Locanabio’s Combo RNA Modification Platform Targets Multiple RNA Dysfunctions with One Injection


Locanabio combines gene therapy with RNA modification for a novel, highly flexible platform that can modify, replace, or eliminate dysfunctional RNA. Gene therapy and RNA modification have each been used before. It’s the combination that makes it unique.

Most RNA targeting platforms are limited to editing RNA only. Locanabio’s platform, in contrast, offers multiple approaches. “Our platform enables us to modulate RNA in a number of different ways, including destruction, replacement, splicing, editing, and translational enhancement,” Kathie Bishop, Ph.D., CSO, told BioSpace. That range of options gives drug developers much more flexibility that simply destroying or replacing RNA.

“What makes us feel good is that we’re taking two validated approaches. There have been drug approvals on the gene therapy and the RNA modification side,” Dr. Bishop said, noting that she led the Spinraza® program – an antisense oligonucleotide that became the first approved treatment for spinal muscular atrophy – when she was at Ionis Pharmaceuticals.

Locanabio uses a variety of RNA binding proteins, including Cas13d to target the RNA precisely. One of the latest is human-derived PUF (Pumilio and FBF). “These RNA binding proteins are very small – about 1 to 2.5 kB,” she said. “That’s the advantage of using the PUF proteins. Because they’re very small, we can fit two proteins into the same adeno-associated viral vector (AAV).” One therapy, therefore, can target two different RNA dysfunctions. AAVs are the same delivery vehicle others use for gene therapy.

Although the AAV may be delivered by injection, the therapy is tightly targeted, going directly to the defective tissue. Results to date suggest a single injection may be sufficient to correct the dysfunctional RNA.

“Gene Yeo, Ph.D., professor at the University of California – San Diego, Locanabio’s founder, was among the first to use gene therapy to have proteins bind to RNA,” Jim Burns, Ph.D., CEO, told BioSpace. Dr. Yeo modified Cas9 to bind to and cut RNA rather than DNA. “That was very different.

“He then showed that researchers could use that method to selectively destroy some of the dysfunctional RNA associated with myotonic dystrophy type 1, and thus reverse some of the measurable causes of toxicity.”

In 2016 Dr. Yeo founded the company. After delivering the proof of concept in animal models, Dr. Yeo raised $55 million Series A funding, and “about a year ago” hired Dr. Bishop and, few months later, Dr. Burns. The company now has 30 employees.

The first therapeutic developed using this platform is expected to enter clinical trials in about 24 months. “If the science continues on its current track we expect to start the IND-enabling programs early next year,” Dr. Burns said.

The specific program hasn’t yet been identified, as several applications are being developed in parallel. “At end of the day, we’ll let the science dictate the lead program,” Dr. Burns said.

The most likely candidates include myotonic dystrophy type 1, caused by mutations in the DMPK gene that result in CUG repeats; Huntington’s and other CAG-repeating diseases; and familial  amyotrophic lateral sclerosis, caused by C9orf72 gene mutations that result in C4G2 and G4C2 repeats. Those programs are at nearly the same stage of development.

“We’re also looking at retinal disease. “This is an exciting area to address with our platform. It shows that in addition to targeting repeat expansion diseases, we also can go after diseases that have a gain of function.”

In retinal disease, a mutation in the RHO gene cause it to make a toxic protein.. Consequently, people with RHO defects cannot see well in low light. “We can destroy the mutations and, with the same product, replace them with the  wild-type rhodopsin,” Dr. Bishop explained. The ability to do this with one product is unique. “There are about 150 mutations in rhodopsin that cause the disease. Other DNA repair platforms would need a unique product for each mutation.”

Locanabio currently controls all of its own intellectual property. “We haven’t partnered anything yet.” Eventually, he continued, “We anticipate working with a strategic, complementary, partner, but have every intention of bringing our programs forward.”

Dr. Burns said Locanabio has the capital to bring at least one program into the clinic.  “With the number of programs we’re bringing forward, we will evaluate the sense of adding capital in the form of public or private placements but for now we’re very well-funded.”

Embarking on the IND-enabling studies next year is the next inflection point. At that time, “We’ll have to start building out our clinical, medical, and regulatory capabilites,” Dr. Burns said.

The company has a great benefit when it comes to manufacturing. “It faces the same challenges as other gene therapy, but because the approaches are validated, the risks already have been addressed. There’s a way forward to treat a number of diseases that haven’t been adequately treated,” he said.

A Locanabio paper detailing the technology has been accepted for publication in Nature or one of its sister journals. Publication is anticipated soon.

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