Unmute Therapeutics engineers ultra-specific, allele-agnostic CRISPR activation (CRISPRa) therapeutics to rescue haploinsufficient neurodevelopmental disorders—beginning with Lamb-Shaffer Syndrome (SOX5).
In haploinsufficient genetic disorders, patients retain one healthy, functional copy of the target gene, but produce only ~50% of required protein levels. Rather than attempting hazardous double-strand DNA cleavage or delivering oversized exogenous transgenes, our platform directs catalytically inactive Cas effectors (dCas) to validated epigenetic promoter islands—boosting endogenous transcription back to healthy stoichiometry.
Exhaustive mismatch and structural DNA/RNA bulge alignment across the complete GRCh38 primary assembly.
Strict elimination of any candidate guide with high-homology off-target binding or protein-coding TSS proximity.
Cross-referenced against dbSNP/gnomAD (MAF ≥ 1%) to ensure universal patient eligibility without genotyping exclusions.
Targeted directly to verified active core promoter regulatory elements driving canonical human neuronal isoforms.
| Program | Target / Isoform | Indication | Modality | Stage |
|---|---|---|---|---|
| UNM-hSOX5-101 | Human SOX5 (Canonical L-SOX5 Promoter) | Lamb-Shaffer Syndrome | dCas-Activator (CRISPRa) | Lead Validated (In Silico) / Wet-Lab Prep |
| UNM-mSox5-201 | Murine Sox5 (Surrogate Promoter) | In Vivo Preclinical Pharmacology | dCas-Activator (CRISPRa) | Surrogate Panel Identified |
* Exact nucleotide spacer sequences, genomic coordinates, and vector architectures are proprietary and disclosed under CDA/NDA for academic subaward and licensing partners.
Standard promoter scanning tools frequently select guide RNAs that fail in living neurons due to microsatellite repeat promiscuity, internal tracrRNA scaffold hairpins, or human genetic polymorphisms. Unmute Therapeutics enforces a deterministic five-stage filtering architecture prior to synthesis:
Dynamic alignment to MANE Select transcripts and Ensembl Regulatory Build active core promoter regions.
Spatial restriction to the optimal proximal promoter activation window upstream of the Transcription Start Site.
Exclusion of dinucleotide microsatellites, U6 termination motifs, and tracrRNA scaffold secondary hairpins.
OpenCL-accelerated Cas-OFFinder screening across 3.1 Gb with mismatch and 1-bp DNA/RNA bulge modeling.
Verification of zero common SNPs (MAF ≥ 1%) and zero 3-mismatch overlap with any protein-coding gene TSS.
Unmute Therapeutics actively partners with academic neurobiology laboratories and rare-disease foundations to advance our validated CRISPRa lead candidates through preclinical human iPSC cortical neuron and murine validation studies, including joint NIH STTR/SBIR initiatives.