Gene-editing technology offers the potential to treat inherited disorders with selective edits and corrections to an afflicted individual’s genetic code. But with such molecular tinkering comes with the risk of unintended changes to the genome.
Biotech startup Trucode Gene Repair is developing technology that it claims can edit genes in a way that reduces the risk of these so-called “off-target effects.” The South San Francisco company is announcing Tuesday that it has raised $34 million to support its research. Trucode disclosed that its investors in the financing include Kleiner Perkins and GV.
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Another innovative gene editing technique, CRISPR, grabs most of the headlines these days about the correction of genetic defects, and experimental therapies that use it are now in clinical trials. The technology employs an enzyme, such as Cas9, to make cuts in the strands of DNA that contain the genetic code. When these cuts happen in places they’re not supposed to, they can do more harm than good. Early research found that inadvertent changes to DNA led to potentially cancer-causing mutations.
There are other concerns about CRISPR. Research published last year suggested that some people’s immune systems might be predisposed to an immune response against Cas9, which might make the gene editing technology ineffective. But some scientists have said that this immune system response can be overcome with modifications to the DNA-cutting enzyme.
Trucode takes an entirely different approach than the CRISPR method. For one thing, it uses a nanoparticle to deliver its gene-editing technology instead of the engineered virus that delivers CRISPR/Cas9. The nanoparticles contain strands of synthetic genetic material called peptide nucleic acids (PNA), along with a DNA correction sequence. Delivered via an intravenous injection, the nanoparticles reach a target organ and are taken up by its cells, where the PNA and DNA correction payloads are released, Trucode says.
Inside a cell, the PNA binds with the double-stranded DNA helix to form three strands. Trucode says this “triplex” DNA structure triggers a natural DNA repair mechanism in the cell. If the technology works as intended, that repair mechanism will fix the DNA by inserting the DNA correction sequence that came inside the nanoparticle. Trucode says that its technology can be used to address many inherited diseases, but its initial focus will be developing therapies for sickle cell disease and cystic fibrosis.
The Trucode technology is based on research of Yale University professors Peter Glazer, Mark Saltzman, and Marie Egan. In results of a preclinical study published last year in the journal Molecules, the scientists said that the PNA and nanoparticle technology led to gene edits in mice with the blood disease beta thalassemia and cystic fibrosis. They added that the occurrence of off-target mutations from triplex gene editing was “substantially lower” than that reported for CRISPR/Cas9 and other gene-editing technologies, such as zinc-finger nucleases and Talens.
Trucode holds an exclusive, worldwide license to the Yale technology, along with additional licenses from Carnegie Mellon University.
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