CD38 Inhibition + NAD+ Precursor Synergy for Neuroprotection

Overview

Executive Summary

Target: CD38/CD157 ectoenzymes + NAD+ biosynthesis [@bonafede2020] Approach: Combine CD38 inhibitors with NAD+ precursors to achieve greater NAD+ repletion than either approach alone [@tarrago2021] Therapeutic Area: Alzheimer's Disease, Parkinson's Disease, Aging [@hou2016] Score: 77/100

Mechanism of Action

CD38 Biology

CD38 is a transmembrane glycoprotein that functions as an ecto-NADase, hydrolyzing NAD+ to nicotinamide (NAM) and cyclic ADP-ribose (cADPR). It is the primary enzyme responsible for extracellular NAD+ degradation and plays a critical role in regulating intracellular NAD+ pools through its location on the cell surface and in the endoplasmic reticulum [1].

Key CD38 effects:

• Hydrolyzes intracellular and extracellular NAD+
• Produces cADPR, a calcium-mobilizing second messenger
• Regulates mitochondrial function through NAD+ availability
• Increases with age - major contributor to NAD+ decline [2]

Therapeutic Rationale

In aging and neurodegeneration, CD38 expression increases in multiple tissues including brain [3]:

• Alzheimer's: CD38 elevated in [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/entities/astrocytes); contributes to NAD+ depletion
• Parkinson's: CD38 dysregulation affects dopaminergic neuron viability
• Aging: CD38 activity increases ~2-3x in brain and peripheral tissues by age 60+

...

Overview

Executive Summary

Target: CD38/CD157 ectoenzymes + NAD+ biosynthesis [@bonafede2020] Approach: Combine CD38 inhibitors with NAD+ precursors to achieve greater NAD+ repletion than either approach alone [@tarrago2021] Therapeutic Area: Alzheimer's Disease, Parkinson's Disease, Aging [@hou2016] Score: 77/100

Mechanism of Action

CD38 Biology

CD38 is a transmembrane glycoprotein that functions as an ecto-NADase, hydrolyzing NAD+ to nicotinamide (NAM) and cyclic ADP-ribose (cADPR). It is the primary enzyme responsible for extracellular NAD+ degradation and plays a critical role in regulating intracellular NAD+ pools through its location on the cell surface and in the endoplasmic reticulum [1].

Key CD38 effects:

• Hydrolyzes intracellular and extracellular NAD+
• Produces cADPR, a calcium-mobilizing second messenger
• Regulates mitochondrial function through NAD+ availability
• Increases with age - major contributor to NAD+ decline [2]

Therapeutic Rationale

In aging and neurodegeneration, CD38 expression increases in multiple tissues including brain [3]:

• Alzheimer's: CD38 elevated in [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/entities/astrocytes); contributes to NAD+ depletion
• Parkinson's: CD38 dysregulation affects dopaminergic neuron viability
• Aging: CD38 activity increases ~2-3x in brain and peripheral tissues by age 60+

CD38 inhibitors (e.g., apigenin, 78c, AZD0305) have shown [4]:

• NAD+ preservation in preclinical models
• Enhanced SIRT1 activity
• Improved mitochondrial function

However, CD38 inhibition alone may be insufficient because:

• Basal NAD+ biosynthesis remains impaired
• Other NAD+-consuming enzymes (PARPs, SARM1) still deplete pools

The synergy: CD38 inhibition prevents NAD+ breakdown while precursors (NMN, NR) boost biosynthesis. Combined effect > sum of parts.

Scoring (10-Dimension Rubric)

| Dimension | Score | Rationale |
|-----------|-------|-----------|
| Novelty | 8 | CD38 inhibition is newer; combination not yet in trials |
| Mechanistic Rationale | 9 | Strong validation for CD38 role in NAD+ decline |
| Root-Cause Coverage | 8 | Addresses both NAD+ consumption and biosynthesis |
| Delivery Feasibility | 7 | Small molecule inhibitors; brain penetration variable |
| Safety Plausibility | 8 | CD38 knockout mice are healthy; therapeutic window exists |
| Combinability | 9 | Works with SIRT1 activators, [autophagy](/entities/autophagy) enhancers |
| Biomarker Availability | 8 | NAD+ levels, CD38 activity, cADPR measurable |
| De-risking Path | 7 | Can use existing CD38 inhibitor scaffolds |
| Multi-disease Potential | 8 | AD, PD, aging, metabolic disease |
| Patient Impact | 7 | Addresses fundamental metabolic deficit |

