Next-Generation alzheImer'S Therapeutics

NCT06372587 | Recruiting

• 1 other identifier: 5502
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

Is this the right time to use next-generation approaches in Alzheimer's disease (AD)? In recent years, several large clinical trials testing treatments for AD have failed, putting the entire field on a reset. AD drug trials have almost exclusively sought to use antibodies targeted toward misfolded amyloid and tau proteins. Of note, although these approaches have failed, they were designed to cover both familial and sporadic forms of AD. On the other hand, the failure in developing new effective drugs is attributed to, but not limited to, the highly heterogeneous nature of AD with multiple underlying hypotheses and multifactorial pathology. The idea underlying this project is based on the assumption that learning and memory disorders can arise when the connections between neurons do not change appropriately in response to experience. Thus, by intervening on the core mechanisms of the cellular correlate of learning and memory, i.e., synaptic plasticity, the investigators expect to preserve some of the essential brain functions in AD. By overcoming the limits of traditional AD therapeutic approaches, the investigators will use genetically encoded engineered proteins (GEEPs), which the investigators developed and tested in vitro and in murine models, to control their activity in living human neurons boosting synaptic plasticity. Indeed, outstanding and relevant progress in understanding synaptic physiology empowers the possibility to prevent or limit brain disease like never before. The investigators designed GEEPs to address some of the leading causes of synaptic plasticity failures documented in AD. Thus, GEEPs will be tested in human induced pluripotent stem cells (hiPSCs)-derived living neurons obtained from reprogrammed peripheral tissues of participants with Alzheimer's diseases. hiPSCs will be obtained from fibroblast-derived from a skin biopsy of participants with AD and controls performed in local anesthesia using a 4 mm punch. The findings will provide the first preclinical study on the effect of genetically engineered proteins to control essential pathways implicated in synaptic plasticity on AD-related cognitive decline.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (4)

• To use genetically encoded engineered proteins to obtain an inducible control of their activity in living human neurons preventing dendritic spines loss

  The primary outcome measure will be the change in synaptic density (i.e., number of spines/micrometers) in living human neurons assessed using two-photon laser scanning microscopy.

  2 years

• To leverage genetically encoded engineered proteins to prevent alterations in the morphology of dendritic spines in living human neurons

  Here the measure will be the change in dendritic spine morphology (evaluating the subtype of spines, i.e., thin, stubby, mushroom, etc.) in living human neurons assessed using two-photon laser scanning microscopy.

  2 years

• To use genetically encoded engineered proteins to obtain an inducible control of their activity in living human neurons promoting functional synaptic plasticity

  The glutamatergic synaptic responses (i.e., AMPA receptor-mediated currents) will be measured in patch-clamp experiments in in living human neurons.

  2 years

• To use genetically encoded engineered proteins to obtain evaluate neuronal excitability in living human neurons

  Neuronal excitability (i.e., number of action potentials recorded with depolarizing current injection) will be measured in patch-clamp experiments in in living human neurons.

  2 years

Study Arms (2)

Alzheimer's disease patients

EXPERIMENTAL

To test engineered proteins in human neurons derived from skin biopsy from Alzheimer's disease patients

Other: genetically encoded engineered proteins

Neurotypical control patients

SHAM COMPARATOR

To test engineered proteins in human neurons derived from skin biopsy from neurotypical control patients

Other: genetically encoded engineered proteins

Interventions

genetically encoded engineered proteins OTHER

using genetically encoded engineered proteins to obtain an inducible control of their activity in living human neurons promoting synaptic plasticity and/or preventing dendritic spines loss

Alzheimer's disease patients; Neurotypical control patients

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Manifest clinical criteria for probable AD;
• Age between 18 and 80 years;
• Signed informed consent obtained;

You may not qualify if:

• Patients suffering from other neurological diseases;
• Patients with coagulation disorders or in treatment with anticoagulant drugs;
• Patients suffering from dermatological diseases and connective tissue diseases;
• Patients suffering from other organic, psychiatric diseases or laboratory abnormalities could preclude participation or invalidate the study results;
• Inability to give informed consent.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

Fondazione Policlinico Universitario A. Gemelli IRCCS

Roma, 00168, Italy

RECRUITING

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2024
• First Posted: April 18, 2024
• Study Start: December 19, 2023
• Primary Completion: December 30, 2024
• Study Completion (Estimated): February 28, 2027
• Last Updated: April 18, 2024

Record last verified: 2024-04

Locations

IT (1)