The Crosstalk Between the Epigenome and Mitochondria in SCI
- Conditions
- Injury, Spinal Cord
- Interventions
- Other: Data collection
- Registration Number
- NCT06537427
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 50
- 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.
- Concomitant TBI;
- major axial or appendicular trauma;
- in case of sedation or intoxication making unreliable the neurological examination.
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Patients with an acute spinal cord injury/SCI Data collection Patients with an acute, traumatic SCI Control group/CTRL Data collection Healthy adults undergoing spinal anesthesia for lower limbs orthopaedic surgery.
- Primary Outcome Measures
Name Time Method Changes from baseline in the proteome profile in serum and CSF samples of SCI patients 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.
- Secondary Outcome Measures
Name Time Method Correlation of the proteome profile of SCI patient's with their clinical profile. 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.