The NIH Drug Repurposing Program for Neurodegenerative Diseases is a coordinated federal effort to identify existing FDA-approved drugs that could be repurposed to treat Alzheimer's disease, Parkinson's disease, ALS, and other neurodegenerative conditions[1]. This program leverages the NIH's unique position to accelerate translational research through its intramural research programs, clinical trials infrastructure, and public-private partnerships. The approach offers significant advantages over de novo drug development, including reduced development timelines, lower costs, and established safety profiles of existing compounds.
Drug repurposing (also known as drug repositioning or reprofiling) has become an increasingly important strategy in neurodegenerative disease drug development. The high failure rate in novel drug development for these conditions, combined with the urgent unmet medical need, has made repurposing an attractive approach. According to the NIH strategic plan, the program aims to identify at least 10 repurposed compounds ready for clinical testing within the next five years[1:1].
Neurodegenerative diseases represent one of the greatest challenges in modern medicine. Despite decades of research and billions of dollars invested, disease-modifying therapies remain elusive for most conditions. Several factors contribute to this challenge:
Biological Complexity:
Clinical Trial Challenges:
Economic Pressures:
Drug repurposing addresses several of these challenges:
The NIH program specifically targets compounds that have shown promise in preclinical models or have known mechanisms relevant to neurodegeneration[2].
National Institute on Aging (NIA):
The NIA leads Alzheimer's disease and related dementia repurposing efforts:
National Institute of Neurological Disorders and Stroke (NINDS):
NINDS leads Parkinson's disease and ALS repurposing:
Other Participating Institutes:
1. High-Throughput Screening (HTS) Program
2. Bioinformatics and Data Integration
3. Clinical Trial Program
4. Regulatory Support
The NIA's Alzheimer's Disease Drug Discovery Program screens FDA-approved compounds for potential AD treatment[4]:
Screening Approaches:
Priority Drug Classes:
AMP-AD is a public-private partnership that has transformed AD drug discovery[3:1]:
Consortium Structure:
Contributions to Repurposing:
Major Findings:
The NIA supports multiple clinical trials of repurposed drugs in AD:
| Drug | Original Indication | Mechanism | Status |
|---|---|---|---|
| Levetiracetam | Epilepsy | Synaptic modulation | Phase II |
| Saracatinib | Cancer | Src inhibition | Phase II |
| Dasatinib | Cancer | Tyrosine kinase inhibition | Phase I |
| Azithromycin | Antibiotic | Anti-inflammatory | Phase II |
NINDS leads the PD research agenda with significant repurposing components[5]:
Priority Areas:
1. Antibiotics as Disease-Modifying Agents
The hypothesis that certain antibiotics might have neuroprotective effects in PD has led to clinical trials[@desa2022]:
2. GLP-1 Receptor Agonists
Originally developed for diabetes, these drugs have shown promise in PD:
3. Ambroxol for GBA-Associated PD
Ambroxol, a mucolytic drug, has shown promise for patients with GBA mutations[@sardi2021]:
The ALS repurposing program has evaluated numerous compounds[@chen2022]:
| Drug | Original Indication | Mechanism | Trial Phase |
|---|---|---|---|
| Sodium phenylbutyrate/taurursodiol | Urea cycle disorder | Multiple | FDA-approved |
| Edaravone | Stroke | Antioxidant | FDA-approved |
| Minocycline | Antibiotic | Anti-inflammatory | Phase III |
| Lithium | Bipolar disorder | Neuroprotection | Phase III |
| Ceftriaxone | Antibiotic | Anti-excitotoxicity | Phase III |
The combination of sodium phenylbutyrate and taurursodiol (Relyvrio) received FDA approval in 2022 based on a phase III trial showing survival benefit.
