Next-Gen Cell Therapies Are Already Here
Recent discoveries laying the groundwork for a cell therapy revolution
Hyperlinks in this text are configured to direct you to the relevant section of the page, excluding articles behind paywalls. This feature might not work immediately with Substack. If the page doesn’t scroll to a relevant section, copy-paste the address back into your search bar and hit enter.
The technology which will push human lifespans past 160 is already here. Its seeds were planted in 1893, the fruit is ripe and unharvested, and its juice is worth the squeeze.
On the surface, pregnancy seems to be all about giving. You endure sickness, cramps, and sudden cravings for bizarre food combinations over the course of nine months, all precipitated by the wonderful little ball of cells feeding off of your blood which will eventually grow into another infinitely complex human.
When observed at the cellular scale, however, a different picture begins to emerge. Beginning at seven weeks post-conception and continuing until delivery, the developing fetus will share its extraordinary regenerative capacities with its mother. This sharing comes through the transfer of Feto-maternal Microchimeric Stem Cells (FMSCs), a class of fetal stem cells capable of traversing the placenta, trafficking to maternal tissues and differentiating into functional tissue-specific cell types. These cells are part of the developing embryo’s gift back to its mother—a powerful, naturally curing regenerative medicine capable of ameliorating a wide range of injuries and disease. While the existence of these cells was first detected in 1893 during George Schmorl’s autopsies of eclamptic women and his later experimentation in healthy animal models of pregnancy, but it was only in the new millennia that the therapeutic potential of these cells began to make itself evident.
One example of this giving back arose from an investigation of pregnancy’s protective effect against heart failure. It has long been observed that women suffering from peripartum cardiomyopathy, which only occurs in late stage pregnancies or soon after delivery, experience far lower mortality rates than any other form of cardiomyopathy.
This observation prompted a series of studies in the Chaudry lab at the Icahn School of Medicine to discover the mechanism behind this protection. The scope of these studies would broaden, however, culminating in the translation of the unique properties of FMSCs into a cell therapy surpassing the weaknesses of current market leaders and setting the stage for the field’s next revolution.
Legacy cell therapies suffer from two core limitations.
First, they lack the ability to travel to where they are needed in the body, and must be delivered directly to sites of injury or disease. Excepting blood or immune cell therapies which can be delivered directly to the bloodstream, most cell therapies require direct injection to the site of injury in an invasive process requiring highly trained personnel.
Complicating things further, they must be autologous in order to prevent immune rejection, meaning that therapeutic cells need to be harvested from the patient, expanded outside of their body, then in a lengthy and expensive process during each treatment. These combined limitations render even the best cell therapies slow, unaffordable, and only available at select medical facilities with expert staff. A new wave of therapies have formed around the observation that stem cells isolated from fetal tissue, cord blood, the placenta, and other sites of interaction between the mother and developing fetus are naturally allogeneic, likely an evolved adaptation to help offspring survive their mother’s immune systems. One class of these cells, however, stands head and shoulders above the rest in its potential to form the basis of the next generation of cell therapies. FMSCs naturally overcome both limitations, a fact demonstrated beautifully by the Chaudry lab’s previously mentioned experiments.
This work began in 2011, when the lab observed increased cell trafficking from fetus to mother in pregnant mice having undergone ligation of the left anterior descending artery to induce a severe form of heart attack known as anterolateral myocardial infarction (MI). Wild-type female mice were crossed with males expressing enhanced green fluorescent protein (eGFP) in their cells, creating fetuses whose cells also fluoresced green. The lab was able to track these cells as they crossed the placenta and migrated to the mother’s heart by watching for this fluorescence, which eventually resulted in the replacement of 1.7% of the maternal heart with eGFP expressing fetal cells on average at two weeks post-MI.
Injured heart tissue displayed 10 times more eGFP than uninjured heart tissue (supplement 6, table IIB), while fetal cells were almost undetectable in other tissues and organs. These FMSCs differentiated into mature endothelial cells, smooth muscle cells, and cardiomyocytes, proving their ability to overcome the first limitation of legacy cell therapies by specifically migrating to sites of injury and differentiating into target cell types without requiring invasive direct injections.
This experiment also suggested FMSCs to be capable of overcoming cell therapy’s second limitation: the time and expense required by autologous treatments. As previously discussed, cell therapies are often created by purifying a target cell population from patients and cloning it outside their bodies in order to avoid immune rejection. The FMSCs evaded the mother’s immune system despite only sharing 50% of her DNA, far above the threshold at which rejection would usually occur. The Chaudry lab would go on to conclusively prove this point in 2019, when they used FMSCs purified from placental tissue to treat induced cardiac damage in unrelated male mice without immune rejection.
This study mirrored their previous work in that they used eGFP+ fetal cells for ease of tracking through the recipient’s body. Instead of being endogenous to the mother, however, these cells were purified from extracted late-term placentas and injected into infarcted and control mice at a dose of 1 million cells. Chaudry’s team observed similar trafficking and engraftment into injured heart tissue in these mice without immune rejection, observing increased cardiac function across multiple metrics at one and three months post-treatment (1, 2, 3).
The study demonstrated that allogeneic FMSCs were able to effect significant cardiac repair when used as a cell therapy. Furthermore, it proved that FMSC-mediated recovery is not inherently tied to the physiological state of pregnancy–a crucial property for a widely-applicable treatment. Since FMSCs know how to play nice with foreign immune systems, they have the potential to form the basis of an off-the-shelf therapy which could be stored and administered on an as-needed basis without requiring lengthy and expensive isolation and expansion phases. Their trafficking ability has the potential to further reduce cost of treatment by eliminating the need for highly trained staff to perform invasive direct injections, resulting in a next-generation therapy which can be stored until needed and immediately delivered off-the-shelf as a simple IV injection in any existing clinic.
FMSCs possess a host of other unique attributes, including a unique transcriptomic and proteomic landscape which drives upregulated survival signaling and migration ability compared to similar adult stem cells. The Chaudry Lab focused on one subtype of these cells (trophoblast-derived stem cells expressing the caudal-type homeobox-2 transcription factor), but a range of other fetal stem cells have been found to traffic and integrate into the maternal body, including highly therapeutically relevant populations such as hematopoietic and mesenchymal stem cells.
Although the increased function of treated hearts was modest compared to untreated hearts in the Chaudry lab’s studies, we believe the demonstrated capacity of these and other FMSC populations positions them at a critical inflection point for the future of cell therapy. Their natural allogenicity and trafficking ability has the potential to drive the cost of their derived therapies down by orders of magnitude, transforming the treatment class from an unaffordable last resort in otherwise intractable cases to a powerful, routine intervention against a wide range of indications. This reduced cost and ease of application would even allow FMSC derived therapies to be administered prophylactically, gradually replacing old, damaged cells with young, functional substitutes long before the advent of disease. And this is only the beginning: increasing the efficiency of these therapies by administering recruitment factors (1, 2 ) and engineering the cells with new abilities enables a future where the adult body can be rebuilt one cell at a time, forestalling disease and death while enhancing our biology with new powers we can now scarcely even imagine.
It was this vision which inspired me to form Sundial Therapeutics.
Our company exists to create the therapy which will catapult human lifespans past 160 years by replacing the aging brain, one cell at a time. We’ll cover the incredible potential this technology holds for brain repair in a future essay.
This will be a long road filled with many firsts. We are committed to sharing the insights gained during this journey into our science, business model, and regulatory path to market in this publication, providing interested readers and future founders alike with knowledge found nowhere else.
A FMSC-derived cardiomyocyte beats to the melody of cell therapy’s next revolution. Kara et al., 2011.