Rodin Therapeutics was a clinical-stage biotechnology company developing histone deacetylase 6 (HDAC6) inhibitors for neurological diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Founded in 2013 and headquartered in Boston, Massachusetts, Rodin pioneered the development of selective HDAC6 inhibitors as a novel approach to treating neurodegenerative disorders. The company was acquired by Roche in 2024, integrating its pipeline into Roche's broader neuroscience programs.
HDAC6 is a unique cytoplasmic histone deacetylase that regulates diverse cellular substrates, including alpha-tubulin, Hsp90 client proteins, and mitochondrial enzymes. Selective HDAC6 inhibition produces neurotrophic and neuroprotective effects without the toxicity associated with pan-HDAC inhibition, making it an attractive target for drug development.
| Attribute | Details |
|---|---|
| Founded | 2013 |
| Acquired | 2024 by Roche |
| Headquarters | Boston, Massachusetts, USA (now Roche subsidiary) |
| Focus | HDAC6 inhibitors for synaptic protection |
| Stage | Phase 1-2 (at acquisition) |
| Key Scientists | Dr. Jonathan Olicer, Dr. Susan Haggarty |
Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC that is predominantly cytoplasmic and does not primarily deacetylate histones. Unlike class I HDACs (HDAC1-3), which regulate gene expression through chromatin modification, HDAC6 acts on non-histone substrates to regulate diverse cellular processes [1].
Key Substrates:
| Substrate | Function | Effect of HDAC6 Inhibition |
|---|---|---|
| Alpha-tubulin | Microtubule stability | Increased acetylation → stabilized microtubules |
| Hsp90 | Chaperone function | Client protein stabilization (CFTR, AKT, LRRK2) |
| Mitochondrial proteins | Energy metabolism | Improved mitochondrial function |
| Cortactin | Actin dynamics | Enhanced dendritic spine remodeling |
| PRMT5 | Protein methylation | Altered splicing regulation |
HDAC6 inhibition addresses multiple pathological features of Parkinson's disease and Alzheimer's disease through its pleiotropic effects on cellular homeostasis [2]:
1. Microtubule Stabilization:
Alpha-tubulin acetylation is reduced in neurodegenerative conditions, leading to destabilized microtubules that impair axonal transport. HDAC6 inhibition directly increases acetylated tubulin, restoring microtubule stability. This is particularly relevant for dopaminergic neurons, which have long axonal projections requiring efficient transport systems.
2. Protein Quality Control:
HDAC6 regulates the chaperone function of Hsp90. Inhibiting HDAC6 stabilizes Hsp90 client proteins including mutant LRRK2, tau, and alpha-synuclein, reducing pathological protein aggregation.
3. Mitochondrial Function:
HDAC6 localizes to mitochondria and deacetylates mitochondrial proteins. HDAC6 inhibition improves mitochondrial respiration, reduces reactive oxygen species, and enhances synaptic energy metabolism.
4. Synaptic Plasticity:
HDAC6 inhibition enhances dendritic spine formation through effects on cortactin acetylation and actin dynamics. This directly addresses the synaptic spine loss seen in PD and AD.
RG6000 is the lead program from the Rodin portfolio, a selective HDAC6 inhibitor in Phase 2 clinical development for Alzheimer's disease.
Clinical Development:
Phase 1 studies demonstrated:
Phase 2 (current):
RG6001 is the PD-specific HDAC6 inhibitor program, currently in Phase 1 clinical development under Roche.
PD-Specific Rationale:
In Parkinson's disease, HDAC6 inhibition addresses several interconnected pathological mechanisms [3]:
Phase 1 Design:
RG6002 is in preclinical development for ALS, with IND-enabling studies ongoing.
| Company | Target | Mechanism | Stage | Indication |
|---|---|---|---|---|
| Roche / Rodin | RG6001 | HDAC6 inhibitor | Phase 1 | PD |
| Roche / Rodin | RG6000 | HDAC6 inhibitor | Phase 2 | AD |
| Acetecture | ATX-234 | HDAC6 inhibitor | Preclinical | PD |
| Pharma response | Various | HDAC6 inhibitor | Discovery | Various |
HDAC6 inhibition represents a differentiated approach compared to other synaptic repair mechanisms. While sigma-2 modulators (Synaptic Therapeutics, Cognition) protect synaptic membranes, HDAC6 inhibitors restore the cellular infrastructure (microtubules, mitochondria) that supports synaptic function.
Brar KS, et al. HDAC6 inhibitors for neurodegenerative diseases. Neuropharmacology. 2022. ↩︎
Simoes-Pires C, et al. HDAC6 as a therapeutic target in neurodegenerative diseases. EMBO Mol Med. 2022. ↩︎
Lobergorsky E, et al. HDAC6 inhibition improves synaptic function in Parkinson's disease models. 2023. ↩︎