Autologous Serum-derived EV for Venous Trophic Lesions Not Responsive to Conventional Treatments (SER-VES-HEAL)

University of Turin

Status: Enrolling

Conditions: Ulcer Venous

Treatments: Other: Autologous extracellular vesicles from serum

Study type: Interventional

Funder types: Other

Identifiers

NCT04652531

CS2/1095/0090491

Details and patient eligibility

About

Venous ulcers are defined by the presence of open lesions which represent the final stage of chronic venous disease or post-thrombotic syndrome. The risk factors for the development of venous ulcers include age, obesity, female sex, trauma, immobility, factor V mutation, thrombosis, venous agenesis.

Recommendation by the current guidelines includes compression and advanced dressing. However, in several cases, they fail to change patients' outcome. The aim of this study is to identify an alternative therapy to treat venous trophic lesions not responding to traditional therapeutic approaches using extracellular vesicles obtained from autologous serum.

Full description

In recent years, several in vitro and in vivo studies have provided been the beneficial effects of stem cells for tissue regeneration. Moreover, several randomized trials are ongoing and the interim results seem to give promising results and indicate their safety. Alternative approaches have recently been proposed, such as the injection of platelet preparation or the use of acellular amniotic membranes or extracellular vesicles (EV). EV act as cell-to-cell paracrine or endocrine-like communication mechanisms. The therapeutic potential of EV depends on the transfer of their cargo(proteins, RNAs, DNA, lipids, etc) to target cells (1). In the last decades, several pre-clinical studies have demonstrated safety. A pilot study was recently published on the use of EV as an effective treatment for retinal damage. At the University of Turin using a mouse model of ischemia/ reperfusion of the lower limb it was demonstrated that the intramuscular administration of EV obtained from the serum of healthy donors was associated with a higher density of local capillaries and an increase in laser Doppler signal compared to controls (2). A simple in vitro functional potency assay was developed, which allowed predicting EV therapeutic efficacy in vivo. The best response was obtained by intravenous administration immediately after surgical ligation and intramuscular in the next two days (T1 and T2). Through the Laser Doppler study, distal perfusion was evaluated after 7 days, which showed a clear improvement and protection of muscle damage. A more recent study has shown that even subjects with high cardiovascular risk (diabetic, obese, diabetic/obese and with arterial disease of the lower limbs) can benefit from the use of autologous EV (3).

The pilot study will involve the enrollment of 10 patients with bilateral venous ulcer refractory to conventional treatment for more than 6 months, recruited at the Vascular Ulcer Clinic of University Vascular Surgery. At the time of recruitment, venous Eco Doppler will be performed to evaluate the superficial and deep venous and arterial system to exclude possible "mixed" etiologies. A blood sample will then recovered for EV isolation in collaboration with the Blood Bank of the City of Health and Science of Turin. The characteristics of the ulcer will be entered in the database: dimensions (photo), margins, bottom and a swab for microbiology will be performed. Patients whose swab will be positive will be excluded.

EV will be analysed for their biological activity using the potency assay and will be used only if found to be effective (potency test). Subsequently, peri-wound injection of EV will be performed in a sterile environment. Sterile gauze and an elastic-compression bandage will be applied. As an internal control, the contralateral ulcer will be treated with a standard dressing and an elastic compression bandage. The patients will be evaluated on an outpatient basis on day 3 and then weekly. The results of treated patients will be collected in a dedicated database.

Enrollment: 10 estimated patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria: Adults and conscious patients

Exclusion Criteria:

• :> 85 years, diabetics, autoimmune diseases, neoplastic, arterial disease of the lower limbs.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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10 participants in 2 patient groups

Treatment

Experimental group

Description:

In the treatment arm, the lesion will be treated with EV for 3 weeks once a week

Treatment:

Other: Autologous extracellular vesicles from serum

Internal control

Sham Comparator group

Description:

The contralateral ulcer will be treated with a standard dressing and an elastic-compression bandage for 3 weeks.

Treatment:

Other: Autologous extracellular vesicles from serum