In the intricate landscape of the human body, microscopic gatekeepers control the fate of modern medicine.
Recent research reveals how manipulating the ABCG2 transporter dramatically improves multiple sclerosis treatment outcomes in animal models.
Imagine a bustling city protected by a sophisticated gate. This gate doesn't just control what enters; it actively expels unwanted visitors. Within our bodies, a microscopic version of this gate exists—the ABCG2 transporter—and it may hold the key to understanding why medications work differently from person to person. For patients with multiple sclerosis (MS), this molecular gatekeeper could explain the variable effectiveness of a common treatment, teriflunomide. Recent research reveals that by manipulating this transporter, scientists have dramatically improved treatment outcomes in animal models of MS, opening new avenues for personalized medicine 1 2 .
To appreciate the discovery, we must first understand the two main players.
An oral disease-modifying therapy approved for relapsing forms of MS. Its primary job is to rein in the overactive immune system that attacks the protective sheath around nerve fibers.
A microscopic bouncer that uses cellular energy to pump substances—including pharmaceuticals—out of cells.
The ABCG2 transporter recognizes teriflunomide as a substrate and actively works to expel it from cells, reducing its therapeutic concentration at target sites.
Teriflunomide is administered orally to the patient.
The drug enters the bloodstream and reaches target immune cells.
ABCG2 transporter identifies teriflunomide as a substrate.
ABCG2 uses cellular energy to pump teriflunomide out of cells.
Lower intracellular drug concentration leads to diminished therapeutic effect.
Researchers hypothesized that inhibiting ABCG2 could increase teriflunomide concentration inside target immune cells.
If ABCG2 transporter activity is inhibited, either genetically or pharmacologically, the intracellular concentration of teriflunomide will increase, enhancing its therapeutic effects in MS treatment.
Using mice genetically engineered to lack the abcg2 gene (abcg2-KO mice).
Using specific chemical inhibitors (Ko143 and Fumitremorgin C) to block transporter activity in normal wild-type mice.
T cells were isolated from both wild-type and abcg2-KO mice. These cells were treated with teriflunomide in the presence or absence of ABCG2 inhibitors.
Researchers used highly sensitive techniques like high-performance liquid chromatography (HPLC) and LS-MS/MS to measure the precise concentration of teriflunomide inside T cells.
They evaluated two key effects of teriflunomide:
Mice with induced Experimental Autoimmune Encephalomyelitis (EAE) were treated with teriflunomide. Clinical severity was scored daily, and spinal cord tissue was analyzed for drug concentration and inflammation.
Inhibiting ABCG2 supercharges teriflunomide's effects in both cellular and animal models.
| Experimental Measure | Wild-Type T Cells | abcg2-KO T Cells | Wild-Type T Cells + ABCG2 Inhibitor |
|---|---|---|---|
| Intracellular Teriflunomide Concentration | Baseline | 2.5-fold higher 1 | Not explicitly quantified (but effects increased) |
| Inhibition of T Cell Proliferation | Baseline | 2-fold increased 1 | Similar enhancement observed |
| Induction of T Cell Apoptosis | Baseline | Analogous increase | 3.1-fold increased 1 |
| Research Tool | Function in the Experiment |
|---|---|
| abcg2-Knockout (KO) Mice | Genetically modified model to study the transporter's function by observing what happens in its absence. |
| ABCG2 Inhibitors (Ko143, Fumitremorgin C) | Pharmacological tools to block the transporter's activity in normal cells, confirming its role. |
| Experimental Autoimmune Encephalomyelitis (EAE) | A standard animal model that replicates the inflammatory demyelination of MS, used to test drug efficacy. |
| CellTrace CFSE | A fluorescent dye that dilutes with each cell division, allowing researchers to track and quantify T cell proliferation. |
| Annexin V / Propidium Iodide (PI) | Fluorescent markers used in flow cytometry to distinguish between healthy, early apoptotic, and dead cells. |
This research stretches far beyond the laboratory bench with significant clinical implications.
The functional relevance of ABCG2 modulation provides a plausible explanation for the variable responses seen in patients' reactions to teriflunomide and potentially other MS therapies 1 .
Natural variations (polymorphisms) in the ABCG2 gene could lead to differences in how efficiently the transporter pumps out the drug.
A 2023 study in humans found that the passage of teriflunomide from the blood into the cerebrospinal fluid is very low (about 0.17%), confirming that getting the drug into the central nervous system is a significant challenge 3 .
While directly inhibiting ABCG2 in patients is not yet a clinical reality—the inhibitors used in research are too toxic for human use—this work illuminates a promising path.
A patient's ABCG2 profile could one day guide treatment choices.
Patients with highly active ABCG2 might be steered toward non-substrate drugs.
Future, safer ABCG2 inhibitors could enhance a whole class of medications 1 .
The story of ABCG2 and teriflunomide is a powerful reminder that a drug's journey through the body is an epic adventure, full of obstacles and gatekeepers. By understanding these hidden battles, we can devise smarter strategies to win the war against complex diseases like multiple sclerosis.