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Beaming toward base editing
CAMBRIDGE, Mass.—Harvard University announced today that it has granted a worldwide license to Beam Therapeutics, Inc., to develop and commercialize a suite of revolutionary DNA base editing technologies for the treatment of human disease. The versatile platform of base editing technologies was invented by David R. Liu, PhD, Professor of Chemistry and Chemical Biology, and visionary postdoctoral fellows and graduate students in his Harvard laboratory. The licensed technology platform, which includes access to base editing technologies and associated technologies that enhance the targeting scope of base editing, opens up a wide range of human genetic conditions to the therapeutic promise of genome editing.
“We developed programmable molecular machines that go to a target site of our choosing in the genomic DNA of a cell and directly convert one base to another base without making a double-stranded break in the DNA,” noted Liu, who is also a cofounder of Beam. Under the terms of the agreement, Harvard will receive a multimillion-dollar upfront licensing payment from Beam Therapeutics, with additional confidential terms.
“Base editing represents a powerful platform for addressing a large class of genetic diseases that are more difficult to tackle with other methods of genome editing,” said Vivian Berlin, Director of Business Development in Harvard’s Office of Technology Development (OTD).
Genome editing technologies using the CRISPR platform in combination with enzymes like Cas9 and Cpf1 have shown great promise for adjusting genes through insertions or deletions of multiple nucleotides, but have had more difficulty correcting single nucleotides cleanly and efficiently. The suite of Harvard technologies licensed to Beam uniquely meets that need.
Existing methods of genome editing which attempt to correct point mutations, including those using the CRISPR/Cas9 system, use CRISPR as molecular scissors to make double-stranded breaks and rely on an introduced DNA template to guide correction. Double-stranded breaks within the cell trigger end-joining processes that reconnect the broken ends, but introduce stochastic insertions and deletions while doing so. As a result, the precise correction of point mutations has to compete with the generation of these other undesired byproducts. Precise correction with CRISPR/Cas9 typically relies on cellular components that are absent in cells not actively dividing.
“Instead of precisely fixing a disease-driving mutation in a specific gene, cutting a target site more often disrupts the gene or creates a mixture of mutated variants of the gene,” Liu explained.
The base editing methods developed in Liu’s Harvard lab use an engineered multi-component protein that includes a modified form of Cas9 to unzip a targeted portion of the DNA helix, without causing double-stranded breaks in DNA. Liu’s base editors directly convert the target base from the mutated form to the corrected form, and in some cases also enlist an additional protein component to prevent the cell from undoing the correction. Meanwhile, the engineered Cas9 nicks the unedited strand of DNA, prompting the cell to mend that second strand with a base that complements the corrected base. The result is a double swap that permanently changes an entire base pair (such as A-T) to a different base pair (such as G-C).
“Over the past year and a half, we’ve greatly expanded the scope of base editing technologies, broadening their targeting scope, improving their target DNA specificity, and creating new classes of base editors that could have a substantial impact on the treatment of genetic diseases,” Liu pointed out. “That’s the ultimate goal: in an unmodified organism, whether it’s a human or a plant or an animal, to be able to change a DNA base to another DNA base at will, cleanly, and with high efficiency. If we can get there, I think the potential for societal benefit is high.”
Liu’s team have reported the development of various base editors in Nature in 2016; Nature Biotechnology in February 2017; Nature Communications in June 2017; Science Advances in August 2017; Nature in October 2017; and Nature in February 2018.
The agreement with Beam Therapeutics stipulates particular diligence obligations under which the company must demonstrate its progress toward developing products. It also stipulates how a third party can propose to develop a therapeutic product, either in partnership with Beam (via collaboration or sublicense) or through a separate agreement with the University, if that program is not of serious interest to Beam. Academic science will remains entirely unhindered; Harvard retains the rights of researchers to continue to use the intellectual property for educational and not-for-profit research purposes, whether at Harvard or elsewhere. The intellectual property is also available for licensing on a non-exclusive basis for industrial research purposes.
“Our goal is to see this innovation develop into transformative treatments for the widest possible range of human diseases,” said Berlin. “Licensing the commercial rights to a new startup ensures a rapid mobilization of resources to fully develop and exploit the technology in this field.”