NIH Drug Repurposing Program for Neurodegenerative Diseases

Introduction

Introduction

<div class="infobox infobox-institution">
{| class="infobox-table"
| colspan="2" class="infobox-header" | NIH Neurodegeneration Repurposing Program
|-
| Administering Body | National Institutes of Health (NIH)
|-
| Lead Institutes | National Institute on Aging (NIA), National Institute of Neurological Disorders and Stroke (NINDS)
|-
| Other Partners | National Institute of Mental Health (NIMH), National Institute of Biomedical Imaging and Bioengineering (NIBIB)
|-
| Focus | Drug repurposing for AD, PD, ALS, and other neurodegenerative diseases
|-
| Program Type | Preclinical and Clinical Repurposing Initiative
|-
| Budget | $50M+ annually (2024)
|-
| Drug Candidates | 150+ compounds in various stages of evaluation
|}
</div>

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](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), ALS, and other neurodegenerative conditions["@nih"]. 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["@nih"].

Program Background and Rationale

The Challenge of Neurodegenerative Disease Drug Development

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:

• Multiple pathological mechanisms contribute to disease
• Interplay between protein aggregation, neuroinflammation, mitochondrial dysfunction, and cellular senescence
• Heterogeneous patient populations with different underlying biology

• Long disease course makes trials lengthy and expensive
• Lack of clear biomarkers for patient selection and outcome measurement
• Late intervention when significant neurodegeneration has already occurred

• High development costs with uncertain returns
• Patent expiration concerns for original indications
• Regulatory complexity for new indications

Advantages of Drug Repurposing

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[@corvol2020].

Program Structure and Governance

Lead Institutes

National Institute on Aging (NIA):
The NIA leads Alzheimer's disease and related dementia repurposing efforts:

• Alzheimer's Disease Drug Discovery Program
• Accelerating Medicines Partnership: Alzheimer's Disease (AMP-AD)[@accelerating]
• NIA-funded clinical trials network

• Parkinson's Disease Research Agenda
• ALS repurposing program
• Center for Advancing Research in Genes and Health

• National Institute of Mental Health (NIMH): Depression and dementia comorbidities
• National Institute of Biomedical Imaging and Bioengineering (NIBIB): Imaging biomarkers

Program Components

1. High-Throughput Screening (HTS) Program

• Cell-based screening of FDA-approved drug libraries
• Phenotypic screening in disease models
• Target-based screening for specific pathways

• Drug-target interaction databases
• Gene expression profiling (Connectivity Map)
• Network medicine approaches

• Phase I/II trials of repurposed compounds
• Basket trials for multiple conditions
• Adaptive trial designs

• FDA consultation for new indications
• Development of regulatory pathways
• Orphan drug designation where applicable

NIA-Funded Repurposing Initiatives

Alzheimer's Disease Drug Discovery Program

The NIA's Alzheimer's Disease Drug Discovery Program screens FDA-approved compounds for potential AD treatment[@baker2021]:

Screening Approaches:

• Cell-based assays for amyloid and tau pathology
• Neuroinflammation models
• Mitochondrial function assays
• Synaptic function screening

• Kinase inhibitors
• Ion channel modulators
• Metabolic agents
• Anti-inflammatory drugs

Accelerating Medicines Partnership: Alzheimer's Disease (AMP-AD)

AMP-AD is a public-private partnership that has transformed AD drug discovery[@accelerating]:

Consortium Structure:

• Broad Institute (lead)
• Sage Bionetworks (data coordination)
• Multiple academic centers

• Identification of novel therapeutic targets
• Biomarker development for patient selection
• Clinical trialready target validation

• Identification of novel AD genes and pathways
• Development of RNA signatures for drug prioritization
• Network-based drug target prediction

NIA-Funded Clinical Trials

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-Funded Repurposing Initiatives

Parkinson's Disease Research Agenda

NINDS leads the PD research agenda with significant repurposing components[@ninds]:

Priority Areas:

• Neuroprotection and disease modification
• Non-motor symptom treatment
• Levodopa complications
• Cognitive dysfunction

Specific Repurposing Programs

1. Antibiotics as Disease-Modifying Agents
The hypothesis that certain antibiotics might have neuroprotective effects in PD has led to clinical trials[@desa2022]:

• Azithromycin: Phase III trial for disease modification
• Minocycline: Multiple trials completed
• Doxycycline: Ongoing investigations

• Exenatide: Phase II completed, showing motor benefits
• Liraglutide: Ongoing trials
• Semaglutide: Planning phase

• Increases glucocerebrosidase activity
• Reduces alpha-synuclein accumulation in preclinical models
• Phase II trial completed with positive results

ALS Repurposing Program

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.

