Light Horse Therapeutics

For decades, drug developers have followed a familiar playbook: isolate a disease-causing protein, develop a biochemical assay, find molecules that bind to it, and then hope those compounds work in living cells. More often than not, they don’t.Light Horse Therapeutics is flipping that approach on its head. The San Diego start-up uses systematic CRISPR-based gene editing to first identify which regions of a protein are functionally critical for driving cancer, and then hunts for small molecules that target those exact sites. The company calls it “function-first” drug discovery.Markus Renschler, Light Horse CEO and a medical oncologist by training, points out that biology is far more complex than test tube assays suggest. Proteins function as part of multiprotein complexes in living cells, not in isolation.Light Horse’s platform addresses this complexity by interrogating proteins in their native cellular environment. Chief scientific officer Laure Escoubet, who spent 14 years leading epigenetic drug discovery at Celgene and Bristol Myers Squibb, describes the approach as “systematic mutagenesis of entire proteins.” Using CRISPR base editors (which introduce point mutations into DNA rather than cutting it), Light Horse scans proteins from end to end, creating thousands of individual mutations simultaneously.The company can screen thousands of mutations across 30–40 genes at once, generating what it calls “site dependency maps” that reveal which amino acids are essential for the function of each protein interrogated. “In these screens, each cell harbors only one mutation, and the phenotype induced by this mutation is interrogated using multiple readouts,” Escoubet says.These maps often