DNA damage repair therapy represents an emerging therapeutic strategy for neurodegenerative diseases based on the understanding that accumulated DNA damage in neurons contributes to aging-related neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)[1][2]. The central nervous system faces constant oxidative stress from mitochondrial metabolism, and neurons' post-mitotic state means they cannot dilute damage through cell division, making DNA repair mechanisms critically important[3].
This therapy approach aims to enhance endogenous DNA repair capacity, reduce DNA damage accumulation, and protect neuronal function through multiple mechanisms including base excision repair (BER), nucleotide excision repair (NER), and ATM/ATR signaling pathway modulation[4][5].
BER is the primary pathway for repairing small, non-helix-distorting base lesions caused by oxidative damage and alkylation[6]. Key enzymes in this pathway include:
Therapeutic strategies include PARP inhibitors to prevent excessive PARP activation that can lead to cell death, and agents that enhance glycosylase expression[11].
NER removes bulky helix-distorting lesions including UV-induced photoproducts and environmental carcinogen adducts[12]. Two NER sub-pathways exist:
TC-NER defects are particularly relevant to neurodegeneration, as shown by Cockayne syndrome patients who exhibit progressive neurological decline[15].
The ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) kinases are master regulators of the DNA damage response[16]:
Small molecule ATM/ATR inhibitors are being explored to enhance DNA repair capacity in neurons[19].
Multiple studies demonstrate DNA repair deficits in AD[20]:
DNA damage accumulation also features prominently in PD[25]:
DNA repair defects are increasingly recognized in ALS[30]:
Clinical development of DNA repair therapies for neurodegeneration is in early stages[35]:
| Agent | Target | Phase | Status | Condition |
|---|---|---|---|---|
| Nicotinamide riboside (NR) | NAD+ precursor | Phase 2 | Recruiting | Alzheimer's disease |
| PARP inhibitors (various) | PARP1/2 | Phase 1/2 | Various | ALS, Alzheimer's |
| ATM inhibitors | ATM kinase | Preclinical | Development | Parkinson's |
NAD+ decline with age impairs PARP and sirtuin function, making NAD+ repletion a promising strategy[36]. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are in clinical trials for AD and PD[37].
Existing PARP inhibitors (olaparib, niraparib) approved for cancer are being repurposed for neurodegenerative disease[38]. Lower doses may provide neuroprotection without anti-cancer effects.
DNA repair therapies may be combined with[51]:
Key safety concerns include[52]:
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