NIH Blueprint Neurotherapeutics Program

The NIH Blueprint for Neurosciences supports drug repurposing through its Neurotherapeutics Program:

Program Features:

• Preclinical development support for repurposed compounds
• Access to contract research organization (CRO) facilities
• Funding for IND-enabling studies
• Expert consultation services

• Neuroprotective compound optimization
• Blood-brain barrier penetration enhancement
• Formulation development for CNS delivery

Blueprint Drug Screening Pipeline

| 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 [@schwarz2023]
| Citicoline | Stroke, traumatic brain injury | Parkinson's Disease | Phase III [@poston2023]
| N-acetylcysteine | Mucolytic | Parkinson's Disease | Phase II/III [@kim2023]
| Tocilizumab | Rheumatoid arthritis | Alzheimer's Disease | Phase II [@cullen2020]
| Amlodipine | Hypertension | Parkinson's Disease | Phase II [@meissner2022]
| Dapagliflozin | Diabetes | Neuroprotection | Preclinical [@jain2022]

Key Repurposed Drug Programs in Detail

Neuroprotection and Anti-inflammatory Agents

Minocycline

• Original indication: Antibiotic (tetracycline class)
• Proposed mechanism: Microglial inhibition, anti-apoptotic, anti-oxidant
• Trials: Multiple Phase II/III in ALS, AD, PD
• Status: Demonstrated safety; mixed efficacy results

• Original indication: Acute ischemic stroke (Japan)
• Proposed mechanism: Antioxidant, reduces oxidative stress
• Trials: FDA-approved for ALS (2017)
• Status: First FDA-approved ALS treatment

• Original indication: Asthma, COPD
• Proposed mechanism: Reduces alpha-synuclein aggregation[@mittal2022]
• Trials: Formoterol showing promise in PD models
• Status: Preclinical; planning clinical trials

Protein Clearance and Autophagy Enhancers

Rapamycin

• Original indication: Immunosuppression
• Proposed mechanism: mTOR inhibition, autophagy induction
• Trials: Phase II in AD and PD
• Status: Safety established; efficacy under investigation

• Original indication: Epilepsy, bipolar disorder
• Proposed mechanism: Autophagy induction via TRPV1
• Trials: Phase I/II in PD
• Status: Safe; ongoing evaluation

• Original indication: Respiratory mucus dissolution
• Proposed mechanism: GCase enhancement, chaperone activity
• Trials: Phase II in PD with GBA mutations
• Status: Promising results; Phase III planned

Mitochondrial Protectors

Coenzyme Q10

• Original indication: Heart failure, mitochondrial disorders
• Proposed mechanism: Electron transport chain support, antioxidant
• Trials: Phase III in PD; Phase II in Huntington's
• Status: Mixed results; continued investigation

• Original indication: Various
• Proposed mechanism: Mitochondrial oxidative stress reduction
• Trials: Early-phase in PD and ALS
• Status: Promising preclinical data

Inflammasome Inhibitors

NLRP3 Inflammasome Inhibitors

• Original indication: Various (none approved)
• Proposed mechanism: Block neuroinflammation[@foll2022]
• Development: Multiple programs in progress
• Status: Preclinical to Phase I

• Anakinra: IL-1 receptor antagonist (rheumatoid arthritis)
• Canakinumab: IL-1beta antibody (autoinflammatory)
• Colchicine: Microtubule inhibitor (gout) - Phase II in AD

Mechanisms of Action in Neurodegeneration

1. Neuroprotection

Repurposed compounds targeting neuroprotection work through multiple pathways:

Anti-apoptotic mechanisms:

• BCL-2 family modulation
• Caspase inhibition
• Growth factor signaling enhancement

• Direct free radical scavenging
• Mitochondrial antioxidant enhancement
• Nrf2 pathway activation

• Heat shock protein induction
• Unfolded protein response modulation
• Autophagy enhancement

2. Anti-inflammatory Mechanisms

Chronic neuroinflammation is a key driver of neurodegeneration:

Microglial modulation:

• TREM2 pathway targeting
• Complement system inhibition
• Cytokine production blocking

• Peripheral immune cell modulation
• Blood-brain barrier restoration
• Anti-inflammatory cytokine induction

3. Protein Homeostasis

Restoring protein clearance is a major therapeutic goal:

