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EP-4735640-A1 - MICRORNAS AS DIAGNOSTIC BIOMARKERS AND THERAPEUTIC AGENTS FOR SMALL FIBER NEUROPATHY

EP4735640A1EP 4735640 A1EP4735640 A1EP 4735640A1EP-4735640-A1

Abstract

The present patent application describes miRNAs in the diagnosis of and as a therapy for small fiber neuropathy (SFN).

Inventors

  • ANDELIC, Mirna
  • LAURIA PINTER, GIUSEPPE
  • SALVI, Erika
  • MARCUZZO, Stefania

Assignees

  • Fondazione IRCCS Istituto Neurologico Carlo Besta

Dates

Publication Date
20260506
Application Date
20240626

Claims (5)

  1. 1. Use of miRNAs in the diagnosis of small fiber neuropathy (SFN) in a patient, wherein said miRNAs are one or both of:
  2. 2. Use of miRNAs in the diagnosis of small fiber neuropathy (SFN) in a patient according to the preceding claim, wherein one or both of said miRNAs are downregulated with reference to a healthy control.
  3. 3. Use of miRNAs in the diagnosis of small fiber neuropathy (SFN) in a patient according to the preceding claim 1 or 2, wherein the concentration of said miRNAs is measured in an isolated epidermis sample of said patient.
  4. 4. MiRNAs for medical use in the therapy of small fiber neuropathy (SFN) in a patient, wherein said miRNAs are one or both of:
  5. 5. Use of miRNAs for identifying therapeutic compounds for the therapy of small fiber neuropathy (SFN) in a patient, wherein said miRNAs are one or both of:

Description

"MicroRNAs as diagnostic biomarkers and therapeutic agents for small fiber neuropathy" DESCRIPTION Small Fiber Neuropathy (SEN) is a multifactorial condition which affects the Aƃ and C fibers. The typical clinical presentation comprises symmetrical, length-dependent, and autonomic sensory symptoms, often accompanied by chronic neuropathic pain, which significantly interfere with the patient's daily life1. Due to the complexity thereof and the lack of evidence on pathophysiological mechanisms, existing treatment strategies remain limited to symptoms, are inefficient and based on a trial and error approach. MicroRNAs (miRNAs) represent potential therapeutic targets in complex diseases, due to the pleiotropic nature thereof and the ability to regulate multiple molecular pathways and mediate intercellular communication. To date, preclinical and clinical studies have identified various miRNAs associated with axonal degeneration which influence axonal guidance signals and mediate local post-transcriptional and post-translational changes in the axonal microenvironment2'3; however, the role of each miRNA is strongly dependent on the microenvironment in which it is expressed, especially in multifactorial diseases. The publication of Huang Chen et al, "Micro RNAs in autoimmune liver diseases: from diagnosis to potential therapeutic targets", BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER, ER, vol. 130, (2020-08-09)) and international patent application WO 2016/144265 describe microRNA-26b-5p and microRNA-20a-5p. Abstract The inventors of the present patent application have surprisingly identified that specific miRNAs significantly correlate with the degree of degeneration of intraepidermal nerve fibers (IENF) under the pathophysiology of SFN. Brief description of the drawings Figure 1 shows the design of the study which led to the present invention. Figure 2 shows the morphological and molecular profiles in the skin biopsy of SFN patients. (A) Model of cutaneous innervation in the lower limb in a healthy subject (HC) and in an idiopathic SFN patient. The skin biopsies were immunostained with antibodies against phosphoglycolate Phosphatase 9.5 (PGP9.5) and acquired with a bright field microscope. Patients with SFN show a reduction in IENF. (B) The unsupervised heatmap shows the differential miRNA expression profiles between SFN and HC patients, represented as ACq values. Figure 3 shows that miR-26b-5p and miR-20a-5p miRNAs are downregulated in the epidermis of SFN patients. A) Box plot of miR- 26b-3p in the exploration and validation cohort showing downregulation in SFN with respect to HC. The comparisons were carried out by applying the Wilcoxon-Mann-Whitney test. The p-values adjusted for BH are shown in the graph; B) and C) Correlation of miR-26b-5p expression and with the delta IENFD values of the subjects recruited in exploration (B) and in the validation step (C). D) Correlation of miR26b-5p and miR20a-5p expression. E) Box plot of miR-20a-5p in the exploration and validation cohort showing downregulation in SEN with respect to HC. The comparisons are carried out by applying the Wilcoxon rank sum test. The unadjusted p-values are reported, as the miRNA did not survive the multiplex test correction analysis F) and G) Spearman's correlation of miR-20a-5p expression and delta IENFD values of subjects recruited in the exploration step (F) and validation step (G). Spearman's correlation coefficients and p-value values are shown in the graphs. H) The ROC analysis shows a significant discrimination capacity for SFN. Figure 4 shows the Pearson correlation showing the functional relationships of miR-20a-5p and miR-26b-5p miRNAs with the gene targets thereof. Figure 5 shows the in situ hybridization revealing that miR- 26b-5p is primarily expressed in the epidermis. Object of the invention In a first object, the present invention describes the use of miRNAs in the diagnosis of small fiber neuropathy (SFN). In a second object, the miRNAs of the invention are described for medical use in the therapy of small fiber neuropathy (SFN). In a third object, the use of the same miRNAs to identify compounds for the therapy of small fiber neuropathy is described. Detailed description of the invention In accordance with a first object, the present invention describes the use of miRNAs in the diagnosis of small fiber neuropathy (SFN). In particular, said miRNAs are: In a first aspect of the invention, small fiber neuropathy is diagnosed when one or both of the above-indicated two miRNAs are identified and downregulated. In a preferred aspect, small fiber neuropathy is diagnosed when miR-26b-5p is downregulated. In a more preferred aspect, small fiber neuropathy is diagnosed when at least miR-26b-5p, and possibly also miR-20a-5p is identified and downregulated. In particular, the concentration of said miRNAs is measured in an isolated sample represented by the epidermis of a patient suspected of suffering from said disease. More in particu