RNA Editing

RSRT’s recruitment and funding of key academics has spawned this promising new therapeutic field

DNA is made up of bases that pair together, A, T, C and G, to make the double helix we are all familiar with. This helix unzips to make an RNA copy, which then exits the nucleus and enters the ribosome in the cytoplasm where proteins are manufactured.

Occasionally, however, the RNA has a mistake in it and it doesn’t match the DNA template. Nature has come up with a solution for this kind of mistake. All of us have an enzyme in our cells called ADAR that acts as an editor, looking for and correcting mistakes in RNA. This process is called RNA editing. This approach will require a unique therapeutic designed for each point mutation.

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What it is

DNA is the genetic instructions to make an organism. In order to access the instructions, they must first be copied to RNA and then translated to protein. During the copying phase errors sometimes happen. The body has an innate editing mechanism that detects and corrects these errors. This naturally occurring mechanism is now being harnessed to correct MECP2 mutations.

Why it matters

RNA editing is an important alternative to DNA editing which can cause unwanted mutations (‘off-target effects). Because unused RNAs are quickly degraded, any errors introduced by a therapeutic would be washed out, rather than staying with a person forever. RNA editing may also be less likely to cause an immune reaction as the editing mechanism is naturally found in humans. Likewise RNA editing might provide a more natural response than introducing an external, engineered gene. A disadvantage is that currently RNA editing can only fix A to G mutations. Scientists are looking for ways to engineer new enzymes that could expand RNA-editing capabilities.

Status

Researchers have successfully edited and corrected the RNA in brain cells in Rett mice to successfully generate normal MECP2 protein at levels that are very encouraging. RSRT is funding scientists at the highest caliber who are consistently making breakthroughs in the RNA editing field. Importantly, a number of biopharmas are now pursuing programs in Rett Syndrome.

Mobilizing
Thought Leaders

Gail Mandel, PhD and post-doctoral fellow, John Sinnamon, PhD, funded through RSRT’s MECP2 Consortium, were the first to pursue RNA editing for Rett. They are introducing their own version of ADAR, a super editor with increased specificity. This therapeutic approach would be a one-and-done intervention.

The Mandel lab has successfully edited and corrected the RNA in brain cells in Rett mice to successfully generate normal MECP2 protein at levels that are very encouraging. They are now administering the RNA editing treatment to Rett mice to see if their symptoms are alleviated.

Peter Beal, PhD is a world expert in RNA editing and understanding of ADAR biology. Rather than introducing ADAR into the cell, his approach recruits ADAR that is already in the cell. This particular approach would eventually lead to an intervention that requires dosing an individual with Rett on a regular basis. The advantage of multiple dosing is that it allows for timing and titration of the dose to be tailored to each patient in a precise way.

Peter Beal, PhD is a world expert in RNA editing and understanding of ADAR biology. Rather than introducing ADAR into the cell, his approach recruits ADAR that is already in the cell. This particular approach would eventually lead to an intervention that requires dosing an individual with Rett on a regular basis. The advantage of multiple dosing is that it allows for timing and titration of the dose to be tailored to each patient in a precise way.

There would be no Vico Therapeutics had RSRT not funded my lab.

Gail Mandel, PhD
Scientific Founder, Vico Therapeutics

Guoping Feng, PhD is a distinguished neuroscientist who has significantly advanced the field of neurodevelopmental and psychiatric disorders through his work in deciphering how neurons communicate with each other. Now, he and his esteemed colleagues are also focused on Rett. He is leading a world-class group of investigators that includes Feng Zhang, PhD, one of the discoverers of CRISPR. The goal is to develop therapeutics using the CRISPR/Cas13 platform that can edit RNA and fix MECP2 mutations via a one-time injection.

The investigators are starting with G > A mutations within MECP2 because the enzyme that can restore the A base to a G base is known. G > A mutations represent an A in the sequence when it should be a G. G > A editing will be accomplished using a two-component protein. One component recognizes the specific RNA sequence where the mutation lurks. The second component is the editing enzyme that can convert the mutated nucleotide base, in this case A back to the correct base, G.

The vast majority of Rett-causing mutations however are C > T mutations. The enzyme that can revert a T base back to the base that should have been there originally, a C, is still unknown. The investigators are taking on the bold challenge of discovering this enzyme and then developing the necessary two-component proteins to address these mutations.

Another group, including Jonathan Watts, PhD, Erik Sontheimer, PhD, Scot Wolfe, PhD, and Anastasia Khvorava, PhD, are working on both RNA editing as well as DNA editing. The RNA editing project will optimize RNA editing guides for use by the naturally occurring RNA editor, ADAR. Optimizing the guide RNA is important to maximize the number of mutant MECP2 RNA molecules that are corrected which will then increase the level of corrected MECP2 protein, and ensure the guide RNA does not cause negative effects. In order to deliver the RNA guide cargoes to cells in the brain, they are also working on developing a novel delivery system that doesn’t rely on a virus.

Another group, including Jonathan Watts, PhD, Erik Sontheimer, PhD, Scot Wolfe, PhD, and Anastasia Khvorava, PhD, are working on both RNA editing as well as DNA editing. The RNA editing project will optimize RNA editing guides for use by the naturally occurring RNA editor, ADAR. Optimizing the guide RNA is important to maximize the number of mutant MECP2 RNA molecules that are corrected which will then increase the level of corrected MECP2 protein, and ensure the guide RNA does not cause negative effects. In order to deliver the RNA guide cargoes to cells in the brain, they are also working on developing a novel delivery system that doesn’t rely on a virus.

Importantly, this group, along with Guoping Feng, recently received a sizable NIH grant from the Somatic Cell Genome Editing program that will expand their platform. RSRT funding will leverage this investment and facilitate applying the learnings specifically to Rett Syndrome.

Biopharma
Makes an Entrance

Based in large part by the exciting progress being made by the RSRT-funded scientists mentioned above, the RNA editing field is becoming high profile. Investors are pumping money into this area and new companies are being launched. This is an important development because although scientific breakthroughs typically emerge from academia, therapeutics are generated by biopharma. Making the leap from academia to biopharma is therefore critical.

Encouraging progress by the RSRT-funded Mandel lab, catalyzed the launch in late 2019 of Vico Therapeutics, a biotech based in The Netherlands. Gail Mandel is a scientific founder of the company and a champion for the Rett program.

Shape Therapeutics, a biotech based in Seattle that launched in 2019, has developed a proprietary RNAfix technology that can precisely target a point or nonsense mutation. In mid 2020 Shape announced a Rett Syndrome program. RSRT influenced Shape’s decision by providing a number of resources including our induced pluripotent stem cell lines (iPSC) with specific MECP2 mutations.

In the next several years we expect additional companies in the RNA editing space to announce Rett Syndrome programs.

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Rett may be a rare disorder but together we are powerful.