Epigenetic editing in primates. Cytokine-expressing AAVs for glioma. Gene therapy for the heart. These were just some of the dozens of preclinical advances shared at the American Society for Gene and Cell Therapy’s 2023 annual meeting, held May 16 through May 20 in Los Angeles.
While it’s impossible to cover all the data presented (for a deeper dive, you can peruse the 1,000-plus abstracts accepted for the conference), here’s a handful of the week’s stand-outs from biotech firms.
Siren's song
Could gene immunotherapy be the key to tackling brain cancer? New preclinical data from Siren Biotechnology suggests it’s possible. Arriving at the event fresh out of stealth mode, the company posted robust results on May 17 for its cytokine-expressing adeno-associated virus (AAV) therapy, showing that it was able to shrink brain tumors in mice. Up to 60% of the models—450 of which received some form of the treatment—showed a complete response.
“If you’re delivering these AAVs locally within tumors, they will stay exactly where you put them, so you get this very precise, direct intratumoral delivery,” Siren founder and CEO Nicole Paulk, Ph.D., explained to attendees. Check out Fierce Biotech Research’s coverage of Siren’s launch here.
Can we get that in (gene) writing?
Building off data first shared at the J.P. Morgan Healthcare Conference in January, Tessera Therapeutics presented updated figures on its RNA gene writing platform on May 19. In addition to new numbers in mice, the company shared that it had improved the ability of its tech to rewrite the gene associated with phenylketonuria in monkeys, bumping efficacy up to 45% from the 35% presented at JPM. This is much higher than the 10% threshold for correcting protein levels enough to functionally cure the inherited disorder.
“Really, this is confirming the readiness of this platform,” Tessera's Head of Platform Cecilia Cotta-Ramusino, Ph.D., told attendees at the event.
Tessera also showed for the first time that its RNA gene writers can edit the gene responsible for the rare liver disease alpha-1 antitrypsin deficiency (AATD) in humanized mice. AATD is a rare inherited condition caused by what’s known as the PiZ mutation. It leads to misfolding of the AAT protein and subsequent fibrosis in the lungs and liver.
Tessera's tech was able to correct the PiZ mutation in mouse models with 28% efficacy. Though the therapy will need efficacy levels of 30% and 50% to prevent lung and liver disease, respectively, the team already saw a decline in AAT protein levels in mouse livers. The biotech is now working on screening for more molecules they could use to target the mutation and improve the therapy for better results, Cotta-Ramusino said.
The RNA gene writers even demonstrated their effectiveness in the multiplex editing of CAR-T cells. Multiplex editing is a technique where two or more genes in a genome are edited at the same time. Tessera was able to show that the RNA writer CAR-T cells—delivered in vivo with the company’s proprietary lipid nanoparticles—cleared tumor cells in mice.
“Taken together with our delivery capabilities, these data represent an important step toward an in vivo correction of sickle cell disease and the in vivo production of CAR-T therapies,” Tessera CEO Mike Severino, M.D., told Fierce Biotech Research via email. “Overall, these results highlight the breadth of our gene writing … and their potential to address a wide range of human diseases.”
Prime editing gets closer to prime time
Speaking of multiplex editing, Prime Medicine—a gene editing biotech co-founded by Harvard chemist David Liu, Ph.D.—presented new preclinical data for the use of its prime editing tech to generate its own multiplex-edited CAR-T cells. Prime editing is a variation of CRISPR gene editing that differs in how it “cuts” DNA: It nicks only one strand, while CRISPR cuts two.
In the same session as Tessera, Prime Medicine’s Head of Prime Editing Platform Andrew Anzalone, M.D., Ph.D., described how the company was able to edit three different sites in T cells and generate CD19 CAR-T cells using its Prime Assisted Site-Specific Integrase Gene Editing (PASSIGE) platform. They were able to insert the CAR construct at 60% efficacy, Anzalone told the conference.
