DYT-SGCE myoclonus-dystonia affects approximately 1 in 500,000 individuals worldwide. There is no approved disease-modifying therapy. Current treatment is limited to symptomatic pharmacology that reaches a ceiling of ~60% symptom control and does nothing to address the underlying molecular defect: complete absence of functional epsilon-sarcoglycan protein in the brain.
Arcivus Lab was founded to change this — first for its founder, then for every rare disease patient whose condition is too small for the pharmaceutical industry to prioritize, yet too devastating to leave untreated.
The company's lead program is an AAV-based gene replacement therapy for DYT-SGCE. The founder is also the index patient: a 21-year-old bioinformatics researcher with a confirmed pathogenic SGCE frameshift mutation (c.108dup) and a decade of systematic self-experimentation generating what may be the most detailed single-patient phenotypic dataset for this condition in existence.
Gene: SGCE (sarcoglycan epsilon), chromosome 7q21.3. Encodes a 437-amino-acid transmembrane protein that functions within the dystrophin-glycoprotein complex in the brain — predominantly in striatal neurons of the basal ganglia.
Imprinting architecture: SGCE is maternally imprinted. Only the paternal allele is expressed. A loss-of-function mutation on the paternal allele produces complete absence of functional protein, with no compensatory expression from the intact but silenced maternal copy. This imprinting mechanism also opens a unique therapeutic axis: epigenetic reactivation of the maternal allele.
Pathophysiology: Loss of epsilon-sarcoglycan disrupts GABAergic interneuron and medium spiny neuron circuits in the striatum, as well as basal ganglia dopaminergic signaling. The clinical result is myoclonus-dominant involuntary movements with secondary dystonia, affecting fine motor function, social interaction, and quality of life across all domains.
| Transcript | NM_003919.3 |
| DNA change | c.108dup |
| Protein effect | p.Val37SerfsTer32 — frameshift → premature stop at position 68 |
| Mechanism | 1 bp duplication in exon 3 → reading frame shift → NMD → complete protein loss |
| Classification | Likely Pathogenic Variant (LPV); absent from gnomAD and KRGDB |
| Inheritance | Autosomal dominant, maternally imprinted (paternal allele affected) |
| Transcript | NM_018105.3 |
| Change | c.496G>A (p.Ala166Thr) — Variant of Uncertain Significance |
| Relevance | DYT6 (torsion dystonia); ClinVar VUS, conflicting in-silico predictions |
| Action | Family segregation study recommended to clarify clinical significance |
Neuroimaging (April 2025): Brain MRI including SWI demonstrated preserved nigrostriatal pathways bilaterally with no structural abnormality, confirming a functional (biochemical/circuit-level) pathology consistent with the DYT-SGCE phenotype.
The patient has systematically evaluated over 50 pharmacological interventions across multiple compound classes. The current regimen — tranylcypromine 20 mg (MAOI), levetiracetam 1,000 mg/day, and clonazepam 1 mg/day — achieves approximately 60% symptom reduction at best. A recent formulation switch (Indian generic → Canadian brand tranylcypromine) was temporally associated with ~40% symptom worsening, with a 2-week lag consistent with MAOI steady-state kinetics. Dose adjustment is underway, and a neurology specialist referral has been initiated.
The pharmacological ceiling has been reached. No further optimization of symptom management can substitute for restoring the missing protein.
Deliver a functional copy of the SGCE gene directly to striatal neurons using an adeno-associated virus (AAV) vector. One injection. Lifelong expression. The same therapeutic logic that earned FDA approval for Kebilidi (AADC deficiency) in November 2024.
SGCE is an ideal gene therapy target. The coding sequence is only ~1.3 kb — fitting comfortably within AAV's 4.7 kb packaging limit with room for a strong promoter, regulatory elements, and validation tags. Neurons are post-mitotic: they do not divide, so AAV-delivered episomal DNA persists indefinitely. A single administration has the potential for permanent therapeutic effect.
Mutation-agnostic. Delivers full-length functional protein via episomal transgene. Strong CNS clinical precedent (Kebilidi). Single-vector packaging.
Reactivate the silenced wildtype maternal allele via targeted epigenetic editing (dCas9-TET1 or ASO). Also mutation-agnostic. Higher complexity, lower clinical validation.
The only editing tool capable of deleting a 1 bp insertion. Could correct c.108dup at the genomic level. Preclinical; requires dual-AAV CNS delivery.
Repeat-dose mRNA delivery. No genome modification. Limited by CNS penetration and dosing frequency. Early-stage for neurological targets.
The confirmed mutation type — a frameshift (1 bp duplication) rather than a nonsense (point) mutation — eliminates two strategies that would otherwise have been viable:
Performs A→G substitutions only. Cannot delete an inserted nucleotide. Mechanistically incompatible with frameshift mutations.
Promotes read-through of premature stop codons — but only works when downstream reading frame is intact. In a +1 frameshift, all downstream codons are wrong. Read-through produces junk protein.
| Criterion | AAV Replacement | Epigenetic Reactivation | Prime Editing | mRNA (LNP) |
|---|---|---|---|---|
| Implementation complexity | Low | Medium | Very High | Very High |
| CNS clinical validation | Strong | Preclinical | Preclinical | Early |
| Genome modification | None | Epigenome only | 1 nt deletion | None |
| Durability (single dose) | Lifelong* | Uncertain | Lifelong* | Transient |
| Vector packaging | Single AAV | N/A | Dual AAV | LNP |
| Off-target risk | Minimal | Moderate | Moderate | Low |
| Compatible with c.108dup | Yes | Yes | Yes | Yes |
* In post-mitotic neurons. AAV episomal DNA persists without cell division.
Arcivus Lab begins with a single patient and a single mutation. But the architecture being built — patient-specific genetic characterization, mutation-informed strategy selection, individualized construct design, and self-quantified outcome measurement — is not specific to DYT-SGCE. It is a framework.
Rare diseases are not rare in aggregate. There are over 7,000 known rare diseases affecting 300 million people globally. Most share a common structural pattern: a single gene, a known mutation, and no approved therapy — because each individual condition is too small for conventional drug development economics.
Arcivus Lab is building toward a future where each patient's molecular identity drives a custom therapeutic — not one drug for one disease, but one therapy for one person. The same mutation class can produce radically different phenotypes; the same phenotype can arise from different mutations. Treatment must match the patient, not the diagnosis code.
AAV-SGCE for a single patient. Build pipeline.
Other mutations in SGCE. Mutation-specific strategies.
Other rare neurological diseases with analogous logic.
AI-driven mutation analysis. Automated construct design.
Personal workstation for molecular simulations; AI-assisted pipeline (Claude AI, Claude Code) for literature analysis, construct design, and automation.
Self-directed bioinformatics training with cross-domain fluency in AI, molecular biology, and computational tools. Extensive first-person clinical data from years of systematic self-experimentation.
Neurology referral in progress (Vancouver); full diagnostic history at Chung-Ang University Hospital (Seoul) including genetic testing and neuroimaging.
Confirmed variant identity, dystonia NGS panel, brain MRI — all documented and available for collaborator review.
BSL-2 cell culture facility for transfection/transduction experiments.
Core facility or CRO access for vector packaging.
AAV construct optimization, neuronal cell culture, in vivo delivery protocols.
SGCE KO mice for phenotype rescue validation.
Navigating compassionate use or n-of-1 frameworks in Canada.
If you have expertise, resources, or shared purpose in rare disease gene therapy — Arcivus Lab is looking for collaborators, advisors, and partners.
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