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NCT Number: NCT06372587

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.

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Key information

Conditions

Alzheimer Disease Brain Diseases Central Nervous System Diseases Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Fondazione Policlinico Universitario A. Gemelli IRCCS

Roma, 00168, Italy

Location status: Recruiting

Location contact

CRISTIAN RIPOLI

CONTACT

[email protected]

+390630154966

CRISTIAN RIPOLI

PRINCIPAL_INVESTIGATOR

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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

Primary outcomes

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

    Time frame: 2 years

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

    Time frame: 2 years

    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.

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

    Time frame: 2 years

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

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

    Time frame: 2 years

    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.

Sponsors and collaborators

Lead sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Other

Registry information

Official study title

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

Acronym: ENERGISE

Important dates

Study start
2023
Primary completion
2024
Study completion
2027
First posted
Apr 18, 2024
Registry last updated
Apr 18, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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