TLR9 Stimulation for Alzheimer's Disease
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: NYU Langone Health
Must not be taking: Corticosteroids, Immunosuppressives, Anticoagulants, others
Disqualifiers: Psychiatric illness, Autoimmune disorders, Renal impairment, others
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.
12345Is 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.
12345How 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.
12346Eligibility 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.
+4 more
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.
+10 more
Trial 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)
Participant Groups
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.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: CpG 1018 0.5 mg/kgExperimental Treatment1 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/kgExperimental Treatment1 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/kgExperimental Treatment1 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: PlaceboPlacebo Group1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
NYU Langone HealthNew York, NY
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Who Is Running the Clinical Trial?
NYU Langone HealthLead Sponsor
Alzheimer's AssociationCollaborator
References
Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. [2021]The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of amyloid beta (Abeta) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Abeta accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p = 0.0001) and vascular (p = 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Abeta42, Abeta40, and Abeta oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Abeta oligomers, without apparent toxicity.
Amyloid β and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation. [2021]Alzheimer's disease (AD) is the most common cause of dementia, and currently, there is no effective treatment. The major neuropathological lesions in AD are accumulation of amyloid β (Aβ) as amyloid plaques and congophilic amyloid angiopathy, as well as aggregated tau in the form of neurofibrillary tangles (NFTs). In addition, inflammation and microglia/macrophage function play an important role in AD pathogenesis. We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. We have previously shown in the Tg2576 AD model that CpG ODN can reduce amyloid deposition and prevent cognitive deficits. In the present study, we used the 3xTg-AD mice with both Aβ and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aβ and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice. Our data indicate that modulation of microglial function via TLR9 stimulation is effective at ameliorating all the cardinal AD related pathologies in an AD mouse model suggesting such an approach would have a greater chance of achieving clinical efficacy.
Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits. [2018]Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-β (Aβ) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN.
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]Soluble oligomeric amyloid beta (oAbeta) 1-42 causes synaptic dysfunction and neuronal injury in Alzheimer's disease (AD). Although accumulation of microglia around senile plaques is a hallmark of AD pathology, the role of microglia in oAbeta1-42 neurotoxicity is not fully understood. Here, we showed that oAbeta but not fibrillar Abeta was neurotoxic, and microglia activated with unmethylated DNA CpG motif (CpG), a ligand for Toll-like receptor 9, attenuated oAbeta1-42 neurotoxicity in primary neuron-microglia co-cultures. CpG enhanced microglial clearance of oAbeta1-42 and induced higher levels of the antioxidant enzyme heme oxygenase-1 in microglia without producing neurotoxic molecules such as nitric oxide and glutamate. Among subclasses of CpGs, class B and class C activated microglia to promote neuroprotection. Moreover, intracerebroventricular administration of CpG ameliorated both the cognitive impairments induced by oAbeta1-42 and the impairment of associative learning in Tg2576 mouse model of AD. We propose that CpG may be an effective therapeutic strategy for limiting oAbeta1-42 neurotoxicity in AD.
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]The interaction of endogenous and exogenous stimulators of innate immunity was examined in primary cultures of mouse microglial cells and macrophages after application of defined Toll-like receptor (TLR) agonists [lipopolysaccharide (LPS) (TLR4), the synthetic lipopeptide Pam3Cys-Ser-Lys4 (Pam3Cys) (TLR2) and single-stranded unmethylated CpG-DNA (CpG) (TLR9)] alone and in combination with amyloid beta peptide (Abeta) 1-40. Abeta1-40 stimulated microglial cells and macrophages primed by interferon-gamma in a dose-dependent manner. Co-administration of Abeta1-40 with LPS or Pam3Cys led to an additive release of nitric oxide (NO) and tumour necrosis factor alpha (TNF-alpha). This may be one reason for the clinical deterioration frequently observed in patients with Alzheimer's disease during infections. In contrast, co-application of Abeta1-40 with CpG led to a substantial decrease of NO and TNF-alpha release compared with stimulation with CpG alone. Abeta1-40 and CpG did not co-localize within the same subcellular compartment, making a direct physicochemical interaction as the cause of the observed antagonism very unlikely. This suggests that not all TLR agonists enhance the stimulatory effect of A beta on innate immunity.
Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. [2011]Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid-beta protein in the aged brain. Inefficient clearance of amyloid-beta from brain tissue is believed to play a major role in the pathogenesis of these deposits. Since amyloid-beta clearance likely involves activation of microglial cells via toll-like receptors and since these receptors and their signaling pathways are regarded as potential therapeutic targets, we have studied the expression of toll-like receptor (tlr) mRNAs in an animal model of AD (APP23 transgenic mice). Laser microdissection was used to harvest plaques, tissue surrounding plaques and plaque-free tissue from cortex of aged APP23 transgenic mice and age-matched controls. Real-time RT-PCR was employed to quantify expression levels of different tlr mRNAs in these tissues. This revealed a strong upregulation of tlr2, tlr4, tlr5, tlr7 and tlr9 mRNAs in plaque material compared to plaque-free tissue. In contrast, tlr3 was not significantly upregulated. Plaque-free tissue did not show an increased expression of any tlr mRNAs compared to age-matched control mice. Double-immunofluorescence for TLR2 and the microglial marker Iba1 was used to demonstrate localization of TLR2 on plaque-associated microglia. Taken together, these data show a strong upregulation of mRNAs encoding surface TLRs in plaque-associated brain tissue of aged APP23 transgenic mice. Since TLR-upregulation is restricted to plaques, modifying TLR-signaling may be a promising therapeutic strategy for plaque removal.