ALS / C9orf72-FTD
LeadLead program. Poly(GR) from the C9orf72 repeat expansion stalls ribosomes directly; ZNF598 titrates it.
Life runs on ribosomes.
Collide Therapeutics is building the first therapeutics against ZNF598 — the rate-limiting checkpoint of ribosome quality control, and the upstream failure point shared by ALS, Alzheimer’s and aging.
All IP cleared by Johns Hopkins Technology Ventures
Pharma has spent a decade failing to recognize these diseases as ribosomopathies.
Ribosomes are the most fundamental machines in biology. They execute all protein synthesis and consume the majority of a cell’s energy. When they stall — on damaged mRNA, rare codons, structured transcripts, poly(A) stretches — trailing ribosomes crash into the stalled one. That collision is the alarm.
Ribosome quality control is the system that answers it. ZNF598 is its most conserved sensor and its rate-limiting step. When ZNF598 is outpaced, unresolved stalls produce CAT-tailed proteins — among the most aggregation-prone species known — which seed TDP-43, SOD1 and tau pathology.
Every approved and failed program in ALS and Alzheimer’s sits either upstream of this checkpoint, silencing one mutation at a time, or downstream of it, clearing damage that has already happened. The checkpoint itself has never been drugged — because the structural basis of its key regulator eluded complete characterization for over a decade. Collide has resolved it.
“Increased ribosome pausing, leading to RQC overload and nascent polypeptide aggregation, critically contributes to proteostasis impairment and systemic decline during ageing.”
Everything downstream has failed.
Map the assets in neurodegeneration onto the disease cascade and a shape appears: dense clusters at the genetic origin and at the downstream wreckage, and nothing at all on the quality-control checkpoint between them.
Gene silencers cover ≤15% of patients — each mutation separately. Downstream drugs have universally failed or shown marginal benefit. RQC is mutation-agnostic.
Gene
mutations
Gene silencing (ASOs)
Biogen – tofersen (SOD1)
Approved 2023 — 2% of patients
Biogen – BIIB078 (C9orf72)
Phase 1 discontinued
Ionis – ION363 (FUS)
Phase 3 positive (Sep 2026) — rare mutation
Biogen – BIIB105 (ATXN2)
Phase 1/2 discontinued (2024)
Translation
initiation
eIF2B activators
Calico/AbbVie – fosigotifator
Ph 2/3 failed (Jan 2025)
Denali – DNL343
Ph 2/3 failed (Jan 2025)
Collide Therapeutics
First to drug RQC / ZNF598
Ribosome / RQC
(quality control)
Undrugged
Collide Therapeutics
First to drug RQC / ZNF598
Protein
aggregation
ER / mitochondrial stress
Amylyx – Relyvrio
Approved 2022 — withdrawn 2024
Mitsubishi – edaravone
Approved 2017 — mixed results
Motor neuron
stress
Glutamate reduction
Sanofi – riluzole
Approved 1995 — ~3mo survival
Degeneration
& paralysis
Supportive care only
No disease-modifying therapy
None available
UpstreamDownstream →
FailedApprovedAdvancingCollide (undrugged)
Nine stages. Under a week.
A single automated run carries a target from an unsolved structure to a synthesizable lead: generate, dock, simulate, measure kinetics, optimize free energy, and plan the route. The two models that do the work that nothing off-the-shelf could — RiBoltz2 and RiboPFlow — are ours.
- Runtime under a week
- $500 – $2,500 per molecule
- 01RiBoltz2
Proprietary target structure
Resolves the ZNF598 binding modality that eluded complete structural characterization for over a decade.
- 02RiboPFlow
Molecule generation
Generates novel chemical matter against the resolved site, conditioned on the target pocket.
- 03
Screen + pose
High-throughput docking and pose selection narrows generated libraries to credible binders.
- 04
MD stability
All-atom molecular dynamics tests whether a pose survives on a physical timescale.
- 05
Steered MD / PPI
Steered simulations probe the protein–protein interface and the force required to break it.
- 06WESTPA · SEEKR2
Kinetics
Weighted-ensemble and milestoning methods estimate residence time, not just affinity.
- 07
FEP optimization
Free-energy perturbation ranks analogues to drive the series toward potency.
- 08
Umbrella sampling
Free-energy landscapes along the binding coordinate confirm the mechanism of engagement.
- 09
Synthesis planning
Retrosynthetic routing converts a computational lead into something a chemist can make.
ZNF598 — a first-in-class target
One checkpoint, two directions. Enhancing ribosome quality control protects neurons that are losing the capacity to clear stalled translation; disrupting it removes the buffer that lets tumor cells tolerate translational stress. Both start from the same resolved structure.
First to drug the collision-sensing arm of RQC
First to enhance rather than ablate quality-control flux
First glue targeting a ribonucleoprotein interface
RQC Enhancement
Alzheimer’s disease
Inefficient stall resolution during APP synthesis generates CAT-tailed species that precipitate AD hallmarks.
Longevity / aging
Age-dependent ribosome pausing overwhelms RQC capacity, driving systemic proteostasis collapse.
Oncology (chemo-sensitization)
Inverting the mechanism: removing the quality-control buffer makes translational stress lethal to tumor cells.
mRNA therapeutics optimization
Stall-aware sequence design to raise yield and lower immunogenicity of synthetic mRNA.
No disclosed clinical or preclinical program targets ZNF598. The lead series is moving out of silico: chemical synthesis and in vitro validation are the next milestone.
Built on a decade of discovery
The link between ribosome quality control and neurodegeneration has been established across model systems and disease contexts — yeast, worm, killifish, fly and human cells; ALS, Alzheimer’s and aging. What this literature left structurally intractable was the druggability of the checkpoint itself. Collide’s models have resolved it, enabling rational design against the RQC pathway for the first time. That work is in preparation for submission to Nature Communications.
- FEBS J.2025
Dysregulated ribosome quality control in human diseases
McGirr, T., Onar, O. & Jafarnejad, S.M. · 292(5):936–959
Diseases as ribosomopathies
DOI ↗ - Nature2022
Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis
Stein, K.C. et al. · 601(7894):637–642
Aging overwhelms RQC capacity
DOI ↗ - EMBO J.2025
Single-protein/RNA imaging reveals ZNF598 as a limiting factor in resolving collided ribosomes
De La Cruz, A.C. et al. · 44(18):5215–5232
ZNF598 is the rate-limiting step
DOI ↗ - Science2025
Altered translation elongation contributes to key hallmarks of aging in the killifish brain
Di Fraia, D. et al. · 389(6759):eadk3079
RQC & aging in vertebrate brain
DOI ↗ - Nucleic Acids Res.2021
ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD
Park, J. et al. · 49(19):11294–11311
ZNF598 rescues the C9orf72 ALS model
DOI ↗ - Acta Neuropathol. Commun.2021
Inefficient quality control of ribosome stalling during APP synthesis generates CAT-tailed species that precipitate hallmarks of Alzheimer’s disease
Rimal, S. et al. · 9:169
RQC failure drives Alzheimer’s pathology
DOI ↗ - Nat. Commun.2024
Stalled translation by mitochondrial stress upregulates a CNOT4–ZNF598 ribosomal quality control pathway important for tissue homeostasis
Geng, J. et al. · 15(1):1637
RQC pathway in tissue homeostasis
DOI ↗ - Neural Regen. Res.2023
Translation stalling and ribosome collision leading to proteostasis failure: implications for neurodegenerative diseases
Lu, B. · 18(1):111–112
RQC & neurodegeneration review
DOI ↗
All IP cleared by Johns Hopkins Technology Ventures (JHTV)