TLR7: A promising drug target for lupus
by Elizabeth Bolitho
Toll-like receptor 7 (TLR7) has long been implicated in lupus. Now scientists are uncovering precisely how.
Toll-like receptor 7 (TLR7) has long been associated with the autoimmune disease, lupus. Genetic polymorphisms that result in higher TLR7 expression are associated with increased risk of developing lupus. Aberrant signaling from the protein, which senses single-stranded RNA viruses, is thought to be a mechanism driving the disease: TLR7 drives B cells to produce ‘auto-antibodies’. The TLR7 gene’s location on the X chromosome may also help explain lupus’ higher prevalence in women.
The discovery in 2022 of a gain-of-function variant of the gene encoding TLR7 in a seven-year old Spanish girl provided more direct evidence of TLR7’s involvement, sparking a flurry of scientific publications. The mutation enhanced TLR7’s sensitivity to its ligand, guanosine, driving enhanced B cell survival and over-activity.
Mice injected with the gene mutation developed characteristics of lupus, including over-production of interferon and other inflammatory cytokines. Although this particular variant is very rare – it has only been found in one patient so far – other variants in neighboring genes also increase TLR7 activation, adding to its promise as a potential lupus drug target. (TLR7 isn’t new to the pharmacopeia: imiquimod, approved in 2004 for basal cell carcinoma, activates TLR7 and TLR8 on macrophages, monocytes and dendritic cells; in this context, boosting the cell-mediated immune response helps fight the cancer.)
The malaria drug hydroxychloroquine, which has been used to treat lupus since the 1950s, may work partly by blocking TLR7, according to recent research. Enpatoran, an oral TLR7/8 antagonist, is being tested in Phase 1 and Phase 2 trials in systemic lupus erythematosus (SLE), the most common form of lupus, and in cutaneous lupus (manifest as skin rashes and soreness). Meanwhile, TLR7 and TLR8 agonists are also being investigated in various cancers. All this research, regardless of therapy area, helps elucidate the mechanisms behind this important signaling pathway and may uncover further promising targets. For instance, deficiencies in myeloid-differentiation primary response 88 (MyD88), a protein downstream of TLR7 and TLR8, are found to reduce autoimmunity in mice. So inhibiting MyD88, which links TLR signals to those further along the signaling cascade, may provide another drug discovery avenue. Other members of the TLR family could also play a role: TLR9, for instance, may protect against lupus by inhibiting TLR7 activity.
According to Causaly, TLR7 was ranked highly among lupus drug targets based on the number of published documents. Transcription factor interferon regulatory factor 5 (IRF5), which helps regulate inflammation, is also the subject of multiple publications. IRF5 is found to be active in lupus patients; inhibiting it slows disease progression in mice and in ex vivo human studies using SLE immune cells. It isn’t an easy target to hit with small molecules, though; transcription factors lack active sites and don’t have deep pockets to accommodate inhibitor molecules.
Still, researchers now have many more tools to investigate disease biology and molecular function in more detail – and to design effective, targeted molecules. Single-cell RNA-sequencing, for example, allows scientists to study the effects of lupus on particular cell types, such as human or mouse primary cells or haematopoietically derived cells. Computer-aided drug discovery approaches can help identify activity points on transcription factor proteins, and generate novel molecular conformations.
There will not be a single solution for everyone: lupus is a complex, polygenic and highly heterogenous group of conditions. But, as work around targets like TLR7 and IRF5 suggests, progress is being made toward a wider range of options.
To find out more about novel target discovery in lupus and other autoimmune diseases, including counts and breakdowns by target type, plus target rankings and broader analysis, download the 2023 Target Discovery Spotlight Report: Lupus and Autoimmune Diseases.