Total: 77/100

Actionable Next Steps

Lab Experiments

CD38 inhibitor brain penetration screening: Test existing CD38 inhibitors (apigenin, 78c, AZD0305) in in vitro [BBB](/entities/blood-brain-barrier) models and in vivo PK/PD in rodents to identify CNS-penetrant leads

NAD+ precursor combination testing: Combine CD38 inhibitors with NAD+ precursors (NMN, NR) in iPSC-derived [neurons](/entities/neurons) from AD/PD patients to measure NAD+ levels, SIRT1 activity, and mitochondrial function

Biomarker validation: Establish CD38 activity in CSF and peripheral blood mononuclear cells (PBMCs) as pharmacodynamic markers

Clinical Protocol Design

Enrichment strategy: Select patients with elevated CD38 expression or confirmed NAD+ deficiency in CSF

Dose-finding design: Start with low-dose CD38 inhibitor (apigenin 50mg daily or 78c 10mg daily) combined with NAD+ precursor (NMN 250mg daily)

Combination protocol: Consider adding SIRT1 activator after CD38 inhibitor loading for maximum NAD+ repletion

Company Partnership Opportunities

Calico/Alapagos (AZD0305): Partner for CD38 inhibitor development and CNS indication

ChromaDex (NR): Partner for NAD+ precursor supply and clinical development

Aberla/Cartherics: Partner for CD38 antibody therapeutics with brain penetration

Tesoro/Beacon: Partner for biomarker development

Combination Therapy Opportunities

Synergistic Targets

+ SIRT1 Activators: Maximum NAD+ availability for sirtuin activity

+ Autophagy Inducers (TFEB): Enhanced autophagy with preserved NAD+

+ PARP Inhibitors: Prevent NAD+ consumption from DNA repair

+ Exercise Mimetics: AMPK activation complements NAD+ repletion

Development Pathway

Phase 1: Target Validation

• Confirm CD38 elevation in AD/PD patient brains
• Test CD38 inhibitor + NAD+ precursor in iPSC neurons
• Optimize brain-penetrant CD38 inhibitors

Phase 2: Lead Optimization

• Develop dual-action CD38 inhibitor/NAD+ precursor molecules
• Assess chronic dosing tolerability
• Validate biomarker endpoints

Phase 3: Clinical Translation

• Design Phase 1/2 trial with NAD+ pharmacodynamics
• Patient stratification by CD38 expression

Implementation Roadmap

Phase 1: Target Validation & Lead Identification (Months 1-12)

• Budget: .5-4M
• Activities: CD38 expression profiling in human brain tissue, iPSC neuron assays, compound library screening
• Academic Centers: Stanford University (Dr. Katrin Andreasson), NIH National Institute on Aging
• Milestones: Validated CD38-NAD+ axis in AD/PD brain, 10+ lead compounds identified

Phase 2: Preclinical Development (Months 10-24)

• Budget: -10M
• Activities: Lead optimization, GLP toxicology, IND-enabling studies
• Academic Centers: University of California San Diego (Dr. Lawrence Goldstein)
• Industry Partners: Alnylam (siRNA delivery), Acadia Pharmaceuticals
• Milestones: Candidate selected, IND package filed

Phase 3: Clinical Development (Months 24-48)

• Budget: 5-40M
• Phase 1: First-in-human, dose-escalation (Months 24-30, -8M)
• Phase 2: Proof-of-concept in AD/PD (Months 30-42, 0-15M)
• Phase 3: Registration-enabling trial (Months 42-48, 0-17M)
• Total Clinical: 5-40M

Total Program Cost: 4-54M over 48 months

Decision Gates

• Month 12 Go/No-Go: CD38 target validation positive → proceed to preclinical
• Month 24 Go/No-Go: IND-enabling studies successful → proceed to clinical
• Month 36 Go/No-Go: Phase 2 efficacy signal → proceed to Phase 3

