Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes involved in DNA repair, cellular stress responses, and cell death pathways. In neurodegenerative diseases, overactivation of PARP (particularly PARP1) leads to excessive NAD+ depletion, energy failure, and programmed cell death. PARP inhibitors, originally developed for cancer, represent a repurposing opportunity for neuroprotection by preventing NAD+ exhaustion and promoting DNA repair in neurons and glia.
PARP1 is rapidly activated by DNA strand breaks that accumulate in neurons due to oxidative stress, mitochondrial dysfunction, and aging[1]. While PARP-mediated DNA repair is essential, overactivation leads to:
Primary Mechanism: PARP inhibitors (particularly PARP1-selective) prevent excessive PARP activation, preserving NAD+ and ATP levels during DNA damage stress[2].
Secondary Mechanism: By maintaining NAD+ pools, PARP inhibitors support sirtuin (SIRT1) activity, promoting cellular stress resistance and mitochondrial function.
Tertiary Mechanism: Some PARP inhibitors also enhance DNA repair fidelity, potentially preventing the accumulation of deleterious mutations in neurons.
| Dimension | Score | Rationale |
|---|---|---|
| Novelty | 6 | Established drug class (cancer); repurposing for neurodegeneration is emerging |
| Mechanistic Rationale | 8 | Strong preclinical data; addresses energy crisis and DNA repair |
| Addresses Root Cause | 7 | Targets oxidative stress response and energy failure; complementary to other approaches |
| Delivery Feasibility | 7 | Many PARP inhibitors have good oral bioavailability; some CNS penetration demonstrated |
| Safety Plausibility | 7 | Well-characterized safety profile from oncology; hematological effects need monitoring |
| Combinability | 8 | Synergistic with NAD+ precursors, sirtuin activators, and mitochondrial protectants |
| Biomarker Availability | 7 | NAD+ levels, DNA damage markers, PAR levels can be measured |
| De-risking Path | 8 | Multiple PARP inhibitors already approved; clear regulatory path |
| Multi-disease Potential | 8 | Strong rationale for AD, PD, ALS, stroke, and traumatic brain injury |
| Patient Impact | 7 | Addresses fundamental cellular energetics; broad applicability |
Total Score: 72/100
| Phase | Timeline | Cost | Key Milestones |
|---|---|---|---|
| Phase 2 repurposing | 18 months | $15-25M | Safety, biomarker validation |
| Phase 3 | 18 months | $40-60M | Registrational trial |
| Total | 36 months | $55-85M |
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Strosznajder JB, Czapski GA, Adamczyk A, Strosznajder RP. Poly(ADP-ribose) polymerase-1 in Alzheimer's disease. J Neural Transm (Vienna). 2012. ↩︎