Autophagy enhancement:

• mTOR inhibition (rapamycin)
• TFEB activation
• Autophagy substrate clearance

• Chaperone enhancement (ambroxol)
• Proteasome modulation
• Lysosomal function enhancement

4. Synaptic Function

Synaptic loss correlates with cognitive decline:

Synaptic protection:

• Synaptic protein stabilization
• Presynaptic function enhancement
• Postsynaptic density modulation

• Neurotrophic factor enhancement
• BDNF pathway activation
• Dendritic spine remodeling

Drug Repositioning Pipeline

The NIH maintains a structured pipeline for drug repurposing:

Accelerating Medicines Partnership (AMP)

AMP-Alzheimer's Disease

The AMP-AD program represents a major public-private partnership:

• Objective: Identify novel therapeutic targets and biomarkers
• Approach: Multi-omics analysis of human brain tissue
• Consortium: NIH, pharmaceutical companies, academic institutions
• Data Sharing: Open-access database of omics data

AMP-Parkinson's Disease

Similar efforts for PD include:

• Objective: Understand PD progression and identify drug targets
• Approach: Longitudinal studies of prodromal PD
• Focus: [LRRK2](/genes/lrrk2), [GBA](/genes/gba), alpha-synuclein

Clinical Trial Infrastructure

NIH Clinical Center

The NIH Clinical Center provides:

• State-of-the-art facilities for early-phase clinical trials
• Expert clinical research staff
• Access to specialized patient populations
• Regulatory support for IND applications

Trial Networks

• Alzheimer's Clinical Trials Consortium (ACTC): NIA-funded network for AD clinical trials
• Parkinson's Study Group (PSG): NINDS-funded network for PD clinical trials
• ALS Clinical Trials Consortium: NINDS-funded network for ALS trials

Repurposing Success Stories

Approved Repurposed Drugs

Several drugs have successfully transitioned from repurposing to approval:

• Memantine: Originally for Alzheimer's, now approved for moderate-to-severe AD
• Riluzole: Originally for ALS, remains the only FDA-approved disease-modifying therapy for ALS
• Donepezil: Originally for AD, now used across dementia types

Promising Candidates in Development

• Ambroxol: Shows promise for increasing [GBA](/genes/gba) activity and reducing alpha-synuclein aggregation
• Isradipine: Dihydropyridine calcium channel blocker with neuroprotective properties
• Minocycline: Antibiotic with anti-inflammatory and anti-apoptotic effects

Computational and AI Approaches

Drug Repurposing Databases

The NIH supports several databases for repurposing research:

• NIH Clinical Center Drug Repurposing Database [@prCED]: Curated database of approved drugs with potential for repurposing
• Repurposing Drug Database: Comprehensive resource for drug repurposing candidates
• Illuminating the Druidome Project: NIH Common Fund initiative mapping drug-target interactions

AI and Machine Learning

Computational approaches accelerating repurposing:

• Target Prediction: Machine learning models predicting drug-target interactions
• Network Analysis: Systems biology approaches identifying disease modules
• Signature Matching: Comparing disease signatures to drug signatures

Funding Mechanisms

Grant Programs

The NIH provides multiple funding opportunities:

• R01 Research Grants: Standard investigator-initiated grants
• U01 Cooperative Agreements: Multi-institutional research projects
• R21 Exploratory Grants: High-risk, high-reward studies
• SBIR/STTR: Small business innovation research

Special Initiatives

• NIH Blueprint for Neurosciences: Funding for neurotherapeutics development
• AMP-AD Target Discovery Program: Partnerships for novel target identification
• NINDS Parkinson's Disease Translational Research Program: Preclinical and clinical repurposing studies

International Collaboration

Global Partnerships

The NIH collaborates internationally on drug repurposing:

• European Innovative Medicines Initiative: Joint programs on neurodegeneration
• Japanese AMED Partnership: Collaboration on AD and PD drug discovery
• Canadian Institute of Health Research: Joint funding for translational research

Data Sharing Frameworks

• International Alzheimer's Disease Research Consortium: Global data sharing
• Parkinson's Progression Markers Initiative (PPMI): Open-access longitudinal data
• Global Parkinson's Genetics Program (GP2): International genetic studies

Challenges and Future Directions

Current Challenges

• Biological Complexity: Neurodegenerative diseases involve multiple pathways
• Clinical Trial Design: Need for sensitive biomarkers and endpoints
• Regulatory Pathways: Clear pathways for repurposed drugs
• Funding Gaps: Translational funding between discovery and clinical development

