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Report for SNP rs244072

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There is one clinical trial.

Clinical Trials


1 Interventional Not Pharmacological Study to Investigate the Role of ADA in Multiple Sclerosis PatientsTreated With an Immune-Reconstitution Therapy (2-CdA)

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), which is highly heterogeneous in terms of clinical symptoms, MS subtypes and treatment response. In each patient with MS, inflammatory, neurodegenerative and reparative processes are intermingled in different proportions, making the disease course unpredictable and the treatment approach challenging. Although MS etiology is still unclear, many studies have demonstrated that T and B cells are crucial cellular determinants of MS pathophysiological processes. Auto-reactive T lymphocytes have been also implicated in excitotoxic synaptopathy, an early hallmark of MS recently emerged to link inflammation and neurodegeneration in a complex and inter-regulated circuit. In addition, several reports published in the last few years show the presence of a link between metabolism and immune responses. Indeed, it is now clear that cell metabolism is able to control T cell survival, growth, activation and differentiation. It has been reported that distinct metabolic pathways are able to support specific T cell activities suggesting that the delicate balance among glycolysis, fatty acid oxidation (FAO) and mitochondrial respiration drives specific effector (Tconv) and regulatory T cell (Treg) differentiation and functions. The individual response to treatment varies widely and their use may be burdened by side effects and major adverse events. An explanation of the clinical and pharmacological individual variability can be sought in the pathological heterogeneity and in different genetic, immunological and metabolomics profiles. With this perspective, the lack of a single predictive or diagnostic test remains a great obstacle in the management of MS at most stages and in the choice of the therapy. Consequently, the availability of biomarkers that reliably capture the different aspects of the disease could be extremely useful.

NCT04121065 Relapsing Multiple Sclerosis Procedure: Blood withdrawal
MeSH: Multiple Sclerosis Sclerosis

In line with this, it has been recently identified an ADA genetic variant (rs244072, non-risk/risk allele: T/C) linked to brain inflammation and MS disease severity (article in preparation), by screening more than 50 SNPs in MS-related genes of 514 MS patients and looking for association with clinical and biochemical parameters.

The primary objective of the study is to evaluate the influence of the ADA SNP rs244072 (non-risk/risk allele: T/C) on lymphopenia induced by Cladribine (2-CdA) in real world setting in patients with relapsing multiple sclerosis (RMS).

Primary Outcomes

Description: Assessment of lymphopenia induced by oral Cladribine (2-CdA) treatment comparing the change in the number of pre-post treatment lymphocytes after oral Cladribine treatment at month 12 (compared with month 0), between two groups (associated with the genetic polymorphism of ADA). Changein the number of lymphocytes measured as number of cells per cubic millimeter (mm3), grades of lymphopenia will be assigned according to the common terminology criteria for adverse events: grade 1 (mild lymphopenia) ALC < lower limit of normal to 800/mm3, grade 2 (moderate lymphopenia) ALC < 800-500/mm3, and grade 3 (severe lymphopenia) ALC < 500-200/mm3.

Measure: 1. Evaluation of lymphopenia, measured by the number of lymphocytes per cubic millimeter (mm3) and associated to ADA polymorphism

Time: Month 0 enrollment compared to month 12; RMS patients

Secondary Outcomes

Description: To investigate the association between SNPs, gene expression and clinical parameters (Expanded Disability Status Score (EDSS), Kurtzke Functional System Score (KFS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modality Test (SDMT), Annualized Relapses Rate (ARR) and the Percentage of "No Evidence of Disease acitivity (NEDA)) at months 0, 6, 12 and 24. Statistical correlations of minor allele presence of each screened SNP with gene expression and/or the clinical parameters. The significance level is established at p<0.05.

Measure: Genotyping of SNPs and gene expression for correlation analysis with disease effectiveness of Cladribine treatment

Time: months 0, 6, 12 and 24

Description: Evaluation of the ratio of DCK and 5'NT genes expression at months 0, 6, 12 and 24 through the mRNA quantification by ddPCR measuring the number of copies / microliter.

Measure: Evaluation of DCK and 5'NT genes expression

Time: months 0, 6, 12 and 24

Description: Correlation of EBV genotypes with responder or non-responder conditions evaluated by clinical parameters (Expanded Disability Status Score (EDSS), Kurtzke Functional System Score (KFS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modality Test (SDMT), Annualized Relapses Rate (ARR) and the Percentage of "No Evidence of Disease acitivity (NEDA)). Statistical correlations of specific EBV genotype with the clinical parameters. The significance level is established at p<0.05.

Measure: Statistical correlation of EBV genotypes with responder or non-responder conditions

Time: month 0

Description: Assessment of cellular content of DCK and cytosolic forms of NT5 and the activity of CD4+ enzymes at months 0, 6, 12 and 24, the protein quantification will be obtained by flow cytometry measuring the relative levels of MFI (mean fluorescence intensity) values. The CD4+ enzymes will be evaluated with the luminescence-based ADP detection, measuring the ADP, based on the detection by luminometer of ATP synthesized during a luciferase/luciferin reaction and the use of an ATP-to-ADP conversion curve.

