The Crosstalk Between the Epigenome and Mitochondria in SCI (CEM-SCI)

August 26, 2024 updated by: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

The Crosstalk Between the Epigenome and Mitochondria as a Novel Therapeutic Target to Counteract Remote Degeneration Induced by Spinal Cord Injury

SCI is a devastating neurological disorder for which there are not yet restorative therapies. Thus, there is a need to explore new therapeutic strategies to treat SCI patients. To this end an appropriate selection and enrolment of suitable participants is crucial for the success of the therapeutic protocol. The selection of participants in SCI trials is often based on injury categories (e.g. sensorimotor complete vs incomplete), and neglects biological aspects (e.g. biomarkers released into the CSF and/or blood) that may be amenable to specific therapeutic interventions. On a biomolecular standpoint, it is renown that CNS lacks the ability to sustain a complete regenerative response after damage, which is partially due to the inability of damaged neurons to sustain an epigenetic pro-regenerative response.

The background of the present protocol study stands in pre-existing data which showed a crosstalk between the epigenome gene and mitochondria activated upon SCI. The clinical branch of this study protocol aims to investigate if and how targeted proteomic changes following the acute and chronic phase of SCI may play a role in determining the severity of neurologic impairments, as determined with ASIA gradingscale system, at the time of patients' presentation and in the conversion of ASIA grade during follow-up. A previous pilot study conducted by Wichmann et al. has shed light on proteomics after SCI enabling a profiling of inflammatory responses after spinal cord injury, timing of proteomics changes involved in inflammatory responses and differences between proteins title in CSF and peripheral blood. On the other hand, authors failed to prove a correlation between inflammatory proteins expression and timing of expression and neurologic status. However, previous studies proved that proteome expression variations SCI-induced can be detected into patients' CSF and serum and that biomarkers released into the CSF and/or blood may provide a plethora of information as to the patients' biological response to SCI. These samples may contain a unique fingerprint that can be used by scientists and clinicians to elucidate the mechanisms underlying irreversible central nervous system (CNS) degeneration following SCI. This could allow treatments to target specific molecules which promote CNS degeneration. Within this context the identification of prognostic biomarkers of SCI will help to assign SCI patients to the correct therapeutic treatment that, in association with canonical therapies, may synergistically act to improve functional recovery.

The aim of the present study is to investigate the presence of prognostic markers in SCI patient-derived serum and CSF with respect to a control group of healthy patients.

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

SCI is a devastating neurological disorder for which there are not yet restorative therapies. Thus, there is a need to explore new therapeutic strategies to treat SCI patients. To this end an appropriate selection and enrolment of suitable participants is crucial for the success of the therapeutic protocol [1,2]. The selection of participants in SCI trials is often based on injury categories (e.g. sensorimotor complete vs incomplete), and neglects biological aspects (e.g. biomarkers released into the CSF and/or blood) that may be amenable to specific therapeutic interventions. On a biomolecular standpoint, it is renown that CNS lacks the ability to sustain a complete regenerative response after damage, which is partially due to the inability of damaged neurons to sustain an epigenetic pro-regenerative response [3].

The background of the present protocol study stands in pre-existing data which showed a crosstalk between the epigenome gene and mitochondria activated upon SCI. In particular, previous experimental studies conducted on mice red nuclei (RN) demonstrated proteome changes at 7 days and 28 days post-SCI. Further pathway analysis pointed out to the epigenetic enzyme KDM5A as the upstream regulator of this phenotype. KDM5A is a H3K4me3 demethylase protein that plays a fundamental role in mitochondria biogenesis and function whose activity is regulated by mitochondrial metabolites [4,5]. Thereby, preliminary data suggest that downregulation of KDM5A activity and increased mitochondrial metabolism are involved in early neuronal response to remote damage. However, its role in brain pathologies such as in SCI remains still unexplored. Since it is well-established that structural and functional damages of mitochondria is an early event that contributed to neuronal cell death, hindering the possibility of axonal regeneration [6], the molecular background of the experimental branch of the present protocol study stands in the investigation of epigenetic regulation by KDM5A and mitochondrial function. The clinical branch of this study protocol aims to investigate if and how targeted proteomic changes following the acute and chronic phase of SCI may play a role in determining the severity of neurologic impairments, as determined with ASIA grading scale system, at the time of patients' presentation and in the conversion of ASIA grade during follow-up. A previous pilot study conducted by Wichmann et al. has shed light on proteomics after SCI enabling a profiling of inflammatory responses after spinal cord injury, timing of proteomics changes involved in inflammatory responses and differences between proteins title in CSF and peripheral blood. On the other hand, authors failed to prove a correlation between inflammatory proteins expression and timing of expression and neurologic status [7]. However, their paper proved that proteome expression variations SCI-induced can be detected into patients' CSF and serum and that biomarkers released into the CSF and/or blood may provide a plethora of information as to the patients' biological response to SCI. These samples may contain a unique fingerprint that can be used by scientists and clinicians to elucidate the mechanisms underlying irreversible central nervous system (CNS) degeneration following SCI. This could allow treatments to target specific molecules which promote CNS degeneration. Within this context the identification of prognostic biomarkers of SCI will help to assign SCI patients to the correct therapeutic treatment that, in association with canonical therapies, may synergistically act to improve functional recovery.

