On Monday, LogicBio Therapeutics unveiled clinical trial results demonstrating the first-ever in vivo, nuclease-free genome editing in little humans.
LogicBio President and CEO Fred Chereau/Courtesy LogicBio Therapeutics
The gene-editing milestones keep coming in 2021. In June, Intellia Therapeutics and partner Regeneron Pharmaceuticals announced the first-ever clinical data supporting the safety and efficacy of in vivo CRISPR genome editing in humans. On Monday, LogicBio Therapeutics unveiled clinical trial results demonstrating the first-ever in vivo, nuclease-free genome editing in little humans.
The Lexington, Mass.-based genetic medicine company is developing gene-editing and gene delivery solutions for pediatric patients with rare diseases
— beginning with rare liver disorders like Methylmalonic acidemia (MMA), a life-threatening genetic condition affecting approximately 1 in 50,000 newborns in the U.S.
In the most common form of the disease, a mutation in the Methylmalonyl-CoA mutase (MMUT) gene prevents the body from properly processing certain fats and proteins. So, from the moment a child is separated from its mother, he or she does not have any exposure to an essential enzyme, leading to metabolic crises that can cause permanent and irreversible damage to the central nervous system (CNS). Thus, MMA is on the newborn screening panel in every state as well as several other countries. There are currently no treatments that address the underlying cause of the disease.
The more these episodes occur, the greater the child’s chance of intellectual impairment and developmental delays. This is why early intervention is critical, and the safety data from the LogicBio’s Phase I/II SUNRISE trial, along with proof of concept, won the approval from the Data Safety Monitoring Board (DSMB) to enroll two patients in ages six months to two years at a lower dose and two patients in a higher dose range.
“When you’re in the early stages of drug development, especially with a very innovative platform, safety is the first thing I would pay attention to,” Fred Chereau, president and CEO of LogicBio, told BioSpace. “It’s another big achievement for a gene-editing company to be able to go into patients as young as six months old.”
LogicBio’s approach is to non-disruptively insert a corrective copy of the MMUT gene into the albumin locus to drive lifelong therapeutic levels of MMUT expression in the liver. Importantly, the company aims to do this with just a single intravenous infusion of the therapy, LB-001.
“These children will hopefully never have to receive any other treatments again if this works as we hope it will,” said Mariana Nacht, Ph.D., LogicBio’s chief scientific officer.
The early data demonstrated measurable levels of a biomarker called albumin-2A, a molecule unique to the company’s GeneRide technology. LogicBio Chief Medical Officer Dr. Daniel Gruskin, M.D., explained why this is critical.
“This technology has a unique feature in that when it is doing what it is supposed to do, this molecule called albumin-2A is produced and it’s measurable in the blood. So, when it is detected in the blood of these patients, that provides us with evidence that we are seeing the integration of the transgene and expression,” Gruskin said.
Also significant, Chereau stated, is the proof of concept for nuclease-free gene editing.
“Today’s announcement is a demonstration that homologous recombination genome editing without the use of nucleases is a potential alternative to genome editing technologies in development that use nucleases, such as CRISPR. The ability to insert the correct version of a gene in a cell’s genome without nucleases is an important step to unlocking the potential of GeneRide to treat a larger number of genetic diseases,” he said.
The GeneRide technology uses homologous recombination, a natural DNA repair process, to enable precise genome editing without the need for exogenous nucleases and promoters, which the company said have been associated with an increased risk of immune response and cancer.
Proof of concept in hand, LogicBio will now be looking for signs of the therapy’s impact on the disease.
“The next step will be to look for those disease-related markers to see the clinical and biochemical efficacy of GeneRide, and that will be LB-001,” Gruskin said. These markers include levels of methylmalonic acid and other toxic metabolites.
While LogicBio would like to measure mutase activity directly, Gruskin said they are not doing that in this study because it would require liver biopsies, something they do not want to do to these fragile children. Instead, “we have an indirect way of measuring mutase activity called propionate oxidation. It’s actually a really cool test that just uses the breath,” he said. The researchers give the patients labeled substrate, then measure how much of that gets metabolized and is evident in the breath.
“It provides a measure of mutase activity, and so we’re able to determine if the activity of that enzyme is increasing after treatment by this breath test,” Gruskin explained.
He added that, on an exploratory level, LogicBio would also be looking to identify clinical endpoints such as growth, appetite, and frequency of hospitalization.
Chereau said that the company aims to provide interim clinical data by the end of 2021, where they will discuss these additional biomarkers. This is a “good starting point to now develop additional clinical problems in other indications for which we already have a preclinical proof of concept,” he added. “It’s just the beginning.”
The therapy has been granted fast track designation, rare pediatric disease designation, and orphan drug designation in MMA by the U.S. Food and Drug Administration (FDA) and orphan drug designation by the European Medicines Agency.
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