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Neuroscience

Atalanta Therapeutics launches to develop RNAi therapies for neurodegenerative diseases

The University of Massachusetts spin-off has $110 million and partnerships with Biogen and Genentech

by Ryan Cross
January 14, 2021

A conceptual illustration of branched RNAi.
Credit: Atalanta Therapeutics
Atalanta is developing branched RNAi therapies made of two chemically linked RNA molecules.

Atalanta Therapeutics has launched with big plans to develop RNA interference (RNAi) therapies that will silence the expression of genes implicated in neurodegenerative diseases. The new company has $110 million in series A financing and partnerships with Biogen and Genentech.

The Boston-based start-up was cofounded by three scientists at the University of Massachusetts Medical School: RNAi discoverer Craig Mello, RNAi therapy developer Anastasia Khvorova, and Huntington’s disease researcher Neil Aronin. The team contends that its branched RNAi technology—in which two RNAi molecules are covalently linked—is key to bringing the potential of RNAi therapies to bear in the brain. The start-up is already working on therapies for several central nervous system diseases, including Huntington’s disease with Biogen and Alzheimer’s disease and Parkinson’s disease with Genentech.

Mello shared the Nobel Prize in Physiology or Medicine in 2006 with Andrew Fire for their discovery of RNAi. Scientists quickly saw the potential for turning the concept into a drug that could silence genes and thus block the production of proteins that cause disease. But the evolution took many years.

Alnylam Pharmaceuticals was the first firm to bring an RNAi drug to market, in 2018; it has since earned two more approvals for RNAi drugs. Yet all three of those therapies, and many more still under clinical development, are designed to inhibit the expression of genes in the liver. Alnylam focuses largely on the liver since the RNAi molecules tend to congregate there after infusion, and also because the company found that attaching a molecule called N-acetylgalactosamine, or GalNAc, to the RNAi helps shuttle it into liver cells.

Although scientists have many ideas for using RNAi to treat diseases of other organs, such as the brain, attempts to deliver RNAi to those parts of the body have been less successful. UMass Medical School’s Khvorova may have found the solution with branched RNAi. “What Alnylam did with GalNAc for the liver, we can do with branched RNAi technology for the brain,” says Alicia Secor, CEO of Atalanta.

In 2019, Khvorova and UMass colleagues published a strategy for chemically modifying RNAi molecules to help them better distribute throughout the spinal cord and brain. The team appended alternating methyl groups and fluorines to the ribose rings along part of the RNAi molecules and replaced some of their phosphodiester bonds with phosphorothioate bonds.

Such chemical modifications are well known in the gene-silencing field, and Khvorova wanted to see how they would affect RNAi’s distribution in the brain. The team attached orange fluorescent labels to the end of the molecules and injected them into a mouse brain. The RNAi was barely visible. But when the researchers made branched RNAi by attaching two RNAi molecules together with a tetraethylene glycol linker, the mouse brain lit up bright orange (Nat. Biotechnol. 2019, DOI: 10.1038/s41587-019-0205-0).

Khvorova’s group found that a single injection of an experimental branched RNAi therapy for Huntington’s disease could inhibit expression of the gene linked to the disease for six months. It also found that branched RNAi could distribute throughout the brains and spinal cords of a monkey.

“The branched structure and the chemical modifications together provide these improved biophysical properties to the molecule,” particularly its distribution and longevity, says Aimee Jackson, Atalanta’s chief scientific officer. “That’s why we are so excited about the potential for this new approach for gene silencing.”

It’s not clear why larger, branched RNAi molecules distribute throughout nervous tissue better than the smaller traditional ones. “We have multiple hypotheses that we are actively interrogating,” Jackson says. The modified molecules may clear from the tissue more slowly, or the molecules might have unique protein-binding properties that improve their uptake in the brain and spinal cord, she says. “We think it is a pretty complex interplay between multiple portions of the molecules’ chemical architecture.”

Atalanta isn’t the only young company with new tricks for delivering RNAi molecules, or chemical cousins known as antisense oligonucleotides. Earlier this month, Aro Biotherapeutics raised $88 million to conjugate RNAi and oligos to proteins for targeted cell delivery. In 2019, Dyne Therapeutics launched with $50 million to develop antibody-oligo conjugates to deliver the gene-silencing therapies to muscle cell. That same year, Eli Lilly and Company struck a deal with Avidity Biosciences to develop antibody-oligo conjugates that target immune cells.

Secor, Atalanta’s CEO, is hopeful that investment in new oligo and RNAi technologies will continue. “The evolution of the field has been ongoing for decades now, and what we are seeing today is smart money investing in [the] next generation,” she says.

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