. We have also made some clarifications around the RNA gene writing technology and its use.