COVID-19 is the latest disease to point at our need to treat immune aging
The search for COVID-19 therapies should revolve around a single question that’s staring us right in the face, and we’re mostly ignoring it:
Why are outcomes so dramatically skewed against older adults?
Old age is the single biggest risk factor for COVID-19 severity. It’s less risky to contract COVID-19 while suffering from obesity, cardiac disease, diabetes, or one of many other comorbidities than it is to do so while simply existing as an older adult.
There are similar relationships between aging and many diseases, of course, from cancer to cardiovascular to neurodegenerative.
We’ve lived with that fact for so long that it’s boring to most — almost invisible. Aging is the single biggest risk factor for the most detrimental diseases on earth. Our vulnerability to viruses like influenza and COVID-19 is “just” one such example.
But COVID-19 is novel. Devastating. It has our attention. And it’s screaming for us to treat a long neglected wound: as we age, our immune system dysfunctions, making us more susceptible to many insults.
Finding novel drugs for this old problem requires new technology that can:
- Better understand how our immune system changes as we age,
- Identify which changes drive disease, and
- Search quickly for drugs that reverse them.
Spring Discovery has been building this for years: a team + tools that combine to form a high-throughput drug discovery machine, laser-focused on therapies for aging. We most recently pointed this machine at the age-related decline of our immune response to viruses and are proud to share more.
Most time and money pouring into COVID-19 therapies is generally flowing into one of three buckets: (1) antivirals that target and disarm the virus itself, (2) therapies that modulate immune function, and (3) antibody treatments. Nothing’s a home run yet, but this problem certainly justifies all of the above shots on goal and more. Biotech’s rallying speed around COVID-19 is inspiring to say the least.
Spring’s approach asks a different question than the rest. It’s a simple question, deceptively important, ignored by too many: Why does an older adult’s immune system fare so much worse than a younger person’s when hit by a virus like COVID-19? And which drugs would help?
“If COVID-19 has the greatest impact on the elderly, rather than targeting the virus, should we not be focusing more on strengthening the host?”
— Vadim Gladyshev
We found ourselves in a unique position when COVID-19 popped up and started disproportionately affecting the elderly. We’ve spent years at Spring building technology to profile the aging immune system. It’s a hard problem — writing “the immune system is complex” doesn’t do it justice, and the nuanced changes our immune system undergoes as we age are not well understood. Our technology squares up against this challenge by combining machine learning with high-throughput lab automation to measure many phenotypes associated with older adults’ dysfunctional immune response. We create “multi-phenotype aging profiles” by capturing changes in cell composition, cell-to-cell interaction, organelle structure, cytokine levels, and other hidden complexities that contribute to age-related dysfunction — all from a single experimental well.
With this machine we can accurately detect differences in old and young immune responses to viruses by exposing donors’ immune cells to a virus and capturing our multi-phenotype aging profile for each. This same technology lets us run unbiased screens on thousands of compounds, searching for drugs that make an older donor’s immune cells respond to a viral infection like a younger donor’s.
Today we’re sharing a preprint describing this immune aging technology and our use of it to screen thousands of compounds to find immune aging therapies.
Importantly, we’re also using this preprint to flag one particular drug surfaced by our machine that we believe is deserving of investment as a treatment for COVID-19 due to (A) its potential for combating immune aging and (B) appropriateness for a pandemic: disulfiram.
Disulfiram is an approved, generic, cheap, widely-available drug with a promising safety profile — all ideal properties for a global pandemic. It was developed in the 1940s to help battle alcohol abuse.
Our machine surfaced disulfiram in an unbiased manner after screening thousands of compounds and running multiple dose response validations. Our immune aging profiles suggest that disulfiram may restore multiple age-related phenotypes to younger states (cytokine levels, T-cell phenotypes, viral infection phenotypes, and more — see preprint). Like any other in vitro work, this requires lots of followup. We’re running in vivo validation with partners as we type.
Leaders in immunology have also recently identified disulfiram as having promising anti-inflammatory properties. Judy Lieberman and Hao Wu’s pivotal discovery that it inhibits inflammasome-mediated pyroptotic cell death and Akiko Iwasaki’s observations on inflammasome targets for COVID-19 both fuel the possibility that it may have direct relevance to root causes of the runaway inflammatory processes of COVID-19 and other inflammatory illness.
And excitingly, a couple days ago UCSF independently announced a small proof-of-concept clinical trial testing disulfiram in COVID-19 patients. We’re thrilled to see this step taken. While others may be interested in the drug for different reasons, we believe it represents a unique approach among the field of COVID-19 therapeutics — a drug that our machine surfaced by starting with the question, “How do we help an older person’s immune system respond to a virus like a younger person’s?”
The health implications of focusing on aging and our immune system extend far beyond a single virus. COVID-19 is just the most novel of many diseases that all point to an important fact: as we age we become dramatically more susceptible to illness.
We need new technology and dedicated teams to measure, understand, and therapeutically target the complex age-related changes behind this.
This is what we build every day at Spring. We’re a cross-functional group of scientists, engineers, drug developers, clinical experts, and computational biologists who love humbly learning from each other — and who believe that by focusing on the diseases of aging we can help “fight back against the grim reaper.”
For those moved to join such a cause, it’s an exciting time to talk.