TLR9 Stimulation for Alzheimer's Disease

Overseen By Anaztasia Ulysse

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: NYU Langone Health

Must not be taking: Corticosteroids, Immunosuppressives, Anticoagulants, others

Disqualifiers: Psychiatric illness, Autoimmune disorders, Renal impairment, others

Compensation: Varies

Number of Visits: 3

Duration: 8 weeks

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety of a new treatment, CpG 1018, for individuals in the early stages of Alzheimer's disease. CpG 1018, a TLR9 stimulator, is under study for its potential effects on the immune system. The study includes three groups, each receiving different doses of the treatment or a placebo (a substance with no active drug). Only individuals with mild memory issues due to Alzheimer's and a positive brain scan for amyloid (a protein linked to Alzheimer's) may qualify. Participants will receive injections and be monitored for their reactions. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop using corticosteroids, immunosuppressive drugs, chloroquine, anti-coagulants, and drugs that are major substrates of cytochrome P450 enzyme 1A2 before joining. If you are taking any of these, you may need to stop or switch medications.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that CpG 1018 is under study to assess its safety and tolerability. In earlier studies, it boosted the immune system in ways that might benefit Alzheimer's disease. Although these studies do not provide specific safety details for humans, CpG 1018 remains in the early testing stages for Alzheimer's, focusing primarily on its safety in people.

As a Phase 1 trial, the main goal is to identify any side effects and observe how participants react to the drug. So far, no serious side effects have been reported. However, since the trial is still in its early stages, more information is needed to fully understand its safety. Phase 1 trials are the initial step in testing new treatments in people, so safety information is limited at this point. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Researchers are excited about CpG1018 for Alzheimer's disease because it brings a fresh approach compared to existing treatments like cholinesterase inhibitors and NMDA receptor antagonists. Unlike these traditional therapies, which mainly focus on managing symptoms, CpG1018 targets the immune system by stimulating TLR9 receptors. This novel mechanism aims to modify the underlying disease process rather than just alleviating symptoms, potentially offering a more effective way to tackle Alzheimer's. Additionally, the treatment is designed to work with precise dosing based on body weight, which might enhance its effectiveness and safety profile.

What evidence suggests that CpG 1018 might be an effective treatment for Alzheimer's?

Research has shown that boosting the immune system with CpG ODN, a component of CpG1018, can help reduce harmful proteins in the brain linked to Alzheimer's disease. In studies with older squirrel monkeys, injections of CpG ODN lowered these proteins and improved Alzheimer's symptoms. This trial will evaluate different dosages of CpG1018, with participants receiving doses of 0.1 mg/kg, 0.25 mg/kg, or 0.5 mg/kg. This approach suggests that CpG1018 might help by activating the body's natural defenses to clear these damaging proteins. Although human studies have provided limited information, these early results are promising for potential Alzheimer's treatment. ^{1 2 3 4 5}

Who Is on the Research Team?

Arjun Masurkar, MD

Principal Investigator

NYU Langone Medical Center

Are You a Good Fit for This Trial?

This trial is for people aged 65-85 with Mild Cognitive Impairment or mild Alzheimer's dementia, who can consent to participate and have a study partner. They must score ≥17 on the MoCA test and show positive amyloid scans. Excluded are those with certain psychiatric illnesses, history of severe immune-related diseases, recent use of anticoagulants or immunosuppressives, inability to undergo MRI, renal impairment, recent strokes or seizures.

Inclusion Criteria

I am between 65 and 85 years old.

Must be willing and able to participate in all study related procedures

I have been diagnosed with early-stage Alzheimer's disease.

Exclusion Criteria

I haven't taken steroids or immunosuppressants in the last 30 days.

Participation in any other current AD investigational interventional trial

I have kidney problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 3 injections at Day 1, Week 4, and Week 8 with dose levels of 0.1 mg/kg, 0.25 mg/kg, or 0.5 mg/kg, followed by a 1-hour post-dose observation period

8 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including plasma and CSF biomarker analysis and cognitive assessments

10 weeks

Multiple visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• CpG1018

Trial Overview The study tests CpG1018's safety at three dose levels against placebo in participants with early-stage Alzheimer's over 8 weeks per group. It aims to stimulate innate immunity via TLR9 as a potential treatment pathway for cognitive impairments associated with Alzheimer’s disease.

How Is the Trial Designed?

Group I: CpG 1018 0.5 mg/kg Experimental Treatment 1 Intervention

3 injections at Day 1, Week 4, and Week 8. Treatment administered as morning injection of dose 0.5 mg/kg, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions.

Group II: CpG 1018 0.25 mg/kg Experimental Treatment 1 Intervention

3 injections at Day 1, Week 4, and Week 8. Treatment administered as morning injection of dose 0.25 mg/kg, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions.

Group III: CpG 1018 0.1 mg/kg Experimental Treatment 1 Intervention

3 injections at Day 1, Week 4, and Week 8. Treatment administered as morning injection of dose 0.1mg/kg, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions.

