Effect of Microvesicles and Exosomes Therapy on β-cell Mass in Type I Diabetes Mellitus (T1DM)

Study Overview
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Brief Summary
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Type 1 diabetes mellitus is strictly autoimmune mediated disease destructing the islets β-cell of the pancreas. Mesenchymal stem cells and its microvesicles are reported as an anti-inflammatory agents. We hypothesis that intravenous infusion of cell free umbilical cord-blood derived MSC microvesicles may reduce the inflammatory state and hence improve the β-cell mass as well as the glycemic control of the patients of T1DM.

Detailed Description
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Twenty T1DM patients, age between 18-60 years with reduction of C-peptide chain more than 50%, C-peptide of more than 0.8 ng/mL at Screening and requiring insulin ≥0.4 IU per kg per day. Twenty T1DM patients of the same entry selection criteria will be subjected to all steps except the microvesicles administration as a control group. Study follow up period: Three months Gender: Both males and females are included Entry selection criteria include: UACR less than 300, BUN between 10-20 mg/dl, serum creatinin between 0.6-1.4 mg/dl and normal liver enzymes, normal serum bilirubin, normal serum albumin and coagulation profile). C-peptide of more than 0.8 ng/mL at Screening. BMI 20-40 kgm/m2 - Exclusion criteria: Other autoimmune diseases. Pregnancy. Previous treatment with stem cells. All patients and controls will be investigated for HBV, HCV & HIV by PCR test before enrollment in the study and positivity for any of these parameters means exclusion of this patient from the study. - The primary end point will be the end of three months follow up. At day (0):All patients and controls will be subjected to the following investigations: Liver functions tests, kidney functions tests, HbA1c, glucose tolerance test (GTT), fasting and 2 hrs.post prandial blood glucose levels, C-peptide chain level and calculated total daily insulin dose. After three months (at the end of the study) the same investigations will be repeated. Two intravenous infusions of cell free cord-blood derived mesenchymal stem cells [CB-MSC] microvesicles: - The first dose will be purified exosomes, ranging between 40-180 nm, in a dose of the supernatant produced from (1.22-1.51) × 10 (6)/kg/IV. (Characterization of exosomes:CD63, CD9, Alix, TSG 101, HSP 70). - The second dose, after 7 days, will be the microvesicles, ranging between 180-1000 nm, in a dose of the supernatant produced from (1.22-1.51) × 10 (6)/kg/IV. (Characterization of microvesicles: (Annexin V, Flotillin-2, selectin,integrin, CD40 metalloproteinase).

Official Title
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Phase 1 Study of The Effect of Cell-Free Cord Blood Derived Microvesicles On β-cell Mass in Type 1 Diabetes Mellitus (T1DM) Patients

Conditions
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Diabetes Mellitus Type 1

Intervention / Treatment
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* Biological: MSC exosomes.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: UACR less than 300, BUN between 10-20 mg/dl, serum creatinin between 0.6-1.4 mg/dl and normal liver enzymes, normal serum bilirubin, normal serum albumin and coagulation profile). C-peptide more than 0.8 ng/mL at Screening. BMI 20-40 kgm/m2. Exclusion Criteria: Other autoimmune diseases. Pregnancy. Previous treatment with stem cells. All patients and controls will be investigated for HBV, HCV & HIV by PCR test before enrollment in the study and positivity for any of these parameters means exclusion of this patient from the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exosomes<br>The exosomes have exosome-associated proteins such as the tetraspanin proteins, CD9 and CD81, Alix, Tsg101, and RNA that consists primarily of short RNAs of less than 300 nm. Some of these RNAs are microRNAs that are predominantly pre-microRNAs..Additionally, CB-SC displayed very low immunogenicity as indicated by expression of a very low level of major histocompatibility complex (MHC) antigens and failure to stimulate the proliferation of allogeneic lymphocytes. | Biological: MSC exosomes.<br>* Exosomes: (Size) 40-100 nm, (markers) CD63, CD9, Alix, TSG 101, HSP 70 Microvesicles: (Size) 100-1000 nm, (markers) Annexin V, Flotillin-2, selectin, integrin, CD40 metalloproteinase<br>* Other names: Microvesicles;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total daily insulin dose | All T1DM patients with identified pre-study insulin dose and exosomes and microvesicles will be given then weekly follow up of the total daily insulin dose will be measured. After 3 months We calculate the total daily dose of insulin that maintain the RBS levels between 120-160 mg/dl at any point of the evaluation period. | Three months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pancreatic β-cell Mass | Pancreatic β-cell Mass levels will be assessed before and after the 3 months study period of time. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus Type 1, Microvesicles, Exosomes, Cord Blood, Mesenchymal Stem Cells