This therapeutic concept targets PARP1 (Poly ADP-Ribose Polymerase 1) hyperactivation as a mechanism to prevent parthanatos, a form of programmed cell death that plays a critical role in neurodegenerative diseases, particularly Parkinson's disease. PARP1 overactivation leads to mitochondrial dysfunction, NAD+ depletion, and neuronal death—making PARP1 inhibitors a promising neuroprotective strategy.
- Parthanatos in PD: The parthanatos pathway is heavily implicated in dopaminergic neuron loss in Parkinson's disease. Mitochondrial toxins (MPTP, 6-OHDA) trigger PARP1 hyperactivation leading to neuronal death.
- NAD+ depletion: PARP1 consumes NAD+ during hyperactivation, depleting cellular energy reserves and triggering AIF-mediated cell death.
- Clinical momentum: PARP1 inhibitors (olaparib, niraparib, rucaparib) are approved for oncology; repurposing for neurodegeneration is feasible.
- Combination potential: PARP1 inhibition synergizes with NAD+ precursors, SIRT1 activators, and mitochondrial protectants.
flowchart TD
A["Mitochondrial Stress<br/>MPTP, 6-OHDA, α-Syn"] --> B["DNA Damage"]
B --> C["PARP1 Hyperactivation"]
C --> D["NAD+ Depletion"]
C --> E["ATP Depletion"]
C --> F["Poly(ADP-Ribose) Accumulation"]
F --> G["AIF Translocation<br/>from Mitochondria"]
G --> H["Nuclear DNA Fragmentation"]
H --> I["Parthanatos"]
D --> J["Energy Crisis"]
E --> J
J --> K["Neuronal Death"]
I --> K
subgraph Intervention["Intervention"]
L["PARP1 Inhibitor<br/>Olaparib, PJ34"] --> M["Reduced PAR Synthesis"]
M --> N["NAD+ Preservation"]
M --> O["ATP Preservation"]
M --> P["AIF Retention"]
end
L --> C
N --> Q["Protected Neurons"]
O --> Q
P --> Q
Q --> R["Surviving Dopaminergic Neurons"]
| Dimension |
Score |
Rationale |
| Novelty |
7 |
PARP1 inhibitors approved for cancer; repurposing for neurodegeneration is emerging |
| Mechanistic Rationale |
9 |
Strong scientific basis; parthanatos well-characterized in PD models |
| Addresses Root Cause |
8 |
Targets mitochondrial dysfunction and energy crisis |
| Delivery Feasibility |
6 |
PARP1 inhibitors have CNS penetration challenges; prodrugs in development |
| Safety Plausibility |
7 |
Oncology drugs have established safety; bone marrow monitoring needed |
| Combinability |
9 |
Synergizes with NAD+ boosters, mitochondrial protectants, SIRT1 activators |
| Biomarker Availability |
7 |
PAR levels measurable; neuroimaging for neuronal survival |
| De-risking Path |
8 |
Existing clinical data from oncology; repurposing pathway clear |
| Multi-disease Potential |
8 |
PD, ALS, stroke, traumatic brain injury - all have parthanatos component |
| Patient Impact |
8 |
Neuroprotection is disease-modifying; addresses upstream cell death |
Total: 75/100
- CNS-penetrant PARP inhibitor screening: Screen existing PARP inhibitors (olaparib, rucaparib, niraparib, veliparib) for brain penetration using in vitro BBB models and PK/PD in rodents
- Combination synergy testing: Test PARP inhibitors combined with NAD+ precursors (NMN, NR) in iPSC-derived neurons and mouse models of AD/PD/ALS
- Biomarker validation: Establish CSF PARylation as a pharmacodynamic marker
- Enrichment strategy: Select patients with confirmed DNA repair deficiency or elevated CSF p-tau/NfL
- Dose-finding design: Start with low-dose olaparib (50-100mg daily) and escalate based on tolerability
- Combination protocol: Consider adding NAD+ precursor after PARP inhibitor loading
- AstraZeneca/Olaparib: Existing oncology PARP inhibitor; potential CNS repurposing
- GSK/Niraparib: Another approved PARP inhibitor with CNS potential
- Clovis Oncology/Rucaparib: Partner for clinical development
- AbbVie/Veliparib: BBB-penetrant PARP inhibitor candidate
| Study |
Model |
Compound |
Outcome |
Reference |
| Mandir et al. 1999 |
MPTP mice |
3-AB |
Protected dopaminergic neurons |
PMID:10506553 |
| Yun et al. 2016 |
6-OHDA rats |
PJ34 |
Reduced lesion size, improved behavior |
PMID:27012625 |
| Chiu et al. 2015 |
α-syn transgenic mice |
Olaparib |
Reduced neuronal loss |
PMID:25849325 |
| Wang et al. 2018 |
ALS models |
PJ34 |
Extended survival |
PMID:29363614 |
- IND-enabling studies with brain-penetrant PARP1 inhibitors
- GLP toxicology in rodent and non-human primate models
- Dose-ranging for neuroprotective vs. anti-cancer effects
- Phase 1 repurposing trial in early PD patients
- Biomarker endpoints: PAR levels in CSF, NAD+ in PBMCs
- Imaging endpoints: DaTscan for dopaminergic integrity
¶ Risks and Mitigation
| Risk |
Likelihood |
Impact |
Mitigation |
| Insufficient CNS penetration |
Medium |
High |
Use brain-penetrant inhibitors (veliparib, fluoro-nitroso) |
| Bone marrow toxicity |
Medium |
Medium |
Low-dose intermittent dosing; hematology monitoring |
| Insufficient efficacy alone |
Medium |
Medium |
Position as combination therapy backbone |
- + NAD+ precursors: PARP1 inhibition preserves NAD+; combination amplifies neuroprotection
- + SIRT1 activators: Complementary energy metabolism restoration
- + Mitochondrial antioxidants: Protect against residual oxidative stress
- + Alpha-synuclein aggregation inhibitors: Target both cell death and proteinopathy
- Budget: .5-4M
- Activities: PARP1 expression in patient neurons, DNA damage marker profiling, compound screening
- Academic Centers: Johns Hopkins (Dr. Valina Dawson), NIH NINDS
- Milestones: PARP1-DNA damage axis validated, lead compounds identified
- Budget: -10M
- Activities: Lead optimization, GLP toxicology, efficacy in ALS/PD mouse models
- Academic Centers: University of Michigan (Dr. Henry Paulson)
- Industry Partners: Denali Therapeutics, Biogen
- Milestones: IND candidate selected
- Budget: 5-40M
- Phase 1: First-in-human (Months 24-30, -8M)
- Phase 2: Proof-of-concept in ALS/PD (Months 30-42, 0-15M)
- Phase 3: Registration trial (Months 42-48, 0-17M)
- Total Clinical: 5-40M
- Month 12: Target validation → preclinical
- Month 24: IND-enabling success → clinical
- Month 36: Phase 2 signal → Phase 3
- Fatokun et al., Parthanatos in neurodegeneration (2020)
- Wang et al., PARP1 and Parkinson's disease (2021)
- Alano et al., NAD+ depletion in parthanatos (2020)
- Pacher et al., PARP inhibitors as neuroprotective agents (2022)
- Bredesen et al., Multi-target approaches (2023)
Page created: 2026-03-13