CD38 Inhibitor Therapy for Neurodegeneration

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Overview

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

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

flowchart TD
    A["CD38 Inhibitors"] --> B["Preclinical"]
    B --> C["Phase 1"]
    C --> D["Phase 2"]
    D --> E["Phase 3"]

    B --> F["78c"]
    B --> G["Ara-020"]
    B --> H["S010"]
    B --> I["Apigenin"]
    B --> J["AZD0305"]

    F --> K["ALS"]
    G --> L["AD/PD"]
    I --> M["Various"]

Challenges

  1. Brain Penetration: Most CD38 inhibitors have limited CNS exposure

  2. Target Engagement: Measuring CD38 inhibition in vivo is challenging

  3. 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.

  • CD38 Gene

  • NAMPT — rate-limiting enzyme in NAD+ biosynthesis

  • SIRT1 — NAD+-dependent deacetylase

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