Group IV: Placebo Placebo Group 1 Intervention

3 injections of sterile saline at Day 1, Week 4, and Week 8, followed by 1-hour post-dose observation period to check for injection site reaction and/or adverse reactions.

Who Is Running the Clinical Trial?

NYU Langone Health

Lead Sponsor

Trials

1,431

Recruited

838,000+

Alzheimer's Association

Collaborator

Trials

103

Recruited

44,300+

Published Research Related to This Trial

Stimulation of the innate immune system through TLR9 in a mouse model of Alzheimer's disease led to a significant reduction in amyloid beta accumulation, with a 66% decrease in cortical and 80% decrease in vascular amyloid burden.

The treatment not only reduced amyloid levels but also improved cognitive performance in the treated mice, indicating potential efficacy without apparent toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. Scholtzova, H., Kascsak, RJ., Bates, KA., et al.[2021]

In an animal model of Alzheimer's disease, researchers found that several toll-like receptors (TLRs) were significantly upregulated in brain tissue associated with amyloid-beta plaques, indicating a potential target for therapy.

The study suggests that enhancing TLR signaling specifically in plaque-associated microglia could be a promising strategy for improving the clearance of amyloid-beta and potentially treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Frank, S., Copanaki, E., Burbach, GJ., et al.[2011]

In a study using 3xTg-AD mice, treatment with TLR9 agonists (CpG oligodeoxynucleotides) significantly reduced both amyloid β and tau pathologies, which are key features of Alzheimer's disease, without causing inflammatory toxicity.

The treatment not only decreased toxic oligomers but also improved cognitive function in the mice, suggesting that stimulating the innate immune system could be a promising strategy for developing effective therapies for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amyloid β and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation. Scholtzova, H., Chianchiano, P., Pan, J., et al.[2021]

Soluble oligomeric amyloid beta (oAbeta1-42) is neurotoxic and causes synaptic dysfunction in Alzheimer's disease, but microglia can help mitigate this toxicity when activated by unmethylated DNA CpG motifs.

Administering CpG in a mouse model of Alzheimer's disease improved cognitive function and learning abilities, suggesting that targeting microglial activation could be a promising therapeutic approach to reduce oAbeta1-42 neurotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease. Doi, Y., Mizuno, T., Maki, Y., et al.[2022]

In a study using the Tg-SwDI mouse model, which has significant cerebral amyloid angiopathy (CAA), the administration of Toll-like receptor 9 agonist CpG oligodeoxynucleotides (ODNs) improved cognitive functions and reduced CAA pathology without causing toxicity.

This research highlights the potential of immunomodulation via CpG ODNs as a safe and effective therapeutic strategy to address multiple aspects of Alzheimer's disease pathology, including amyloid-β plaques and cognitive deficits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits. Scholtzova, H., Do, E., Dhakal, S., et al.[2018]

Co-administration of amyloid beta peptide (Abeta1-40) with certain Toll-like receptor (TLR) agonists like LPS or Pam3Cys increases the release of inflammatory markers (nitric oxide and TNF-alpha), which may worsen clinical outcomes in Alzheimer's patients during infections.

In contrast, when Abeta1-40 is combined with CpG, there is a significant reduction in these inflammatory markers, indicating that not all TLR agonists have the same effect on innate immune responses related to amyloid beta.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amyloid beta peptide 1-40 enhances the action of Toll-like receptor-2 and -4 agonists but antagonizes Toll-like receptor-9-induced inflammation in primary mouse microglial cell cultures. Lotz, M., Ebert, S., Esselmann, H., et al.[2010]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8502485/

Innate immunity stimulation via CpG oligodeoxynucleotides ... Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer's disease pathology in aged squirrel monkeys.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05606341

Innate Immunity Stimulation Via TLR9 in Early AD This single-center, double-blind, placebo-controlled study will recruit in total 39 participants with either Mild Cognitive Impairment due to Alzheimer's ...

3. withpower.com withpower.com/trial/phase-1-mild-cognitive-impairment-mci-10-2022-5f79e

TLR9 Stimulation for Alzheimer's Disease Research shows that stimulating the immune system with CpG ODN, a component of CpG1018, can reduce harmful proteins in the brain linked to Alzheimer's disease ...

4. reporter.nih.gov reporter.nih.gov/search/FqR_vt0tFUaPm0jXl4MEWg/project-details/10665767

scholtzova, henrieta - NIH RePORTER The collective studies are designed to provide a comprehensive portrayal of CpG 1018 efficacy and long-term safety by integrating biofluid biomarker signatures ...

5. tandfonline.com tandfonline.com/doi/full/10.1080/13543784.2025.2551352?src=

Nonamyloid-beta active immunization for the treatment of ... In 17- to 19-year-old squirrel monkeys, CpG ODN subcutaneous injections in monthly intervals over 2 years exhibited reductions in vascular Aβ loads and ...