Next-Generation alzheImer'S Therapeutics (ENERGISE)

Leveraging Genetically Encoded engiNeered protEins foR Next-Generation alzheImer'S Therapeutics

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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Other: genetically encoded engineered proteins

• Study Type: Interventional
• Enrollment (Estimated): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Roma, Italy, 00168
    • Recruiting
    • Fondazione Policlinico Universitario A. Gemelli IRCCS
    • Contact: CRISTIAN RIPOLI; Phone Number: +390630154966; Email: cristian.ripoli@policlinicogemelli.it
    • Principal Investigator: CRISTIAN RIPOLI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

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

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alzheimer's disease patients; To test engineered proteins in human neurons derived from skin biopsy from Alzheimer's disease patients	Other: genetically encoded engineered proteins; 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
Sham Comparator: Neurotypical control patients; To test engineered proteins in human neurons derived from skin biopsy from neurotypical control patients	Other: genetically encoded engineered proteins; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2023
• Primary Completion (Estimated): December 30, 2024
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: April 4, 2024
• First Submitted That Met QC Criteria: April 17, 2024
• First Posted (Actual): April 18, 2024

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: 5502

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No