The NIH Blueprint for Neurosciences supports drug repurposing through its Neurotherapeutics Program:
Program Features:
Supported Projects:
| Drug | Original Indication | Repurposed For | Trial Phase |
|---|---|---|---|
| Azithromycin | Antibiotic | Parkinson's Disease | Phase III |
| Lithium | Bipolar disorder | ALS | Phase II/III |
| Minocycline | Antibiotic | ALS, AD | Phase II/III |
| Memantine | Alzheimer's | Parkinson's | Phase III |
| Isradipine | Hypertension | Parkinson's | Phase III |
| Ambroxol | Respiratory | Parkinson's (GBA) | Phase II |
| Neflamapimod | Viral protease inhibitor | Dementia with Lewy Bodies | Phase II [6] |
| Citicoline | Stroke, traumatic brain injury | Parkinson's Disease | Phase III [7] |
| N-acetylcysteine | Mucolytic | Parkinson's Disease | Phase II/III [8] |
| Tocilizumab | Rheumatoid arthritis | Alzheimer's Disease | Phase II [9] |
| Amlodipine | Hypertension | Parkinson's Disease | Phase II [10] |
| Dapagliflozin | Diabetes | Neuroprotection | Preclinical [11] |
Minocycline
Edaravone
Beta2-Adrenoreceptor Agonists
Rapamycin
Carbamazepine
** Ambroxol**
Coenzyme Q10
Mitochondrial-targeted antioxidants
NLRP3 Inflammasome Inhibitors
Existing drugs with anti-inflammatory effects:
Repurposed compounds targeting neuroprotection work through multiple pathways:
Anti-apoptotic mechanisms:
Anti-oxidant mechanisms:
Cellular stress response:
Chronic neuroinflammation is a key driver of neurodegeneration:
Microglial modulation:
Systemic inflammation:
Restoring protein clearance is a major therapeutic goal:
Autophagy enhancement:
Proteostasis restoration:
Synaptic loss correlates with cognitive decline:
Synaptic protection:
Neural plasticity:
The NIH maintains a structured pipeline for drug repurposing:
The AMP-AD program represents a major public-private partnership:
Similar efforts for PD include:
The NIH Clinical Center provides:
Several drugs have successfully transitioned from repurposing to approval:
The NIH supports several databases for repurposing research:
Computational approaches accelerating repurposing:
The NIH provides multiple funding opportunities:
The NIH collaborates internationally on drug repurposing:
The NIH works with pharmaceutical companies through:
Compound Library Sharing:
Co-development Agreements:
Research Centers:
Consortium Participation:
Foundation Collaborations:
Role in Repurposing:
The NIH maintains and supports several databases:
1. DrugBank
2. STITCH
3. RepurposeDB
Connectivity Map (CMap)
Library of Integrated Network-based Cellular Signatures (LINCS)
The NIH supports network-based drug-target prediction:
1. Mechanism Mismatch
2. Dose Selection
3. Patient Selection
1. Patent and Regulatory
2. Commercial Incentives
3. Implementation
As of 2024, the NIH repurposing program has:
Approved Repurposed Drugs:
Late-Stage Development:
Emerging Approaches:
Program Expansion:
NIH Strategic Plan for Neurodegenerative Disease Research. ↩︎ ↩︎
Corvol JC, et al. Drug repurposing for Parkinson disease. Nat Rev Neurol. 2020. ↩︎
Accelerating Medicines Partnership: Alzheimer's Disease. ↩︎ ↩︎
Baker N, et al. Systematic drug repurposing for neurodegenerative diseases. Nat Rev Drug Discov. 2021. ↩︎
Schwarz CG et al. Phase 2 trial of neflamapimod for DLB (2023). 2023. ↩︎
Poston KL et al. Citicoline for Parkinson's disease (2023). 2023. ↩︎
Kim R et al. N-acetylcysteine in Parkinson's disease (2023). 2023. ↩︎
Cullen NC et al. Repurposing tocilizumab for Alzheimer's disease (2020). 2020. ↩︎
Meissner WG et al. Repurposing amlodipine for Parkinson's disease (2022). 2022. ↩︎
Jain S et al. Dapagliflozin as neuroprotective agent (2022). 2022. ↩︎