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

Trial Summary

What is the purpose of this trial?

This trial tests the safety of CpG 1018 in people with early stages of Alzheimer's disease. Different doses are given to see how well it is tolerated. It works by stimulating the immune system, which may help manage Alzheimer's.

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.

What data supports the effectiveness of the treatment CpG1018 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 in mice, improving memory and cognitive function without causing harmful inflammation. ^{1 2 3 4 5}

Is TLR9 stimulation with CpG ODN safe for humans?

Research in mouse models of Alzheimer's disease suggests that TLR9 stimulation with CpG ODN can reduce harmful brain deposits without causing toxicity, indicating it may be safe for use. ^{1 2 3 4 5}

How does the drug CpG1018 work differently from other Alzheimer's treatments?

CpG1018 is unique because it stimulates the body's innate immune system through Toll-like receptor 9 (TLR9) to reduce harmful proteins in the brain associated with Alzheimer's, like amyloid beta and tau, without causing inflammation. This approach is different from other treatments that mainly target the adaptive immune system or focus on symptoms rather than the underlying pathology. ^{1 2 3 4 6}

Research Team

Arjun Masurkar, MD

Principal Investigator

NYU Langone Medical Center

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Amyloid β and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation. [2021]

3. United States 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. [2018]

4. United States 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. [2022]

5. England 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. [2010]

6. Ireland pubmed.ncbi.nlm.nih.gov

Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. [2011]