Nature Reviews Drug Discovery Review Positions SLC Transporters as Untapped Frontier in CNS Drug Development
核心洞察
A new Nature Reviews Drug Discovery review led by Giulio Superti-Furga highlights solute carrier transporters (搜索) as promising targets for epilepsy (搜索), autism, Alzheimer's and Parkinson's disease (搜索).
Of 464 known human SLC transporters across 70 families, only a small fraction have been successfully targeted by approved drugs, leaving most of the family therapeutically unexplored.
First therapeutic candidates that activate rather than block SLC transporters are already in clinical development for epilepsy (搜索), autism spectrum disorders (搜索) and chronic pain.
A comprehensive review published in Nature Reviews Drug Discovery argues that solute carrier (SLC) transporters — a protein superfamily of 464 members across 70 families in humans — represent one of the most consequential untapped target classes in central nervous system medicine. The review, led by Giulio Superti-Furga, founding scientific director of the Austrian Academy of Sciences (搜索) (OeAW) institutes CeMM (搜索) and Cori, examines the therapeutic potential of SLC transporters for epilepsy (搜索), autism spectrum disorders (搜索), Alzheimer's disease (搜索) and Parkinson's disease (搜索).
SLCs are specialized transport proteins that control the movement of nutrients, ions and neurotransmitters across cell membranes and are essential for brain metabolism and neuronal communication. They act as both gatekeepers and workhorses at cell membranes, determining what enters the cell and when — sugars that provide energy, amino acids that serve as building blocks, ions, vitamins, and the chemical messengers that enable communication between nerve cells. Collectively, they control a vast network of molecular traffic across the lipid bilayer surrounding every cell.
Neurons have high energy demands and must tightly regulate the concentration and distribution of neurotransmitters. SLCs help ensure that the right molecules are available in the right place at the right time. When this transport system is disrupted, both neuronal metabolism and communication can be severely affected, making SLCs attractive therapeutic targets.
Established Targets and a Largely Unexplored Landscape
A limited number of SLCs have long been established as effective drug targets. Selective serotonin reuptake inhibitors (SSRIs), for example, block the serotonin transporter, preventing serotonin from being taken back up into cells and thereby increasing its availability between neurons — a mechanism widely used in the treatment of depression, anxiety disorders and other psychiatric conditions. In epilepsy (搜索), tiagabine inhibits an SLC transporter for GABA, the brain's principal inhibitory neurotransmitter, increasing GABA availability and helping to reduce excessive neuronal activity. Other approved drugs target SLCs involved in the transport or storage of dopamine and other neurotransmitters.
Yet these established medicines address only a small fraction of the SLC family. According to the review, SLC transporters constitute an estimated 3% of human protein targets of approved drugs, and only two SLCs rank in the top 20 drug targets by sales and NIH funding. Out of a superfamily exceeding 400 members, roughly a third have no known ligand at all.
Activating Rather Than Blocking Transporters
Most drugs targeting SLCs work by inhibiting transporter activity. But in many disorders, the underlying problem is the opposite: a transporter may be insufficiently active, expressed at abnormally low levels or located in the wrong part of the cell. Researchers are therefore exploring new strategies to activate, stabilize or restore the function of SLC transporters. The first candidates are already in clinical development, including potential therapies for epilepsy (搜索), autism spectrum disorders (搜索) and chronic pain, acting on transporters that regulate the balance between excitatory and inhibitory signals in the brain.
The therapeutic potential of SLCs extends beyond neurotransmission. These transporters regulate the supply of energy and nutrients to neurons as well as the movement of glucose, ions and metabolic products. Disrupted energy metabolism is increasingly recognized as an important feature of neurodegenerative diseases such as Alzheimer's and Parkinson's disease (搜索), and transport pathways involved in cellular metabolism could provide additional points of therapeutic intervention, although many of these approaches remain at an early stage of research.
For diseases caused directly by the loss of function of an SLC gene, research is already going a step further. Gene therapies aim to provide a functional copy of the affected gene and thereby correct the underlying transport defect. The first approaches are already being evaluated in clinical trials, including therapies for SLC6A1 (搜索)-related neurodevelopmental disorders, GLUT1 deficiency syndrome (搜索) and a rare disorder caused by mutations in the SLC13A5 (搜索) gene.
