Sodium phenylbutyrate (NaPBA, marketed as Buphenyl® and later as generic) is a small molecule that has been evaluated in amyotrophic lateral sclerosis (ALS) clinical trials. Originally developed for the treatment of urea cycle disorders, it acts as a histone deacetylase (HDAC) inhibitor and may have neuroprotective properties through epigenetic modulation and stress response activation[@cudkowicz2009].
The rationale for testing NaPBA in ALS stems from its dual mechanism of action: HDAC inhibition may normalize aberrant gene expression patterns observed in ALS, while its role as a chemical chaperone may reduce endoplasmic reticulum stress, a known contributor to motor neuron degeneration.
Trial Details
Phase: Phase 2
Status: Completed
Drug: Sodium phenylbutyrate (Buphenyl®)
Dosage: 3-9 grams daily (divided doses)
Patient Population: Adults with definite or probable ALS (El Escorial criteria)
Duration: 12-24 weeks (short-term safety and biomarker study)
ClinicalTrials.gov Identifier: NCT00145574 (shared with creatine trial)
Enrollment: 90 patients (dose-escalation design)
Background and Rationale
Epigenetic Dysregulation in ALS
Growing evidence supports a role for epigenetic changes in ALS:
HDAC Activity: Altered HDAC activity in ALS motor neurons and spinal cord
Gene Expression: Aberrant expression of genes involved in neuronal survival
Histone Modifications: Reduced histone acetylation in ALS tissue
Therapeutic Target: HDAC inhibitors can normalize some of these changes
...
Overview
Sodium phenylbutyrate (NaPBA, marketed as Buphenyl® and later as generic) is a small molecule that has been evaluated in amyotrophic lateral sclerosis (ALS) clinical trials. Originally developed for the treatment of urea cycle disorders, it acts as a histone deacetylase (HDAC) inhibitor and may have neuroprotective properties through epigenetic modulation and stress response activation[@cudkowicz2009].
The rationale for testing NaPBA in ALS stems from its dual mechanism of action: HDAC inhibition may normalize aberrant gene expression patterns observed in ALS, while its role as a chemical chaperone may reduce endoplasmic reticulum stress, a known contributor to motor neuron degeneration.
Trial Details
Phase: Phase 2
Status: Completed
Drug: Sodium phenylbutyrate (Buphenyl®)
Dosage: 3-9 grams daily (divided doses)
Patient Population: Adults with definite or probable ALS (El Escorial criteria)
Duration: 12-24 weeks (short-term safety and biomarker study)
ClinicalTrials.gov Identifier: NCT00145574 (shared with creatine trial)
Enrollment: 90 patients (dose-escalation design)
Background and Rationale
Epigenetic Dysregulation in ALS
Growing evidence supports a role for epigenetic changes in ALS:
HDAC Activity: Altered HDAC activity in ALS motor neurons and spinal cord
Gene Expression: Aberrant expression of genes involved in neuronal survival
Histone Modifications: Reduced histone acetylation in ALS tissue
Therapeutic Target: HDAC inhibitors can normalize some of these changes
Endoplasmic Reticulum Stress
ALS is associated with evidence of ER stress:
Unfolded Protein Response: Activation of UPR in ALS motor neurons
Protein Aggregation: ER stress from mutant SOD1 accumulation
Calcium Dysregulation: ER calcium homeostasis disruption
Apoptotic Signaling: ER stress-mediated cell death pathways
Sodium Phenylbutyrate as Dual-Action Agent
NaPBA offers potential benefits through two mechanisms:
HDAC Inhibition: May normalize gene expression and promote neuroprotective pathways
Chemical Chaperone: May reduce ER stress through protein folding assistance
This dual mechanism made NaPBA an attractive candidate for ALS.
Mechanism of Action
Sodium phenylbutyrate works through multiple pathways:
Epigenetic Modulation
HDAC Inhibition: Inhibits class I and IIa histone deacetylases[@ryu2020]
Gene Expression Alteration: Alters expression of protective genes
Chromatin Remodeling: Opens chromatin structure for transcription
[Axonal RNA Transport Reconstitution](/hypothesis/h-8196b893) — <span style="color:#81c784;font-weight:600">0.63</span> · Target: HNRNPA2B1
Related Analyses:
[TDP-43 phase separation therapeutics for ALS-FTD](/analysis/SDA-2026-04-01-gap-006) 🔄
[RNA binding protein dysregulation across ALS FTD and AD](/analysis/SDA-2026-04-01-gap-v2-68d9c9c1) 🔄
Pathway Diagram
The following diagram shows the key molecular relationships involving Sodium Phenylbutyrate ALS Trial discovered through SciDEX knowledge graph analysis: