CD38 Inhibitor Therapy for Neurodegeneration

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CD38 Inhibitor Therapy for Neurodegeneration

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CD38 Inhibitor Therapy for Neurodegeneration

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">CD38 Inhibitor Therapy for Neurodegeneration</th>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Microglia</td>
<td>High (activated)</td>
</tr>
<tr>
<td class="label">B cells</td>
<td>High</td>
</tr>
<tr>
<td class="label">NK cells</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Neurons</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Astrocytes</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Company</td>
</tr>
<tr>
<td class="label">78c</td>
<td>Academic/Ruth L.

...

CD38 Inhibitor Therapy for Neurodegeneration

Overview

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">CD38 Inhibitor Therapy for Neurodegeneration</th>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Microglia</td>
<td>High (activated)</td>
</tr>
<tr>
<td class="label">B cells</td>
<td>High</td>
</tr>
<tr>
<td class="label">NK cells</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Neurons</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Astrocytes</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Company</td>
</tr>
<tr>
<td class="label">78c</td>
<td>Academic/Ruth L. Kirschstein</td>
</tr>
<tr>
<td class="label">Ara-020</td>
<td>Academic</td>
</tr>
<tr>
<td class="label">S010</td>
<td>Academic</td>
</tr>
<tr>
<td class="label">Apigenin</td>
<td>Natural compound</td>
</tr>
<tr>
<td class="label">AZD0305</td>
<td>AstraZeneca</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">CD38 inhibitor + NMN</td>
<td>Inhibits NAD+ consumption + provides substrate</td>
</tr>
<tr>
<td class="label">CD38 inhibitor + NR</td>
<td>Inhibits consumption + alternative precursor</td>
</tr>
<tr>
<td class="label">CD38 inhibitor + nicotinamide</td>
<td>Inhibits consumption + endogenous precursor</td>
</tr>
<tr>
<td class="label">CD38 inhibitor + SIRT1 activator</td>
<td>Dual NAD+ preservation + activation</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Disease Relevance</td>
</tr>
<tr>
<td class="label">NAD+ depletion</td>
<td>Universal in neurodegeneration</td>
</tr>
<tr>
<td class="label">Microglial activation</td>
<td>AD, PD, ALS, CBS, PSP</td>
</tr>
<tr>
<td class="label">SIRT1/SIRT2 dysfunction</td>
<td>AD, PD, HD, FTD</td>
</tr>
<tr>
<td class="label">Mitochondrial dysfunction</td>
<td>PD, ALS, HD</td>
</tr>
<tr>
<td class="label">DNA repair</td>
<td>Age-related neurodegeneration</td>
</tr>
<tr>
<td class="label">Trial ID</td>
<td>Intervention</td>
</tr>
<tr>
<td class="label">[NCT06162013](/clinical-trials/nadapt-study-nad-replenishment-parkinsonism-nct06162013)</td>
<td>NAD+ precursor (NMN/NR)</td>
</tr>
</table>

CD38 is an ecto-enzyme with NAD+ glycohydrolase activity that plays a central role in regulating cellular NAD+ levels. It is highly expressed in immune cells (B cells, NK cells, macrophages, microglia) and degrades NAD+ to ADP-ribose and cyclic ADP-ribose. CD38 inhibition preserves NAD+ pools, making it a promising therapeutic strategy for neurodegenerative diseases where NAD+ depletion is a common feature.

CD38 Biology and NAD+ Regulation

CD38 Enzymatic Activity

CD38 catalyzes:

NAD+ → ADP-ribose + nicotinamide
NAD+ → cyclic ADP-ribose (cADPR) + nicotinamide
cADPR → ADP-ribose

This activity makes CD38 a major consumer of cellular NAD+, particularly in immune cells and inflamed tissues.

CD38 Expression in Neurodegeneration

Evidence in Neurodegenerative Diseases

Alzheimer's Disease

CD38 expression increases in AD microglia surrounding amyloid plaques
NAD+ depletion in AD brain correlates with cognitive decline
CD38 KO mice show improved cognitive function in AD models
SIRT1 activity (NAD+-dependent) is reduced in AD — CD38 inhibition could restore it

Parkinson's Disease

Microglial CD38 activation contributes to neuroinflammation in PD
NAD+ levels decline in PD substantia nigra
CD38 inhibition protects dopaminergic neurons in MPTP models
Combined with NAD+ precursors (NMN, NR) shows synergy

Amyotrophic Lateral Sclerosis (ALS)

CD38 elevated in ALS microglia and peripheral immune cells
NAD+ depletion in motor neurons contributes to degeneration
CD38 inhibition improves survival in SOD1 mouse models
Clinical trial: CD38 inhibitors being evaluated for ALS

CBS/PSP (Corticobasal Syndrome / Progressive Supranuclear Palsy)

4R-tauopathies show microglial activation with CD38 upregulation
NAD+ metabolism impaired in tauopathy models
CD38 inhibition could reduce neuroinflammation and preserve neuronal NAD+
No direct clinical trials yet — therapeutic potential identified

Frontotemporal Dementia (FTD)

CD38 elevated in FTD brain tissue
NAD+ depletion contributes to transcriptional dysregulation
SIRT1/2 activity reduced — CD38 inhibition could restore deacetylase function

Huntington's Disease

CD38 expression increases in HD microglia
NAD+ levels decline in HD models and patient tissue
CD38 inhibition improves motor function in HD mouse models
Energy metabolism deficits in HD may benefit from NAD+ preservation

Drug Candidates

Clinical-Stage CD38 Inhibitors

Development Pipeline

Mermaid diagram (expand to render)

Challenges

Brain Penetration: Most CD38 inhibitors have limited CNS exposure

Target Engagement: Measuring CD38 inhibition in vivo is challenging

Immune Effects: CD38 inhibition affects immune function — monitoring needed

Therapeutic Strategy

Combination Approach

CD38 inhibitors work best in combination with NAD+ precursors:

Dosing Considerations

Low-dose CD38 inhibitors may be sufficient (e.g., apigenin 50mg daily)
Combined with NAD+ precursor (NMN 250mg daily or NR 300mg daily)
Timing: Morning dosing to align with circadian NAD+ rhythms

Cross-Disease Therapeutic Potential

CD38 inhibition addresses common mechanisms across neurodegenerative diseases:

Clinical Trials

Note: While no specific CD38 inhibitor trials are registered for neurodegeneration, the NADAPT study (NCT06162013) evaluates NAD+ replenishment therapy in Parkinsonian syndromes, providing indirect evidence for the CD38 inhibition therapeutic approach.

Cross-Links

[NAD+ Metabolism in Neurodegeneration](/mechanisms/nad-metabolism-neurodegeneration)
[SIRT1 Pathway in Alzheimer's Disease](/mechanisms/sirt1-alzheimer-pathway)
[NAD Signaling in Neurodegeneration](/mechanisms/nad-signaling-neurodegeneration)

[NAD+ Boosters](/therapeutics/nad-boosters-neurodegeneration)
[Nicotinamide Riboside](/therapeutics/nicotinamide-riboside)
[NAD+ Precursors](/therapeutics/nad-precursors-neurodegeneration)

[CD38 Gene](/genes/cd38)
[NAMPT](/genes/nampt) — rate-limiting enzyme in NAD+ biosynthesis
[SIRT1](/genes/sirt1) — NAD+-dependent deacetylase

[CD38 Inhibition and NAD+ Synergy](/ideas/cd38-inhibition-nad-synergy)

References

[Roboon J, et al, (2019) CD38 in neurodegenerative diseases](https://pubmed.ncbi.nlm.nih.gov/31490623/)

[Zocchi E, et al, (2019) CD38 in age-related neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/31141273/)

[Hattori T, et al, (2016) CD38 and its role in the brain](https://pubmed.ncbi.nlm.nih.gov/27572028/)