Measure: Quantification of DCK and cytosolic forms of NT5 and evaluation of CD4+ enzyme activity

Time: months 0, 6, 12 and 24

Description: Analysis of molecular and biochemical parameters (miRNA, mRNA and circulating exosomes), performed comparing patients responder and non-responder. miRNA and mRNA detection will be assessed by qRT-PCR, measuring the relative quantification by using the 2^(-ddCt) method.

Measure: Genes expression

Time: months 0, 6, 12 and 24

Description: Measure of T cell glycolytic (Extracellular Acidification Rate, ECAR) and mitochondrial respiration (Measurement of Oxygen Consumption Rate, OCR) at months 0, 6, 12 and 24.

Measure: Measure of T cell extracellular acidification rate and mitochondrial respiration

Time: months 0, 6, 12 and 24

Description: Characterize the metabolic profile induced by Cladribine of responder/non-responder or to presence/absence of lymphopenia at months 0, 6, 12 and 24, performing a multivariate statistical analysis. The significance level is established at p<0.05.

Measure: Measure of metabolic profile

Time: months 0, 6, 12 and 24

Description: Establish the blood levels of B-Cell Activating Factor (BAFF) and Proliferating-Inducing Ligand (APRIL), which have a regulatory role in B cells biology, at months 0, 6, 12 and 24. The proteins quantification will be measured in picograms/ milliliter.

Measure: Blood levels of B-Cell Activating Factor (BAFF) and Proliferating-Inducing Ligand

Time: months 0, 6, 12 and 24

Description: Assess whether Cladribine treatment affects effector and regulatory NK, T and B cell subsets at months 0, 6, 12 and 24. The composition of cell subpopulation will be measured by the levels of MFI.

Measure: Assessment of MFI (Mean Fluorescence Intensity) levels in NK, T and B cell subsets

Time: months 0, 6, 12 and 24

Description: Assess a possible neuroprotective action of Cladribine in counteracting synaptic excitotoxicity by modulation of T-cell-released cytokines at month 12. The variable assessed will be the spontaneous corticostriatal excitatory currents (sEPSCs) and the spontaneous corticostriatal inhibitory currents (sEPSCs).

Measure: Assessment of synaptic alterations induced by T-cell-released cytokines

Time: month 12

Description: Assessment of disease progression after oral Cladribine treatment by means of Expanded Disability Status Scale (EDSS)/Kurtzke at month 6, 12 and 24 compared to month 0. The variable assessed will be the change in Expanded Disability Status Scale (EDSS) compared to month 0.The EDSS is widely used in clinical trials to quantify disability and monitor the changes in the level of disability over time. The EDSS scale ranges from 0 to 10.

Measure: Assessment of disease progression measuring the change in the Expanded Disability Status Scale (EDSS)/Kurtzke

Time: months 0, 6, 12 and 24

Description: Assessment of Functional System (KFS) at month 6, 12 and 24 compared to month 0. KFSS is half of a 2-part system evaluating the type and severity of neurologic impairment in MS and is based on neurologic examination of independent functions. The KFSS rates 7 functional systems (plus "other"), including pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral (or mental), and other. Each of the FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6.

Measure: Assessment of Kurtzke Functional System Score (KFS) evaluating the type and severity of neurologic impairment

Time: months 0, 6, 12 and 24

Description: Assessment of 9-Hole Peg Test (9HPT) at month 6, 12 and 24 compared to month 0. The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. Both the dominant and non-dominant hands are tested twice. Two consecutive trials of the dominant hand, followed immediately by two consecutive trials of the non-dominant hand will be executed.

Measure: Assessment of upper extremity (arm and hand) function performing the 9-Hole Peg Test (9HPT)

Time: months 0, 6, 12 and 24

Description: Assessment of Timed 25-Foot Walk (T25FW) at month 6, 12 and 24 compared to month 0. The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task. The average score of two 25-Foot Timed Walk trials will be measured.

Measure: Assessment of of lower extremity function, performing the Timed 25-Foot Walk test (T25FW)

Time: months 0, 6, 12 and 24

Description: Assessment of Symbol Digit Modality Test (SDMT) at month 6, 12 and 24 compared to month 0. The SDMT is designed to measure divided attention and information processing speed. The examinee has 90 seconds to pair specific numbers with given geometric figures by using a reference key. The SDMT score is the sum of the correct substitutions within the 90 second interval.

Measure: Assessment of attention and information processing speed, performing the Symbol Digit Modality Test (SDMT)

Time: months 0, 6, 12 and 24

Description: Evaluation of Annualized Relapse Rate (ARR) at month 6, 12 and 24 compared to month 0. Change in Annualized Relapse Rate (ARR) measured by the total number of relapses divided by the total person-time at risk of relapse.

Measure: Evaluation of the change in Annualized Relapse Rate (ARR).

Time: months 0, 6, 12 and 24

Description: Evaluation of the Percentage of "No Evidence of Disease Activity" (NEDA) at month 6, 12 and 24 compared to month 0. No Evidence of Disease Activity" (NEDA) will be measured as number of NEDA subjects / total number of recruited patients *100

Measure: Evaluation of Disease Activity measuring the Percentage of "No Evidence of Disease Activity" (NEDA) .

Time: months 0, 6, 12 and 24

Description: Collection of safety and tolerability data on RMS patients treated with Cladribine. Number of patients with Adverse

Measure: Collection of safety and tolerability data: number of patients with treatment related adverse events classified by MedDRA

Time: months 0, 6, 12 and 24


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