When Adrian Woolfson was head of R&D at Sangamo, he began contemplating starting his own company. His goal? Solve some of the key challenges plaguing genomic medicine he’d seen while working on a wide spectrum of Sangamo’s programs.
Then, he met Lachlan MacKinnon, a biotech investor, in London, and the two realized they shared a similar vision, despite their “orthogonal” backgrounds, he told Endpoints News.
Replay, their new hub-and-spoke startup, looks to change the way gene therapies are made. With $55 million in seed money, the biotech has collected a series of platforms, including an HSV vector, protein rewriting algorithm and a DNA writing tool from George Church’s lab.
“We identified essentially three key challenges that we’re solving for, which we think will define the future,” Woolfson, who is the chairman and president, said. “The first of those is payload capacity; the second is the need for an off-the-shelf, low cost scalable, and extensively genomic engineered cell therapy platform; and the third is the ability to assemble big DNA.”
Replay’s primary technology is its HSV delivery system. While AAV vectors can generally only hold about 4.7 kilobases of a gene, HSV vectors can hold about 150 kilobases. With that increased capacity, therapies using the viral vector could extend to diseases with bigger genes, like muscular dystrophy, and genes with their introns (and regulatory parts) intact, Woolfson noted.
Woolfson added Replay has two classes of HSV vectors. “We’ve got our gene-deleted HSV, but we’ve also got what we call an amplicon — which is an HSV in which we’ve stripped out virtually all of the genes — and this is almost a non-viral vector,” Woolfson said. “And we think that will actually be probably the most compelling of all.”
However, the jury remains out on whether an HSV-based therapy will be safer than the standard AAV, as the viral vector triggers a dangerous immune response. Woolfson acknowledged that like for AAV, the body has neutralizing antibodies against HSV, though he added that HSV has evolved to better evade the immune system.
A suite of biotechs has grown out of the effort to solve the various problems related to gene therapies. SpliceBio is trying to solve the payload limitation through protein splicing, and Apertura is working on custom-designed AAV vectors that it hopes can get AAVs to difficult-to-access areas.
Replay has also licensed a DNA writing technology, used for building synthetic strands of DNA. “We think we can recapitulate what we’re seeing with DNA sequencing and dramatically bring down the cost of writing to help to pioneer a new era of genome writing,” Woolfson said.
So far, the platform company has spun out five different product companies — four HSV gene therapy companies focused on monogenic disorders, including one for Parkinson’s and one for Duchenne muscular dystrophy, and one enzyme writing company.
Replay’s seed round was led by KKR and OMX Ventures, and also included ARTIS Ventures and Lansdowne Partners, SALT, DeciBio Ventures, and Axial.