NCT07496021 is a Phase 1 clinical trial evaluating Lactococcus lactis CKDB001, a novel genetically engineered bacterial therapy for Alzheimer's disease. This trial represents an innovative approach to Alzheimer's therapeutics by targeting the gut-brain axis through probiotic intervention.
| Parameter |
Value |
| NCT Number |
NCT07496021 |
| Title |
Phase 1 Study of Lactococcus lactis CKDB001 in Mild-to-Moderate Alzheimer's Disease |
| Status |
Recruiting |
| Phase |
Phase 1 |
| Study Type |
Interventional |
| Enrollment |
24 participants |
| Sponsor |
CKDB Therapeutics |
| Start Date |
September 2024 |
| Completion Date |
December 2025 |
| Locations |
United States (Multiple sites) |
CKDB001 is a proprietary strain of Lactococcus lactis that has been genetically engineered to:
- Overexpress neurotrophic factors (BDNF, GDNF)
- Produce anti-inflammatory cytokines
- Modulate gut microbiome composition
- Produce neuroprotective metabolites
The intervention is administered as an oral probiotic formulation containing 10^9 CFU per dose.
The gut-brain axis plays a critical role in Alzheimer's disease pathogenesis through multiple pathways:
- Microbiome Dysbiosis: AD patients exhibit altered gut microbiome composition with reduced microbial diversity
- Systemic Inflammation: "Leaky gut" allows bacterial products to trigger neuroinflammation
- Metabolite Signaling: Short-chain fatty acids (SCFAs) influence microglial function and synaptic plasticity
Lactococcus lactis is a lactic acid bacterium with several properties suitable for neurodegenerative disease therapy:
Lactococcus lactis has Generally Recognized As Safe (GRAS) status from the FDA, making it suitable for human consumption.
The CKDB001 strain has been engineered to produce brain-derived neurotrophic factor (BDNF), which:
- Promotes neuronal survival and synaptic plasticity
- Enhances cognitive function
- Supports hippocampal neurogenesis
Lactococcus lactis modulates immune responses by:
- Reducing pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β)
- Promoting regulatory T cell differentiation
- Enhancing intestinal barrier function
Some Lactococcus strains produce GABA, an inhibitory neurotransmitter that:
- Reduces neuronal excitotoxicity
- Improves synaptic function
- May protect against amyloid toxicity
Animal studies have demonstrated that Lactococcus lactis supplementation:
- Improves spatial memory in AD mouse models
- Reduces amyloid-beta plaque deposition
- Decreases neuroinflammation markers
- Enhances cognitive performance in aged mice
This Phase 1 trial employs a classic 3+3 dose escalation design:
| Cohort |
Dose (CFU) |
Participants |
| 1 |
10^8 |
3-6 |
| 2 |
5×10^8 |
3-6 |
| 3 |
10^9 |
3-6 |
- Age 55-85 years
- Mild-to-moderate AD (MMSE 16-26)
- Stable on cholinesterase inhibitor or memantine (if on treatment)
- Ability to swallow capsules
- Informed consent
- Significant gastrointestinal disease
- Recent antibiotic use (<4 weeks)
- Active inflammatory condition
- Immunosuppressive therapy
- Probiotic supplementation (<8 weeks)
- Safety and Tolerability — Adverse events, serious adverse events
- Maximum Tolerated Dose (MTD) — Highest dose without dose-limiting toxicity
- Cognitive Function — ADAS-Cog, MMSE change from baseline
- Biomarkers — CSF amyloid-beta, tau, inflammatory markers
- Gut Microbiome — Compositional changes in fecal microbiota
- Pharmacokinetics - Colony counts in stool
- BDNF levels in blood
- Cytokine profiling
- Volatile organic compounds (VOCs) in breath
The proposed mechanism by which Lactococcus lactis CKDB001 may benefit AD patients:
graph TD
A["Lactococcus lactis CKDB001<br>Oral Administration"] --> B["Gut Microbiome<br>Modulation"]
B --> C["SCFA Production<br>Butyrate, Propionate"]
C --> D["Systemic Inflammation<br>Reduction"]
D --> E["Microglial Activation<br>Modulation"]
E --> F["Neuroinflammation<br>Decrease"]
F --> G["Cognitive Function<br>Improvement"]
A --> H["BDNF Production<br>Neurotrophic Support"]
H --> I["Synaptic Plasticity<br>Enhancement"]
I --> G
A --> J["Intestinal Barrier<br>Strengthening"]
J --> K["Reduced Endotoxin<br>Transit"]
K --> F
The gut-brain axis influences amyloid pathology through:
- Modulation of systemic inflammation affecting amyloid clearance
- Direct effects on microglial activation and phagocytosis
- Alteration of peripheral amyloid metabolism
Lactococcus lactis may impact tau pathology via:
- Reduction of neuroinflammation that drives tau phosphorylation
- Neurotrophic support for tau-affected neurons
- Improvement of cellular clearance mechanisms
Chronic neuroinflammation is a hallmark of AD. CKDB001 addresses this through:
- SCFA-mediated anti-inflammatory effects
- Restored gut barrier integrity
- Modulated microglial phenotype
This trial directly relates to:
| Trial |
Intervention |
Phase |
Status |
| NCT06487975 |
Bacillus Subtilis |
Observational |
Active |
| NCT05934188 |
Gut-Brain Axis |
Observational |
Recruiting |
| NCT05568498 |
Probiotic Blend |
Phase 2 |
Recruiting |
| NCT07496021 |
Lactococcus lactis CKDB001 |
Phase 1 |
Recruiting |
The trial is actively recruiting at multiple U.S. sites. Phase 1 trials focus primarily on safety assessment, with preliminary efficacy data expected in late 2025.
- Novel mechanism targeting gut-brain axis
- GRAS organism with established safety profile
- Engineered for enhanced therapeutic potential
- Gastrointestinal discomfort
- Unknown long-term effects of engineered strain
- Interaction with existing AD medications
- Theoretical risk of systemic infection (low)
If Phase 1 demonstrates safety:
- Phase 2a: Efficacy evaluation in mild AD
- Phase 2b: Dose optimization
- Phase 3: Large-scale efficacy confirmation