Discovery, Gene Therapy

Penn team-biotech collaboration highlights promise of gene editing in targeting PCSK9, liver diseases

James Wilson. Penn News

PCSK9 cardio drugs may still be having a tough time building a market among stubborn payers, but they’re nevertheless considered a remarkable advance in slashing levels of LDL in at-risk patients. And now one of the pioneers in gene therapy — working in collaboration with an upstart biotech company — has completed a primate study to show that a unique gene editing approach can hit the same target, with positive effects.

We know through extensive human studies that a drug that inhibits the PCSK9 protein will lower LDL, the bad cholesterol that’s a culprit in cardio deterioration. James Wilson at Penn, whose advances and setbacks in gene therapy helped birth the field, used a meganuclease developed at Precision Biosciences in Durham, NC, put the enzyme in an AAV vector, and dispatched it to the liver, where it targeted PCSK9 to good effect.

Using a vector that’s already demonstrated its safety in human hemophilia studies, the research team at Penn concluded that their approach reduced PCSK9 levels by 45% to 84%, cutting LDL levels by 30% to 60%, “both clinically relevant and stable reductions. Molecular analyses of biopsied liver tissue also demonstrated that genome editing induced mutations in 40% to 65% of the PCSK9 genes.”

Lili Wang

“Most often these patients are treated with repeated injections of an antibody to PCSK9,” said first author Lili Wang, a research associate professor of medicine. “But, our study shows that with successful genome editing, patients who cannot tolerate inhibitor drugs might no longer need this type of repeat treatment.”

Success here also points to the promise of gene editing in a range of liver metabolic diseases beyond hypercholesterolemia, they note. A range of startups have been using new gene editing techniques, with the first forays in humans underway at Penn and in several hospitals in China.

This is the second time in just a matter of days that Precision has made a splash. The biotech just wrapped a whopping $110 million crossover round with a broad syndicate of backers. The crew also split off its ag operations into a separate company, likely flagging that the CEO has an S-1 in his briefcase.

Animal studies in the field, though, haven’t always been so successful. Wilson triggered safety alarms when he reported early this year that one of his vector-delivered gene therapy studies using three rhesus macaque monkeys and three pigs ran into a toxic disaster.

Four days after one of the macaques had received 2×1014 GC/kg AAVhu68 vector expressing human SMN, the monkey experienced a severe crisis, going into shock after suffering severe liver damage, which forced researchers to euthanize the primate. The two other macaques survived, but also suffered a toxic reaction.

All three piglets treated with a high, systemic IV dose were also euthanized, with the first experiencing ataxia and the other two responding with neurological symptoms.

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