Spotlight Therapeutics, a startup with a bold vision for delivering CRISPR therapies into the body without the need for viral vectors or lipid nanoparticles, has shut down, Endpoints News has learned.
The San Francisco-based company had more than 40 employees at its peak and raised $66.5 million in two rounds of funding since its debut in 2020. Former CEO Mary Haak-Frendscho said Spotlight “was a moonshot ambition” that would “build on the learnings” of antibody-drug conjugates to shuttle CRISPR treatments to their target tissues.
“Many of us thought that a lot of the learnings of the ADC field would translate more readily into the gene editing field,” Haak-Frendscho told Endpoints in an exclusive interview. “That did not pan out. It was an even bigger technical challenge than we appreciated.”
A preprint published on bioRxiv on New Year’s Eve reveals that the company struggled to get enough of its CRISPR treatment into cells. Even when the therapy was injected directly into the eye, only 7% of retinal cells were edited, on average, in mice. The editing rate was less than 1% in minipigs, a larger lab animal sometimes used as a stepping stone to clinical trials.
Haak-Frendscho said that although scientists disagree on how many retinal cells need to be fixed to treat inherited vision disorders, the results fell below the company’s threshold for moving forward. “We would not have been comfortable with anything below 10 percent,” she said.
Last summer, the company quietly began laying off its employees and looking for a “strategic alternative” for the company’s assets — including its remaining funds.
Haak-Frendscho said the company “executed a transaction that was good for our investors” in late December. A source familiar with the move said that Spotlight was folded into a16z-backed Stipple Bio, a spinout of the Fred Hutchinson Cancer Center that’s still in stealth. Haak-Frendscho declined to comment.
CRISPR as a biologic
Spotlight’s shutdown comes amid the toughest year for the gene editing industry since CRISPR was invented in 2012. Nearly every gene editing company has reduced its workforce or trimmed its drug pipeline as investors grow increasingly impatient with the business challenges posed by pricey one-time therapies and the lingering scientific hurdles in making CRISPR work for more diseases.
Ironically, Spotlight was one of the few companies devoted to CRISPR’s biggest technical bottleneck: delivering it to the right part of the body.
Most gene editing companies are packaging the genetic blueprints for CRISPR treatments into the viral vectors used by more traditional gene therapy companies or in the lipid nanoparticles popularized by the Covid-19 vaccines. Both approaches have limitations, including the high cost and immune reactions to the viruses and the unsolved challenge of getting nanoparticles unstuck from the liver, which soaks them up like a sponge.
Spotlight was based on a radically different idea that would treat CRISPR just like any other biologic drug that’s injected or infused into the body as a protein.
By attaching an antibody to the CRISPR enzyme and its guide RNA — jointly known as a ribonucleoprotein — Spotlight would direct the therapy to the desired cell. Another molecule called a cell-penetrating peptide would help the whole thing slip through the cell’s protective walls.
“It was not something that was fully de-risked in the academic setting,” Spotlight co-founder Alex Marson told Nature Biotechnology in 2021. Marson declined to comment on Spotlight’s shutdown.
Moving too quickly
Spotlight was founded by a trio of gene editing scientists: Marson from the University of California, San Francisco, Patrick Hsu from the University of California, Berkeley, and Jacob Corn, then at Berkeley but now at ETH Zürich. The company made its big debut in 2020 with a $30 million Series A led by GV, the venture arm of tech giant Alphabet.
The startup’s first lead program was an injection to reprogram the tumor microenvironment. By editing immune cells to knock out an enzyme called ADAR, the company hoped to enhance the immune response to checkpoint inhibitors. The preclinical studies were “compelling,” Haak-Frendscho said, although the company ditched the program after struggling to get investors and potential pharma partners excited about it.
Haak-Frendscho blamed the broader industry-wide shift away from immuno-oncology as one reason for the disinterest. But she also noted the initial version of the treatment was an injection in the tumor — a procedure that complicates the administration of the treatment and may have blunted excitement about the new delivery approach.
The company pivoted to eye diseases, another area where local injections help lower the bar on delivery challenges. Spotlight didn’t have an antibody to target retinal cells, but hoped that the cell-penetrating peptide would be enough to help the therapy seep across the relatively small surface of the retina. That didn’t happen, and the disappointing results led to the company’s closure.
“We tried to move quickly. Obviously too quickly,” Haak-Frendscho said.
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