Morca Bio

Some brain tumors carry a mutation that changes how they work at a fundamental level.

In IDH-mutant gliomas — the type of tumor we are working on — a single genetic change causes a normal enzyme to produce a molecule it was never supposed to make. That molecule is called 2-hydroxyglutarate (2-HG). The tumor accumulates it in large quantities.

2-HG is not passive waste. It actively changes the tumor's behavior in two ways.

It reprograms the tumor's DNA. 2-HG blocks the enzymes that control gene expression, locking tumor cells into an aggressive, proliferating state. This is one reason IDH-mutant tumors are hard to stop.

It hides the tumor from the immune system. T cells — the immune cells that would normally recognize and attack a tumor — are suppressed by 2-HG. The tumor creates its own immune-evasion zone by flooding its environment with this metabolite. When you remove 2-HG, the immune response comes back. That has been demonstrated in animal models.

What the existing drug does

A drug called vorasidenib (Voranigo) blocks the mutant enzyme from producing new 2-HG. It is approved, it is effective, and it reduces tumor 2-HG by about 93%. But it cannot remove 2-HG that is already present, and it leaves a residual — roughly 7% of baseline — that may be enough to maintain partial immune suppression.

What the bacterial construct does

We are engineering a bacterium to eliminate the residual.

The bacterium — a clinically-used probiotic strain called E. coli Nissle 1917 — is modified to carry a three-part genetic circuit:

Sense. A molecular switch that activates only when 2-HG is present.
Deplete. Enzymes that break down 2-HG when the switch is on.
Self-limit. A kill switch that triggers when 2-HG is depleted, causing the bacterium to die.

The result is a living therapeutic that turns itself on in the disease environment and turns itself off when the job is done. It acts locally — at the tumor site — not systemically throughout the body.

Vorasidenib blocks production of 2-HG. Our construct eliminates the product. Together, they attack the same target from two different directions.

Why this approach, not something simpler?

The bacterial approach offers something a drug cannot: resistance-proofing. Vorasidenib can be defeated by new mutations in the enzyme it targets. Our construct targets the metabolite that enzyme produces — so if resistance mutations cause 2-HG to spike again, the bacterium becomes more active, not less.

This program is at the preclinical stage. We are building and testing the construct now.

The disease target: IDH1 R132H and the oncometabolite D-2-HG

IDH1 R132H is a recurrent somatic mutation in Grade 2–3 gliomas, present in approximately 70–80% of cases. The mutation confers a neomorphic enzymatic activity: whereas wild-type IDH1 catalyzes isocitrate → α-ketoglutarate, the R132H variant converts α-KG → D-2-hydroxyglutarate (D-2-HG) via NADPH-dependent reduction. Tumor D-2-HG accumulates to 5–35 mM in bulk tissue, measurable by MR spectroscopy (Choi et al. 2012, Nat Med, PMID 22281806).

D-2-HG drives tumor biology through two clinically relevant mechanisms:

Epigenetic reprogramming: D-2-HG competitively inhibits α-KG-dependent dioxygenases including TET2 and KDM histone demethylases, establishing the G-CIMP methylation phenotype and locking cells in an undifferentiated, proliferating state.

T cell suppression: D-2-HG is taken up by T cells, where it disrupts NFAT signaling and polyamine biosynthesis (Bunse et al. 2018, Nat Med, PMID 29988124). Reducing D-2-HG by IDH inhibition rescues CD4+/CD8+ T cell infiltration and IFN-γ production in a T cell-dependent manner (Chuntova et al. 2022, J Immunother Cancer, PMID 35606087).

The vorasidenib residual

Vorasidenib (Voranigo) — an oral allosteric inhibitor of mutant IDH1/2 — achieves approximately 92.6% reduction in tumor D-2-HG at the 50 mg/day dose (Mellinghoff et al. 2022, Nat Med, DOI: 10.1038/s41591-022-02141-2; perioperative Phase 1, NCT03343197). Clinical efficacy — extended progression-free survival — was validated in the INDIGO Phase 3 trial (Mellinghoff et al. 2023, NEJM, PMID 37272516) at the approved 40 mg/day dose; the precise PD reduction at that dose has not been separately published. The derived residual at 50 mg/day: 0.37–2.6 mM (arithmetic from baseline 5–35 mM × 7.4%). Whether this floor is sufficient to maintain partial immune suppression is the central clinical question our program is designed to address.

Vorasidenib also carries a structural vulnerability: second-site resistance mutations at the IDH1 allosteric pocket can restore D-2-HG production.