[Quarona V, et al, (2013) Unraveling the contribution of CD38 to neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/24157387/)

[Chiollaz M, et al, (2020) CD38 in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/32568176/)

[Lee HC, et al, (2014) CD38 and CD157 as therapeutic targets](https://pubmed.ncbi.nlm.nih.gov/25033901/)

[Lund FE, et al, (2019) CD38 and calcium signaling in immune cells](https://pubmed.ncbi.nlm.nih.gov/31063967/)

[Malavasi F, et al, (2008) CD38: a target for immunotherapeutic approaches](https://pubmed.ncbi.nlm.nih.gov/18760607/)

[Ruggieri A, et al, (2015) CD38 in neuroinflammation](https://pubmed.ncbi.nlm.nih.gov/26369749/)

[Garlisi CG, et al, (2003) CD38 as a therapeutic target](https://pubmed.ncbi.nlm.nih.gov/15175742/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Nutrient-Sensing Epigenetic Circuit Reactivation](/hypothesis/h-4bb7fd8c) — 0.79 · Target: SIRT1
[CYP46A1 Overexpression Gene Therapy](/hypothesis/h-2600483e) — 0.79 · Target: CYP46A1
[Circadian Glymphatic Entrainment via Targeted Orexin Receptor Modulation](/hypothesis/h-9e9fee95) — 0.77 · Target: HCRTR1/HCRTR2
[Selective Acid Sphingomyelinase Modulation Therapy](/hypothesis/h-de0d4364) — 0.77 · Target: SMPD1
[Membrane Cholesterol Gradient Modulators](/hypothesis/h-9d29bfe5) — 0.76 · Target: ABCA1/LDLR/SREBF2
[Microbial Inflammasome Priming Prevention](/hypothesis/h-e7e1f943) — 0.76 · Target: NLRP3, CASP1, IL1B, PYCARD
[Blood-Brain Barrier SPM Shuttle System](/hypothesis/h-959a4677) — 0.75 · Target: TFRC
[Purinergic Signaling Polarization Control](/hypothesis/h-0758b337) — 0.74 · Target: P2RY1 and P2RX7

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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

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📗 Cite This Artifact

CD38 Inhibitor Therapy for Neurodegeneration

CD38 Inhibitor Therapy for Neurodegeneration

Overview

CD38 Inhibitor Therapy for Neurodegeneration

Overview

CD38 Biology and NAD+ Regulation

CD38 Enzymatic Activity

CD38 Expression in Neurodegeneration

Evidence in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

CBS/PSP (Corticobasal Syndrome / Progressive Supranuclear Palsy)

Frontotemporal Dementia (FTD)

Huntington's Disease

Drug Candidates

Clinical-Stage CD38 Inhibitors

Development Pipeline

Challenges

Therapeutic Strategy

Combination Approach

Dosing Considerations

Cross-Disease Therapeutic Potential

Clinical Trials

Cross-Links

See Also

References

💬 Discussion

📗 Cite This Artifact

CD38 Inhibitor Therapy for Neurodegeneration

CD38 Inhibitor Therapy for Neurodegeneration

Overview

CD38 Inhibitor Therapy for Neurodegeneration

Overview

CD38 Biology and NAD+ Regulation

CD38 Enzymatic Activity

CD38 Expression in Neurodegeneration

Evidence in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

CBS/PSP (Corticobasal Syndrome / Progressive Supranuclear Palsy)

Frontotemporal Dementia (FTD)

Huntington's Disease

Drug Candidates

Clinical-Stage CD38 Inhibitors

Development Pipeline

Challenges

Therapeutic Strategy

Combination Approach

Dosing Considerations

Cross-Disease Therapeutic Potential

Clinical Trials

Related NAD+ Trials

Cross-Links

Related Mechanisms

Related Therapeutics

Related Genes

Related Ideas

See Also

References

Related Hypotheses

💬 Discussion