Emerging Strategies

• Combination Therapies: Using multiple repurposed drugs targeting different pathways
• Personalized Medicine: Biomarker-driven patient selection
• Preventive Interventions: Targeting prodromal stages
• Open Science: Precompetitive data sharing to accelerate discovery

Collaboration Models

Public-Private Partnerships

The NIH works with pharmaceutical companies through:

Compound Library Sharing:

• Pharmaceutical company compound libraries
• FDA-approved drug collections
• Failed clinical candidate libraries

• Joint clinical trial development
• Data sharing arrangements
• Commercialization rights negotiations

Academic Collaborations

Research Centers:

• Alzheimer's Disease Research Centers
• Parkinson's Disease Research Centers
• ALS Centers

• International Parkinson's Disease Genomics Consortium
• European Alzheimer's Disease Consortium
• Global Amyotrophic Lateral Sclerosis Genetics Consortium

Patient Advocacy Partnerships

Foundation Collaborations:

• Michael J. Fox Foundation (Parkinson's)
• Alzheimer's Association
• ALS Association
• Cure Alzheimer's Fund

• Patient registry access
• Clinical trial recruitment support
• Funding for clinical trials
• Regulatory advocacy

Data Resources and Bioinformatics

Drug-Target Databases

The NIH maintains and supports several databases:

1. DrugBank

• Comprehensive drug information
• Target information
• Mechanism of action

• Chemical-protein interactions
• Metabolic pathways
• Literature mining

• Compilation of repurposing success stories
• Failed repurposing attempts
• Clinical trial information

Gene Expression Resources

Connectivity Map (CMap)

• Gene expression profiles for compounds
• Disease signature matching
• Mechanism of action identification

• Perturbagen signatures
• Cell type specificity
• Dose-response data

Network Medicine Approaches

The NIH supports network-based drug-target prediction:

Challenges and Limitations

Scientific Challenges

1. Mechanism Mismatch

• Drugs effective in one indication may not work through same mechanism in another
• Target engagement difficult to demonstrate
• Off-target effects may be relevant

• Optimal dose for CNS indication may differ from approved dose
• Chronic dosing requirements
• Brain penetration assessment

• Biomarkers for patient stratification lacking
• Genetic subtypes may respond differently
• Disease stage matters

Practical Challenges

1. Patent and Regulatory

• Exclusivity issues for new indications
• Regulatory pathway complexity
• Data exclusivity concerns

• Limited commercial return for some compounds
• Manufacturing challenges
• Liability concerns

• Clinical trial design for repurposing
• Outcome measure selection
• Combination therapy considerations

Current Status and Future Directions

2024 Program Status

As of 2024, the NIH repurposing program has:

• 150+ compounds in various stages of evaluation
• 20+ compounds in clinical trials
• 5 compounds approved for new neurodegenerative indications
• $50M+ annual budget across all institutes

Success Stories

Approved Repurposed Drugs:

Late-Stage Development:

Future Directions

Emerging Approaches:

Program Expansion:

• Focus on atypical parkinsonian disorders
• Expand to multiple system atrophy
• Prioritize frontotemporal dementia
• Include ALS variants

Resources and References

NIH Resources

• [NIA Drug Repurposing Program](https://www.nia.nih.gov/research/drug-repurposing)
• [NINDS Parkinson's Disease Research](https://www.ninds.nih.gov/Disorders/All-Disorders/Parkinsons-Disease-Information-Page)](/proteins/parkin)
• [NIH Blueprint for Neurosciences](https://neuroscienceblueprint.nih.gov/)
• [NIH Clinical Center Drug Repurposing](https://clinicalcenter.nih.gov/drugrepurposing)

See Also

• [Drug Repurposing for Neurodegenerative Diseases](/therapeutics/drug-repurposing-neurodegeneration)](/therapeutics)
• [Parkinson's Disease Therapeutics](/therapeutics/parkinsons-disease-therapeutics)](/therapeutics)
• [Alzheimer's Disease Drug Development](/therapeutics/alzheimers-disease-drug-development)](/therapeutics)
• [NIH - National Institute on Aging](/institutions/nih-nia)](/institutions)
• [NIH - National Institute on Neurological Disorders and Stroke](/institutions/nih-ninds)](/institutions)
• [Michael J. Fox Foundation](/institutions/michael-j-fox-foundation)](/institutions)
• [Alzheimer's Association](/institutions/alzheimers-association)