The construct

Chassis

E. coli Nissle 1917 (EcN) is selected for three reasons: facultative anaerobic metabolism (critical for the variable-oxygen tumor microenvironment), established clinical and regulatory precedent for intratumoral delivery of engineered EcN in solid tumors (SYNB1891 Phase I, Luke et al. 2023, Clin Cancer Res, PMID 37227176; CNS precedent is first-in-class), and full compatibility with the E. coli synthetic biology toolkit.

Colibactin deletion: EcN carries the pks genomic island encoding colibactin, a genotoxin producing DNA double-strand breaks. For a CNS therapeutic, pks is incompatible with any regulatory submission. Experiment E-01 constructs a colibactin-null chassis via dual deletion of clbP and clbS. Kalantari et al. (2023, PLoS ONE, PMID 36730255) confirmed no fitness cost from pks deletion.

Depletion enzyme — three parallel paths

Path	Enzyme	Chemistry	Genes	O₂	Km (D-2-HG)
E-03	LcdA/FldA (C. sporogenes)	Anaerobic dehydratase (promiscuity hypothesis)	3	Strictly anaerobic	Unknown
E-04	HgdABC + gctAB (A. fermentans)	Anaerobic 2-hydroxyglutaryl-CoA dehydratase	5	Strictly anaerobic	~0.5–2 mM
E-02	D2HGDH (human, ΔmTS)	FAD-dependent oxidoreductase	1	Micro-aerobic	~0.1–0.5 mM*

D2HGDH (E-02) has the highest substrate affinity and lowest gene burden. Its Km of ~0.1–0.5 mM (*estimated from structural analogy to characterized family members; direct kinetic data for human D2HGDH to be measured in E-02) is well-matched to the vorasidenib residual floor of 0.37–2.6 mM. Oxygen dependence under tumor micro-aerobic conditions (2–5% O₂) is the key experimental question.

Biosensor

Two validated D-2-HG-responsive transcriptional regulators are under evaluation:

HgcR (Liu et al. 2025, Nat Commun, DOI: 10.1038/s41467-025-62225-8): transcriptional activator enabling spatiotemporal D-2-HG sensing in living bacteria and human cells.
DhdR (Xiao et al. 2021, Nat Commun, PMID 34876568; Wang et al. 2025, Cell Chem Biol, PMID 41202821): detection range 0.3–30 mM for the genetically encoded biosensor (Wang et al. 2025), spanning from the vorasidenib floor to the untreated tumor maximum. Note: DhdR's lower limit (0.3 mM) closely approaches the vorasidenib residual (0.37 mM). A peri-operative vorasidenib hold (estimated 3-day washout; precise D-2-HG rebound kinetics are unpublished) is the recommended clinical priming protocol to achieve 1–5 mM local D-2-HG prior to injection.

Kill switch

Dual mechanism targeting <10⁻⁸ escape frequency per cell per generation:

Auxotrophic containment — thyA deletion, thymidine synthesis made 2-HG-dependent
Improved toxin-antitoxin — Cryodeath-class design (Stirling et al. 2017, Mol Cell, PMID 29149596)

Single-mechanism kill switches (e.g., CcdB/CcdA, escape frequency ~10⁻⁵ under standard conditions) are likely insufficient for CNS deployment where any escape is a serious safety event. The dual mechanism combines two independent escape probabilities, yielding theoretical 10⁻⁸ to 10⁻⁹, to be confirmed empirically in E-07.

Mechanistic rationale: orthogonal combination

Vorasidenib inhibits D-2-HG production (mutant IDH1 allosteric site). Our construct eliminates D-2-HG product directly. These mechanisms are independent: no shared binding site, no competitive interaction. Crucially, vorasidenib resistance mutations (allosteric pocket variants that restore 2-HG production) increase substrate available to the bacterial depletion circuit — bacterial efficacy improves precisely when the drug fails. Combined depletion potentially exceeds 99%, compared to 92.6% for vorasidenib alone.

Delivery

Stereotactic intratumoral injection with alginate hydrogel encapsulation. Precedent: DTI-015 (Hassenbusch et al. 2003, Neoplasia, PMID 12659665) and locoregional CAR-T delivery (Brown et al. 2024, Nat Med, PMID 38454126). No published EcN intracranial pharmacokinetic data exists — this is a first-in-class data void the program must generate.

Program stage

Preclinical. E-01 (colibactin-null chassis construction) is the first queued experiment. Enzyme path selection (Gate G1) targets Week 14–16 of the experimental program.

The science, in plain language.