From the Human Transportome to New Medicines
Superti-Furga was among the researchers who recognized the broader therapeutic potential of SLCs early on. For many years, his research has focused on the human "transportome" — the complete set of transport proteins in the human body. He also led RESOLUTE, a major international initiative established to systematically investigate the biology of SLC transporters and make them more accessible for drug discovery.
To translate these findings into new medicines, he co-founded the biotechnology company Solgate (搜索) together with Ariel Bensimon, Gaia Novarino, Stefan Kubicek and Georg Winter. Bensimon and Solgate's Chief Scientific Officer, Enrico Girardi, are also co-authors of the review. The first author is Yee Kwan Law, a PhD student in Superti-Furga's research group at CeMM (搜索).
Superti-Furga is now expanding this research in Graz as founding scientific director of the new Carl and Gerty Cori Institute of Molecular and Computational Metabolism (Cori) of the Austrian Academy of Sciences (搜索). Cori aims to systematically decipher human metabolism and its role in health and disease. SLCs are central to this effort because they determine which nutrients and metabolic products enter and leave cells.
Persistent Technical and Regulatory Challenges
Despite their potential, SLCs remain challenging drug targets. The biology of many transporters remains poorly understood, while developing suitable assay systems and compounds is technically demanding. As a result, only a small fraction of this large protein family has so far made its way into drug development.
The landscape is beginning to change, however. Advances in structural biology, cryo-electron microscopy, computer-aided drug design and screening technologies are improving researchers' ability to selectively target transporters that have previously been difficult to access.
From a clinical development perspective, the field also faces an undefined regulatory pathway for demonstrating CNS transporter pharmacodynamics in humans. The FDA's existing guidance on transporter-mediated drug-drug interactions focuses primarily on pharmacokinetic gatekeeping — whether a compound inhibits transporters that affect the exposure of co-administered drugs — rather than establishing proof-of-concept for transporter-mediated pharmacodynamics in the CNS. Existing guidance documents do not specify what a valid pharmacodynamic biomarker for SLC engagement looks like in a CNS indication, and the field lacks established precedent for what the agency expects as evidence that a novel SLC modulator reaches its target in the brain at therapeutically relevant concentrations.
The fedratinib case illustrates the consequences of incompletely characterized SLC interactions. During the JAKARTA and JAKARTA-2 trials, the FDA placed a clinical hold on fedratinib in 2013 after cases of Wernicke's encephalopathy (搜索) emerged, a thiamine-deficiency syndrome later attributed partly to the drug's inhibition of a thiamine transporter. The drug was targeting JAK2 (搜索); the transporter was an off-target casualty.
The review notes that numerous SLC transporters show dysregulated expression specifically in CNS tissue compared to peripheral tissues, a selectivity profile that is pharmacologically attractive because it reduces the theoretical risk of systemic off-target effects. However, tissue selectivity in expression data does not automatically translate to CNS selectivity in drug distribution, and the blood-brain barrier transport characteristics of SLC-targeted compounds add another layer of mechanistic work.
For trial designers, the practical implication is that CNS-targeted SLC programs need centrally assessed pharmacodynamic endpoints tied to the specific transport mechanism rather than surrogate clinical endpoints borrowed from approved drug classes with different mechanisms. Drug-drug interaction characterization must also be extended to cover the SLC isoforms most relevant to CNS co-medications, since neuropsychiatry patients rarely take a single drug. Biomarker strategies need to be locked before Phase I rather than retrofitted at Phase II, because the window to establish transporter engagement in early human studies is narrow.
Rather than focusing exclusively on individual neurotransmitters or receptors, future therapies could specifically correct the molecular transport pathways that determine the metabolism and chemical balance of nerve cells. Whether this will ultimately lead to new treatments for epilepsy (搜索), autism, Alzheimer's or Parkinson's remains to be demonstrated in clinical trials. But with the first therapeutic candidates already in development, SLC transporters are moving from a relatively overlooked protein family toward the forefront of neuroscience drug discovery.