Science
Restoring immune function at the level of RNA.
Our scientific rationale in seven steps — from the biology of microglia to a cell-targeted antisense strategy directed at SRSF3.
Microglia and CNS immunity
Microglia are the principal immune cells of the brain and spinal cord. Under physiological conditions they are essential for maintaining tissue homeostasis and continuously survey their environment.
After injury or in disease, microglia initiate and regulate innate immune responses. A timely, well-controlled microglial response helps limit damage to the nervous system.
Sources Boutej et al., Cell Reports, 2017 (DOI 10.1016/j.celrep.2017.11.058, opens in a new tab)Rahimian et al., Molecular Therapy, 2024 (DOI 10.1016/j.ymthe.2024.01.004, opens in a new tab)
Chronic disease and functional dysregulation
In ALS, activated microglia are a prominent feature of pathology. Studying microglia at different disease stages in the SOD1-G93A mouse model, the team found that cells from advanced disease showed markedly reduced phagocytic capacity and a diminished response to innate immune challenge.
At the protein level, advanced-stage microglia developed an unconventional signature whose top functions were linked to RNA metabolism rather than immunity. The picture is not simply “good” or “bad” inflammation: chronically activated microglia gradually lose their immune identity and become functionally inefficient.
Conceptual transition of microglial function in chronic disease. Conceptual illustration — not experimental data.
Sources Barreto-Núñez et al., Glia, 2024 (DOI 10.1002/glia.24531, opens in a new tab)Béland et al., Brain Communications, 2020 (DOI 10.1093/braincomms/fcaa124, opens in a new tab)
RNA translation as a therapeutic control point
Genes are transcribed into messenger RNA (mRNA), which ribosomes translate into protein. Measuring mRNA alone assumes that more message means more protein.
In activated microglia, that assumption breaks down. The most highly upregulated innate immune transcripts were bound to ribosomes yet were not detected as protein — while unregulated transcripts were translated normally. Translation itself becomes a point of control.
- DNA
- mRNA
- Ribosome
- Protein
The gap
High mRNA, little or no protein
Source Boutej et al., Cell Reports, 2017 (DOI 10.1016/j.celrep.2017.11.058, opens in a new tab)
SRSF3
SRSF3 (serine/arginine-rich splicing factor 3, also known as SRp20) is the smallest member of the SR protein family of RNA-binding proteins. Like other SR proteins it participates in alternative splicing, and it also has roles in mRNA export, stability and translation.
The team’s published work implicates SRSF3 in the translational repression of selected, highly upregulated innate immune transcripts in microglia/macrophages. Repression acts through the transcripts’ 3′ untranslated region (3′UTR), which contains many putative SRSF3 binding sites. SRSF3 does not control every immune gene — its effect is selective.
The phosphorylated form of SRSF3 increases in activated microglia/macrophages after immune challenge and after experimental stroke.
Sources Boutej et al., Cell Reports, 2017 (DOI 10.1016/j.celrep.2017.11.058, opens in a new tab)Rahimian et al., Molecular Therapy, 2024 (DOI 10.1016/j.ymthe.2024.01.004, opens in a new tab)
RNOVA’s therapeutic hypothesis
Disease / chronic activation
- SRSF3 regulatory state increased or dysregulated
- Translation of selected immune mRNAs restrained
- Fewer functional immune proteins produced
- Dysfunctional immune phenotype
RNOVA concept
- SRSF3-directed antisense
- Modulation / reduction of SRSF3
- Release of selected translational repression
- De novo immune protein synthesis (experimental systems)
- Restored, reprogrammed functional response
In published experimental models, reducing SRSF3 with RNA-silencing tools restored translation of selected immune proteins in microglia/macrophages. Whether this translates into therapeutic benefit in patients has not been established.
Sources Boutej et al., Cell Reports, 2017 (DOI 10.1016/j.celrep.2017.11.058, opens in a new tab)Rahimian et al., Molecular Therapy, 2024 (DOI 10.1016/j.ymthe.2024.01.004, opens in a new tab)
Cell-targeted antisense
Antisense oligonucleotides (ASOs) are short, synthetic nucleic-acid strands that bind a specific RNA sequence. RNOVA Tx uses antisense chemistry to reduce SRSF3 production.
Because SRSF3 has functions in many cell types, where the drug goes matters. RNOVA Tx is developing delivery strategies intended to favour uptake by innate immune cells — including a peptide-conjugated antisense approach (TAT2-SRSF3) and a next-generation, cell-selective targeting strategy (EAT-ME-SRSF3).
EAT-ME-SRSF3
EAT-ME-SRSF3 is an emerging targeting strategy under development. It is designed to improve delivery of SRSF3-directed antisense to selected innate immune cell populations. Technical details are not disclosed at this stage.
Why this approach is different
Many approaches to neuroinflammation aim to dampen inflammatory signalling. RNOVA Tx is exploring a complementary idea: restoring the protective functions that chronically activated microglia lose, by acting on how immune messages are translated.
| Broad suppression | RNOVA approach | |
|---|---|---|
| Level of action | Signalling pathways, cytokines or receptors | RNA translation of selected immune transcripts |
| Goal | Reduce inflammatory activity | Restore functional immune protein output |
| Target cell | Often broad | Designed for innate immune cells |
Conceptual comparison only. No clinical superiority is claimed.
Advancing a new paradigm in CNS immunotherapy.
RNOVA Tx welcomes conversations with pharmaceutical, biotechnology, scientific and development partners interested in RNA therapeutics and neurodegenerative disease.