The aim of the present study is to investigate the presence of prognostic markers in SCI patient-derived serum and CSF with respect to a control group of healthy patients.

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.
50

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

SCI patients will receive at admission an intrathecal lumbar drain below L2, that will remain in place for 5 days. Intensive care clinical setting will allow MAP continuous monitoring, whose augmentation above 85 mmHg is a well-established standard of care in SCI patients. CSF drainage will be employed for 5 days maintaining intrathecal pressure at a mean value of 5.3 mmHg with respect to the CTRL group in which the intrathecal pressure had a mean value of 15 mmHg .Lumbar intrathecal insertion will have the dual clinical objective of 1) monitoring CSFP for evaluation of SCPP and 2) collecting CSF samples if needed in order to reduce CSFP and to keep SCPP above 85 mmHg. 3 ml of blood serum will be collected daily for exams.

Description

Inclusion Criteria:

  • ASIA impairment scale grade A, B, or C upon admission;
  • neurological level of injury between C1-L1;
  • patient older than 18 years;
  • ability to collect a valid, reliable baseline neurologic examination within 24h of injury.

Exclusion Criteria:

  • Concomitant TBI;
  • major axial or appendicular trauma;
  • in case of sedation or intoxication making unreliable the neurological examination.

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.
Control group/CTRL
Healthy adults undergoing spinal anesthesia for lower limbs orthopaedic surgery.
Other: Data collection

The data to be collected are the following:

  • Demographic data: gender and age of the patient at diagnosis of SCI;
  • Drug assumption and drug abuse at the time of SCI;
  • A complete assessment of patients' comorbidities;
  • Complete neurological examination on admission and at 6-8 months follow-up according to ASIA protocol;
  • Neuro-radiological data: spinal CT and MRI performed within 48 hours of admission to document the type, level and extent of the lesion of the spine and the spinal cord;
  • CSF pressure, chemical and biological markers;
  • Serum chemical and biological markers;
  • Data coming from surgical procedure: type of decompression, type of stabilization, extension of the stabilization, surgical approach, staged surgery, timing of surgery, length of surgery, eventual intraoperative, postoperative or long-term surgical-related complications [13];
  • Data on hospitalization: length of stay, hospital-acquired infections, any adverse event occurred during hospitalisation.
Patients with an acute spinal cord injury/SCI
Patients with an acute, traumatic SCI
Other: Data collection

The data to be collected are the following:

  • Demographic data: gender and age of the patient at diagnosis of SCI;
  • Drug assumption and drug abuse at the time of SCI;
  • A complete assessment of patients' comorbidities;
  • Complete neurological examination on admission and at 6-8 months follow-up according to ASIA protocol;
  • Neuro-radiological data: spinal CT and MRI performed within 48 hours of admission to document the type, level and extent of the lesion of the spine and the spinal cord;
  • CSF pressure, chemical and biological markers;
  • Serum chemical and biological markers;
  • Data coming from surgical procedure: type of decompression, type of stabilization, extension of the stabilization, surgical approach, staged surgery, timing of surgery, length of surgery, eventual intraoperative, postoperative or long-term surgical-related complications [13];
  • Data on hospitalization: length of stay, hospital-acquired infections, any adverse event occurred during hospitalisation.

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
Changes from baseline in the proteome profile in serum and CSF samples of SCI patients
Time Frame: Months 1-24
To evaluate molecular variations in CSF and/or serum SCI-derived patients, both in acute and chronic phase after injury, patients with acute SCI will be enrolled and they will be followed until the chronic stage. CSF and serum biomarkers of SCI-group will be compared to those of the control group (non-SCI group) undergoing spinal anesthesia for lower limbs orthopedic surgery, in which few milliliters of CSF and serum will be collected.
Months 1-24

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
Correlation of the proteome profile of SCI patient's with their clinical profile.
Time Frame: Months 1-24

Once identified key biomarkers in the CSF and/or the serum of SCI patients, data on proteome profile will be combined with clinical data. This correlation will allow to gain new insights into molecular aspects of the disease and ultimately to draw a complete overview of each single patient for designing personalized treatments.

- Comparative proteomic and metabolic analysis of data on mice samples with data on patients' samples. This analysis aims at addressing specific elements of the translational response which could represent novel prognostic biomarkers in future experimental studies.
Months 1-24

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

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.
August 30, 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 30, 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 30, 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).
August 1, 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.
August 1, 2024

First Posted (Actual)

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.
August 5, 2024

Study Record Updates

Last Update Posted (Actual)

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.
August 28, 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.
August 26, 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.
  • 6884 (CTEP)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

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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