The Functional Consequences of the CTNS-deletion for the TRPV1-receptor in Cystinosis Patients

Universitaire Ziekenhuizen KU Leuven

Status and phase: Completed; Early Phase 1

Conditions: Cystinosis

Treatments: Other: Challenge agent: capsaicin; Other: Challenge agent: placebo; Device: Temperature sensitivity measurement with Advanced Thermal Stimulation; Device: Mechanical stimulation with Von Frey filaments

Study type: Interventional

Funder types: Other

Identifiers

NCT02533076

CCP13-3302-CYST

Details and patient eligibility

About

Cystinosis is a rare autosomal recessive disorder, characterized by the abnormal accumulation of cystine in the lysosomes. Cystinosis is mostly caused by mutations in the cystinosin gene (CTNS). The major mutation, which is present in almost 50% of the cystinosis patients, is a 57-kb deletion. This deletion removes the first 9 exons and a part of exon 10 of the CTNS gene. Exon 10 of the CTNS gene is a upstream 5' region that encodes for the CARKL gene and also for the first two noncoding exons of the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1) gene.

TRPV1 belongs to the transient receptor potential (TRP) superfamily of cation channels. TRPV1 is primarily expressed in sensory nerves and is activated by heating (>43°C) and a wide range of chemical stimuli. One of these chemical stimuli is capsaicin, the pungent ingredient in hot chilli peppers. The effect of binding of the exogenous ligand capsaicin with the TRPV1 receptor is well known to provoke the release of a number of bioactive substances including calcitonin gene-related peptide (CGRP). These substances, in turn, act on target cells in the surrounding tissue such as mast cells, immune cells and vascular smooth muscle cells. The resulting response is characterized by redness and warmth (secondary to vasodilatation), swelling (secondary to plasma extravasation) and allodynia (i.e. hypersensitivity to heat and touch secondary to alterations in the excitability of primary sensory neurons).

The present study wants to test the following hypotheses:

(i) The DBF response to topical applied capsaicin is decreased in cystinosis patients, compared to matched control subjects.

(ii) The skin sensitivity response after topical applied capsaicin is decreased in cystinosis patients, compared to matched control subjects.

(iii) The temperature sensitivity is decreased in cystinosis patients, compared to matched control subjects.

Enrollment: 50 patients

Sex: All

Ages: 8+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Only healthy controls: Subject is in good health, based on medical history and physical examination
• White (Caucasian) male or female subjects, aged > or = 8 year.
• Subject is capable and willing to give informed consent.

Exclusion criteria

• Any abnormality of the skin which may interfere with the study assessments.
• Excessive hair growth on the volar surface of the forearm.
• Excessive tanning (any exposure to sunlight or a tanning bed which would cause a sunburn reaction) throughout the study and incapable to cover the forearms for 24 hours prior to the study period.
• Subject using topical treatments on the forearm.
• History of sensitivity to the fruits of capsicum plants (e.g. chilli peppers).
• Any situation that can compromise the study, including a predictable lack of cooperation from the volunteer.
• Female subject is pregnant or breastfeeding.

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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50 participants in 2 patient groups

Cystinosis Patients

Other group

Description:

Cystinosis patients

Treatment:

Other: Challenge agent: placebo

Device: Mechanical stimulation with Von Frey filaments

Other: Challenge agent: capsaicin

Device: Temperature sensitivity measurement with Advanced Thermal Stimulation

Healthy volunteers

Other group

Description:

Healthy volunteers

Treatment:

Other: Challenge agent: placebo

Device: Mechanical stimulation with Von Frey filaments

Other: Challenge agent: capsaicin

Device: Temperature sensitivity measurement with Advanced Thermal Stimulation