Prime Medicine also shared new data showing the efficacy of prime editing for correcting the gene mutation that leads to chronic granulomatous disease, a rare genetic disorder that causes severe immunodeficiency and early death. After prime editing human stem cells from four donors to correct the mutation, the researchers grafted the cells into mice. Over the course of 16 weeks, the edited cells repopulated the bone marrow, formed into blood cells and spread into the spleen and peripheral circulation. The efficacy rate for editing was 90%.
“We think this is strong preclinical work supporting moving this program forward,” Anzalone said.
All edits, no breaks
Want to alter gene expression without the potential consequences of DNA strand breaks? Enter epigenetic editing, a technique that bypasses this risk by targeting the epigenome. For the first time, it’s been done in primates: Tune Therapeutics presented data on May 19 demonstrating how the biotech successfully used its epigenome editing platform, dubbed TEMPO, to alter the expression of the PCSK9 protein in macaque monkeys.
PCSK9 regulates levels of “bad” low-density lipoprotein (LPL) cholesterol and is a common target of cholesterol-lowering medications. However, these require repeat administration to keep PCSK9 and cholesterol levels at bay. Gene editing has been put forth as a potential permanent solution as well.
“We wanted to test an alternative approach,” Jennifer Kwon, Ph.D., senior scientist at Tune, said as she presented the findings. The company’s platform is meant to work permanently with just a single dose, but without actually altering the structure of the DNA itself.
The researchers started by testing TEMPO in liver cells, where they were able to achieve up to 98% repression of PCSK9 expression for six months. They then turned to the macaques, dosing two animals with a control solution and three with the company’s therapy.
The treated group had a 75% reduction in PCSK9 expression, accompanied by a 56% drop in LDL cholesterol. The effects endured until the end of the four-month study, and are still ongoing, according to Kwon.
“These data suggest the possibility that a single epi-editing event could be sufficient for reducing LDL cholesterol,” she said.
Heartfelt gene therapy
Arrhythmogenic cardiomyopathy is a rare structural heart condition caused by a mutation in the PKP2 gene, which leads to the loss of the PKP2a protein. Patients are prone to life-threatening heart arrhythmias on account of ventricular dilation and progressive fat infiltration into the heart muscle. They often don’t present until their mid-30s—and when they do, there’s little that can be done apart from antiarrhythmic medications, defibrillator transplantation and, eventually, a heart transplant.
Rocket Pharmaceuticals hopes to add gene therapy to the list. On May 19, Associate Vice President of AAV R&D Christopher Herzog, Ph.D., presented data showing that Rocket’s gene therapy RP-A601, an AAV that expresses the PKP2a protein, could restore cardiac function and improve survival in mice.
In the experiment that produced the results, the scientists used a tamoxifen-induced PKP2a knockout mouse model (a standard model for the condition). Between seven and 14 days later, they gave a group of 10 mice two doses of the therapy intravenously, while a second group received a control solution. All of the treated mice were still alive at the end of the five-month study period. All nine of the untreated mice died by day 50.
The treated mice showed clear benefits to their cardiac function. Their right ventricles, typically dilated on account of the condition, were roughly the same size as those of healthy controls; while they still had slightly reduced left ventricular ejection fractions, they were much closer to normal than in the mice that were untreated. The differences were apparent as soon as seven days after the therapy was given and persisted out to five months. Arrhythmias, too, were much less frequent in the treated mice.
RP-A601 is already on its way to the clinic. During the presentation, Rocket noted that the FDA had approved its investigational new drug application as of this month. The company will carry out a phase 1 clinical trial on the therapy at the University of California San Diego Medical Center and the Children’s Hospital of Pennsylvania.
Editor's note: A previous version of this article misspelled Tune's Jennifer Kwon's last name and indicated that Tessera's RNA Gene Writers would need 80% efficacy to prevent liver disease in AATD. They will need 50% efficacy.