Dose reductions may be necessary in case of toxicities or overdoses, which will be monitored at each visit; this request will be made by online CRF through extradispensation or at drug dispensation. follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale – Revised (ALSFRS-R) at baseline and at treatment end. Secondary (S)-(-)-5-Fluorowillardiine aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and (S)-(-)-5-Fluorowillardiine respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources. Ethics and dissemination The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals. Trial registration number EUDRACT 2017-004459-21;”type”:”clinical-trial”,”attrs”:”text”:”NCT03693781″,”term_id”:”NCT03693781″NCT03693781; Pre-results. and genes, respectively). The protein quality control (PQC) system has a crucial role in dealing with the above-mentioned aggregates, in particular with TDP-43 proteinopathy, which is a hallmark of more than 95% of non-mutated ALS cases.7 The PQC system is based on chaperones and degradative pathways, which include the ubiquitinCproteasome systems (UPSs), the autophagy and the endoplasmic reticulum-associated degradation (ERAD). Disruption of autophagy in the brain results in inclusion bodies with ubiquitinated proteins and early neuronal death.8 In ALS, several gene products have links with protein degradation pathways as (S)-(-)-5-Fluorowillardiine they contribute to recruitment of ubiquitinated proteins to the autophagosome: UBQLN2, VCP, OPTN and SQSTM1/p62 function as adapters that deliver polyubiquitinated proteins to the proteasome or the autophagosome for degradation. OPTN serves as a receptor for autophagy, and VCP has a role in ERAD and sorting endosomal proteins, in autophagy and UPS. Protein aggregation and autophagy inhibition may also induce clearance of pathological TDP-43 via secretion of exosomes, small extracellular vesicles, which may play a key role in TDP-43 aggregate disposal and/or the propagation of TDP-43 proteinopathy.8 Autophagy is also required for the removal of aberrant stress granules (SGs),9 10 which have been involved in ALS pathology. Finally, in ALS models and patients, activation of inflammasome complexes in both astrocytes and microglia is critically involved in neuroinflammation.11 There is a crosstalk between autophagy and neuroinflammation: autophagy downregulates inflammasome activity, which is activated in response to cellular inclusions formation,12 and TBK1, OPTN and SQSTM1/p62 gene products converge on autophagy and neuroinflammation, suggesting that compounds addressing both pathways may be promising for ALS treatment. Preliminary data With our study, we aim to assess the role of colchicine as a therapeutic agent for ALS. Colchicine is a Food and Drug Administration-approved drug that we identified in a high-throughput screening performed by using the promoter region of the gene encoding for a specific chaperone, the heat shock protein B8 (HSPB8).13 HSPB8 acts in conjunction with the co-chaperone Bcl2-associated athanogene 3 (BAG3), and the HSPB8CBAG3CHSP70 complex enhances the intracellular clearance of all motor neuron disease-associated misfolded proteins tested so far.14C16 The role of HSPB8 in the stress response in ALS has been elucidated in animal models and humans, indicating that HSPB8 is upregulated in the spinal cord of patients with ALS and in surviving MNs of ALS mice.15 17 In mutant models of ALS, HSPB8 recognises and promotes the removal of the misfolded mutant SOD1 and TDP-43 fragments, as well as aggregating dipeptides produced in C9ORF72-related neurodegenerative diseases, by Mouse monoclonal to CD4.CD4, also known as T4, is a 55 kD single chain transmembrane glycoprotein and belongs to immunoglobulin superfamily. CD4 is found on most thymocytes, a subset of T cells and at low level on monocytes/macrophages promoting their autophagic removal from MNs.18C20 As for.