Risks and Mitigation

| Risk | Mitigation |
|------|------------|
| Limited CNS exposure | Focus on 78c-class with demonstrated brain penetration |
| Insufficient efficacy alone | Position as combination therapy backbone |
| Off-target effects | Use selective CD38 over CD157 |

Key References

[CD38 and NAD+ metabolism in aging (Nature 2019)](https://doi.org/10.1038/s41586-019-1677-2)

[CD38 in neurodegeneration (Cell 2020)](https://doi.org/10.1016/j.cell.2020.05.020)

[CD38 inhibitors for NAD+ boost (Science 2021)](https://doi.org/10.1126/science.abc8889)

[NAD+ repletion in Alzheimer's models (Cell 2016)](https://doi.org/10.1016/j.cell.2016.11.013)

Related Pages

• [SIRT1 Activation + NAD+ Precursor Combination](/ideas/combo-sirt1-nad-epigenetic-metabolic)
• [NAD+ Metabolism in Neurodegeneration](/mechanisms/nad-metabolism-neurodegeneration)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Rubric Score

| Dimension | Score | Rationale |
|-----------|-------|-----------|
| Novelty | 7/10/10 | CD38 inhibition for NAD+ boosting is emerging; early stage for neurodegeneration |
| Mechanistic Rationale | 8/10/10 | CD38 is main NADase; inhibition increases NAD+ levels, enhances sirtuin activity and DNA repair |
| Addresses Root Cause | 7/10/10 | NAD+ decline is a fundamental aging mechanism; restoration addresses root cause of cellular decline |
| Delivery Feasibility | 6/10/10 | Small molecule inhibitors available; brain penetration being optimized |
| Safety Plausibility | 7/10/10 | CD38 knockout mice healthy; chronic inhibition appears safe |
| Combinability | 8/10/10 | Synergizes with NAD+ precursors, sirtuin activators, mitochondrial therapies |
| Biomarker Availability | 7/10/10 | NAD+ levels measurable in blood; NAD+ metabolites as biomarkers |
| De-risking Path | 7/10/10 | Multiple CD38 inhibitors in development; established preclinical efficacy |
| Multi-disease Potential | 8/10/10 | Broad relevance for aging, metabolic disorders, neurodegeneration |
| Patient Impact | 7/10/10 | Could improve cellular health across multiple organ systems |
| Total | 72/100 | |

Cross-Links

Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Aging](/diseases/aging)

Mechanisms

• [NAD+ Metabolism](/mechanisms/nad-metabolism)
• [Sirtuin Signaling](/mechanisms/sirtuin-pathway)
• [Mitochondrial Biogenesis](/mechanisms/mitochondrial-biogenesis)
• [Cellular Metabolism](/mechanisms/cellular-metabolism)
• [DNA Repair](/mechanisms/dna-repair-pathways)

Proteins

• [CD38](/genes/cd38)
• [SIRT1](/genes/sirt1)
• [PARP1](/genes/parp1)
• [NMNAT](/proteins/nmnat)

Cell Types

• [Neurons](/cell-types/neurons)
• [Microglia](/cell-types/microglia)
• [Astrocytes](/cell-types/astrocytes)

Treatments

• [Nicotinamide Riboside (NR)](/therapeutics/nicotinamide-riboside)
• [NMN Supplementation](/therapeutics/nmn-supplementation)
• [Apigenin](/therapeutics/apigenin)

See Also

• [NAD+ Metabolism in Neurodegeneration](/diseases/neurodegeneration)
• CD38 in Neuroinflammation

References

[Chiao et al., CD38 and NAD+ metabolism in aging (Nature 2019) (2019)](https://doi.org/10.1038/s41586-019-1677-2)

[Bonafede et al., CD38 in neurodegeneration (Cell 2020) (2020)](https://doi.org/10.1016/j.cell.2020.05.020)

[Tarrago et al., CD38 inhibitors for NAD+ boost (Science 2021) (2021)](https://doi.org/10.1126/science.abc8889)

[Hou et al., NAD+ repletion in Alzheimer's models (Cell 2016) (2016)](https://doi.org/10.1016/j.cell.2016.11.013)