Targeting zDHHC Enzymes to Counteract Alzheimer's Disease (zTARGETAD)

November 5, 2024 updated by: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Developing New Therapeutic Strategies to Counteract Synaptic and Cognitive Deficits in Alzheimer's Disease by Targeting zDHHC Enzymes

Alzheimer's disease (AD) is a growing problem for aging populations worldwide and represents one of the most demanding challenges for biomedical and pharmacological research. All therapeutic attempts made so far based on current knowledge have proven scarcely effective, probably because the molecular mechanisms underlying the onset and progression of the disease remain poorly understood. Neuroinflammation and alteration of brain insulin signaling have been demonstrated to induce an AD-like phenotype and accelerate neurodegeneration in the hippocampus and neocortex of experimental models of AD. An increasing number of studies have shown the role of palmitoylated proteins in the regulation of synaptic plasticity and neuronal functions. Aberrant protein S-palmitoylation plays a pivotal role in brain insulin resistance (BIR)-dependent cognitive decline. Moreover, protein S-palmitoylation can target immune signaling pathways (e.g., STING, NOD1/2, JAK-STAT, T cell receptor signaling) and modulate inflammatory responses. Accordingly, S-palmitoylation has been shown to regulate localization and activity of several enzymes involved in cytokine receptor-mediated signaling and neuroinflammation.

Unpublished results showed aberrant protein S-palmitoylation in hippocampal tissues of both AD post-mortem brains and mouse experimental models of AD. Preliminary data reveal a key role of palmitoyltransferase enzymes (zDHHCs), which catalyze the S-palmitoylation of substrate proteins, in the development of neurodegeneration and cognitive deficits, suggesting that counteracting aberrant protein S-palmitoylation can be a novel therapeutic strategy for AD. Nevertheless, to date, therapeutic approaches targeting protein S-palmitoylation have not yet been attempted in AD and there are currently no available drugs specifically targeting zDHHCs.

The goal of this study is to develop novel therapeutic strategies targeting zDHHC enzymes to counteract S-palmitoylation-dependent synaptic and cognitive deficits in AD. Additionally, new biotechnological approaches aimed at inhibiting zDHHCs and their targets will be set up to expand the range of tools capable of interfering with altered protein S-palmitoylation in AD. To this end, a combination of different in vitro and in vivo techniques (electrophysiology, molecular biology, behavioral tests, microscopy studies) will be used in both animal and human models of AD, concurrent with innovative biotechnological strategies.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

S-palmitoylation is a protein post-translational modification involving the attachment of a palmitic acid molecule to cysteine residues. This modification influences protein trafficking toward cellular membranes and is finely regulated by a class of enzymes named zinc finger DHHC domain containing (zDHHC) S-acyltransferases. Proteins critically involved in Alzheimer's disease (AD), such as APP and BACE1, are targets of S-palmitoylation. Higher levels of S-palmitoylated proteins have been found in both post-mortem brain samples and brain organoids derived from induced pluripotent stem cells (hiPSCs) obtained from AD patients. Notably, both neurons and brain organoids derived from human AD hiPSCs exhibited molecular, morphological, and functional alterations reminiscent of AD. Intranasal administration of the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly counteracted LTP and memory deficits in 3×Tg-AD mice, extended lifespan, and decreased Aß deposition. Higher levels of zDHHC7 and zDHHC21 were also found in the hippocampus of 3×Tg-AD mice. Silencing of zDHHC7 in the hippocampus of 3×Tg-AD mice prevented cognitive deficits and Aß accumulation, along with counteracting palmitoylation of proteins critically involved in neuronal function. This confirms that modulation of zDHHC activity may be exploited for AD treatment.

The idea underlying this project is based on the assumption that zDHHC enzymes and alteration of protein S-palmitoylation play a key role in the onset and progression of AD. Dysregulated zDHHC activity and aberrant S-palmitoylation of neuronal proteins critically involved in the regulation of brain plasticity, neuroinflammation, and Aß metabolism can affect synaptic function, protein homeostasis, and mitochondrial activity, leading to the development of neurodegeneration and cognitive deficits. A druggable target, zDHHC7, has been identified to test the efficacy of novel therapeutic approaches. This study aims to validate a new strategy targeting zDHHC enzymes in human experimental models of AD. Human models will allow an understanding of the translation potential of these approaches to human disease, to be validated in subsequent clinical trials whose implementation exceeds the duration of the present project.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
14

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Italy
      • Roma, Italy, 00168
        • Fondazione Policlinico Universitario A. Gemelli IRCCS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

The study population will be drawn from adults receiving care at Clinica della Memoria at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome, Italy

Description

Inclusion Criteria:

  • Clinical diagnosis of Alzheimer's Disease
  • 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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Alzheimer's disease patients
TO DETERMINE THE EXPRESSION OF zDHHC ENZYMES AND CHANGES OF PROTEIN S- PALMITOYLATION IN THE hiPSC-DERIVED NEURONS AND BRAIN ORGANOIDS OBTAINED FROM AD PATIENTS
Other: Palmitoylation Enzyme Expression Profiling Study
The expression of 23 zDHHC enzymes will be studied in human post-mortem hippocampi of AD patients and controls that have already been collected from UK brain biobanks. zDHHC enzymes will be analyzed at both mRNA and protein levels by Real Time PCR and Western blotting techniques, respectively

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Differences in zDHHC mRNA and protein expression levels between Alzheimer's disease (AD) models and control samples
Time Frame: Year 1
Levels of zDHHC enzymes will be quantified in AD models and controls to measure potential differences. Real-Time PCR will be used to assess mRNA expression, while Western blotting will measure protein levels, providing detailed profiles of zDHHC expression.
Year 1
Change in AD-associated deficits following zDHHC7 downregulation
Time Frame: Year 1
Measurable changes in AD-associated deficits will be assessed after zDHHC7 downregulation, with a focus on alterations in cellular or molecular markers relevant to Alzheimer's pathology.
Year 1

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Decrease in zDHHC enzyme expression in human experimental models of Alzheimer's disease
Time Frame: Year 2
Levels of zDHHC enzyme expression will be measured to assess the impact of biotechnological interventions aimed at reducing zDHHC activity, with the goal of improving synaptic function in Alzheimer's disease models.
Year 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Claudio Grassi, Fondazione Policlinico Universitario A. gemelli, IRCCS

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 11, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 31, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 31, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 31, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 5, 2024

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
November 7, 2024

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 7, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 5, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 6858 (CTEP)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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