NEW YORK – Backed by a recent $40 million in funding from Foresite Capital and GV (formerly Google Ventures), San Francisco-based TenSixteen Bio is exploring clonal hematopoiesis and other forms of somatic mosaicism as drug targets for conditions including cancer and cardiovascular disease.
The company, which formally launched at the end of January, is developing next-generation sequencing-based assays to diagnose clonal hematopoiesis of indeterminate potential, or CHIP, a condition in which mutated hematopoietic stem cells replicate at greater than normal rates, leading to expanded populations of these cells.
Present in around 10 percent of people 70 and older, CHIP is not itself an illness, but individuals with CHIP are at increased risk of conditions including various cancers and cardiovascular disease. Scientists first observed CHIP several decades ago, but in recent years have used improved sequencing and informatics tools to begin characterizing CHIP and CHIP-linked mutations on a large scale.
TenSixteen believes that by targeting CHIP therapeutically it can more effectively address diseases that develop downstream from the condition.
"It's about intercepting and diagnosing disease earlier and also treating it at an earlier stage," said Mark Chao, the company's cofounder and CEO.
Chao was previously cofounder of immune-oncology firm Forty Seven, which Gilead acquired in 2020 for $4.9 billion.
He said there are roughly 10 to 15 specific mutations linked to CHIP, including in a number of genes commonly profiled in cancer sequencing panels such as JAK2 and TP53. TenSixteen is developing NGS-based assays for those CHIP-linked mutations that Chao said it will initially offer in a research setting followed by the development of a CLIA assay and, ultimately, a companion diagnostic.
Part of the challenge is identifying the best candidates for treatment among individuals with CHIP.
"There are those who are at very high risk for developing cancer, and then there are those at a lower risk," Chao said, noting that some individuals harboring CHIP have an almost 100 percent chance of developing cancer in several years.
"Those are the ones that we are trying to capture in terms of really having a precision medicine approach," he said. "So how do we identify those patients?"
To address this and other aspects of its drug-development work, TenSixteen is building a resource containing multiomic profiles of individuals with CHIP along with phenotypic and clinical data. It is collecting this information from a combination of public databases and collaborations with academic partners and healthcare institutions, Chao said, the goal being "to create a very extensive dataset from which we can derive novel targets, [identify] who are the right patients to target, and what is the biomarker and companion diagnostic that we associate [with treatment]."
Another factor to take into consideration is that certain CHIP mutations appear to have benefits. For instance, at the American Society of Hematology annual meeting in December, Siddhartha Jaiswal, an assistant professor of pathology at Stanford University and a TenSixteen cofounder, presented data indicating that certain CHIP mutations are protective against Alzheimer's disease.
Jaiswal and colleagues also published their findings in a medRxiv preprint. Across multiple cohorts with multiple CHIP mutations, they found that the condition offered protection against Alzheimer's dementia greater than that provided by carrying the APOE ἐ2 allele (which they noted is "the most protective common inherited variant" for Alzheimer's) and was also linked to lower levels of the amyloid plaques and neurofibrillary tangles associated with the disease.
The observation suggests that in some cases, targeting CHIP mutations could prove harmful, rather than beneficial to patients, or could have mixed effects.
"It's a fair question, and I think this is where it really depends on how you target [anti-CHIP therapies]," Chao said. "Different pathways and different targets will have less concern."
Another consideration is the fact that individuals with CHIP don't yet have a condition like cancer or heart disease, which changes the risk-benefit calculus in treating those people.
"You need to have the right risk-benefit profile from a toxicity perspective," Chao said, noting that repurposing existing drugs with good safety profiles will be part of the company's strategy.
"There are certain targets where there are approved drugs that have been in clinical use with very well-accepted safety profiles that we could repurpose to use in high-risk subgroups," he said.
Chao said TenSixteen is exploring two primary therapeutic avenues, the first being to target the CHIP mutations themselves with small molecule or monoclonal antibody drugs.
"You target a mutation and you eliminate that adverse subclone," he said. "By doing that you can reduce the burden of CHIP, and by reducing the burden of CHIP you reduce the risk of disease."
The second route is to target the downstream consequences of CHIP. For instance, CHIP has been shown to drive a pro-inflammatory state that researchers have found increases an individual's risk of a cardiovascular event twofold independent of traditional risk factors.
"If you can treat in terms of anti-inflammatory pathways, that is another route to eliminate the downstream sequelae," he said.
The observation that CHIP significantly increases a patient's risk of cardiovascular events suggests that it could be useful as a tool for assessing cardiovascular disease risk even separate from any specific drug development efforts. Chao said, however, that in terms of diagnostics the company plans to primarily focus on developing companion diagnostics to guide the use of its therapies.
Chao said that TenSixteen is also looking for targets within pathways that appear to encompass multiple CHIP mutations.
"We are trying to develop what would be in some ways a 'magic bullet' for multiple CHIP mutations," he said. "The idea here is, can we target regulators that control the growth of multiple CHIP genes? Internally, we've identified a few targets that we are really excited about."