spliceosomal-peptide-p140 and Disease-Models--Animal

Nowadays, pharmacologic treatments of autoinflammatory diseases are largely palliative rather than curative. Most of them result in non-specific immunosuppression, which can be associated with broad disruption of natural and induced immunity with significant and sometimes serious unwanted injuries. Among the novel strategies that are under development, tools that modulate the immune system to restore normal tolerance mechanisms are central. In these approaches, peptide therapeutics constitute a class of agents that display many physicochemical advantages. Within this class of potent drugs, the phosphopeptide P140 is very promising for treating patients with lupus, and likely also patients with other chronic inflammatory diseases. We discovered that P140 targets autophagy, a finely orchestrated catabolic process, involved in the regulation of inflammation and in the biology of immune cells. In vitro, P140 acts directly on a particular form of autophagy called chaperone-mediated autophagy, which seems to be hyperactivated in certain subsets of lymphocytes in lupus and in other autoinflammatory settings. In lupus, the "correcting" effect of P140 on autophagy results in a weaker signaling of autoreactive T cells, leading to a significant improvement of pathophysiological status of treated mice. These findings also demonstrated ex vivo in human cells, open novel avenues of therapeutic intervention in pathological conditions, in which specific and not general targeting is highly pursued in the context of the new action plans for personalized medicines.

Topics: Animals; Antibodies, Monoclonal; Antigens, CD; Autophagy; B-Cell Activating Factor; Clinical Trials as Topic; Disease Models, Animal; Gene Expression Regulation; Humans; Immune Tolerance; Immunologic Factors; Lupus Erythematosus, Systemic; Lymphocyte Subsets; Mice; Molecular Targeted Therapy; Peptide Fragments; Precision Medicine

Over the last decade there has been a rapid expansion in the use of peptides as drugs. Nowadays, they are being used therapeutically in such diverse areas as endocrinology, neurology, haematology and some types of allergies. In the field of autoimmunity, a few candidates have emerged. Thus, in the pipeline of novel strategies designed to treat patients with systemic lupus erythematosus, the 21-mer peptide P140/Lupuzor raises hopes for the generation of an efficient, specific and safe treatment. This phosphopeptide has successfully completed a phase IIb clinical trial and will enter into a multi-centre, double-blind, placebo-controlled phase III clinical trial. The phase IIb trial showed that after three months of therapy (three subcutaneous injections of 200 µg peptide/patient in addition to standard of care), Lupuzor improved Systemic Lupus Erythematosus Disease Activity Index score of lupus patients under active treatment by 67.6% versus 41.5% in the placebo group (p < 0.025). After three additional months of follow-up, the improvement rate was 84.2% versus 45.8% (p < 0.025). The side-effect profile was unproblematic and the drug was well tolerated as evidenced by a very low drop-out rate. P140 does not behave as an immunosuppressant, it acts primarily as a fine immunomodulator of autoreactive CD4(+) T cells. Its underlying mechanism of action involves autophagy, a cellular process that implicates lysosomal-dependent recycling of intracellular components and controls the pool of major histocompatibility complex class II-displayed peptides that is presented to CD4(+) T cells.

Topics: Animals; Autoimmunity; CD4-Positive T-Lymphocytes; Clinical Trials, Phase II as Topic; Disease Models, Animal; Humans; Immunologic Factors; Lupus Erythematosus, Systemic; Mice; Peptide Fragments

Autoimmune diseases are illnesses that occur when the body's tissues are attacked by its own immune system. This review describes the path between the discovery of a synthetic peptide able to delay the development of lupus in mouse models that spontaneously develop lupus-like disease, and the results of multicenter phase IIb clinical trials including lupus patients. If the 2nd phase IIb and phase III results confirm the 1st phase IIb clinical trial, this therapeutic peptide could have a major impact in the treatment of patients with lupus, an autoimmune disease affecting at least five million patients in the world, in majority young women for whom there is no specific treatment today.

Topics: Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Models, Animal; Humans; Lupus Erythematosus, Systemic; Mice; Peptide Fragments

It is well recognised that the historical timeline required for developing a drug, beginning with target identification and validation, is long and often tedious. It requires a large set of competences in various areas of molecular and cellular biology, chemistry, pharmacology, imaging, and model animal experimentation. Once the active molecule appears to be ready for human testing in controlled clinical trials, then the question arises of how to formulate it to render it stable, adequately packaged, according to the chosen route of administration, and bioavailable to reach its target in the affected organs. Historically, excipients have been considered inert and devoid of medicinal effect or influence. In fact, excipients are seldom neutral and some of them have been found to play a significant role, for example by initiating or participating in chemical and physical interactions with the active substance, leading in certain cases to compromise its therapeutic activity. It is difficult today to appreciate the number of potential drugs that have been discarded as a result of limited efficacy due to inappropriate excipients. This matter is presented here, with the peptide P140 (Lupuzor™) as example. Two formulations of P140, differing in the excipients used (mannitol or trehalose), have been evaluated in patients affected by systemic lupus erythematosus in two successive phase IIb clinical trials. P140 was shown to reduce excessive autophagy activity discovered in some lupus immune cell subsets. One of the two excipients, namely trehalose, has been claimed to exert an intrinsic stimulating activity on autophagy process, which was found therefore to counteract the beneficial peptide effects.

Topics: Animals; Autophagy; Disease Models, Animal; Excipients; Humans; Lupus Erythematosus, Systemic; Mice; Peptide Fragments; Trehalose

Sjögren's syndrome is a multifactorial systemic autoimmune disorder characterized by lymphocytic infiltrates in exocrine organs. Patients present with sicca symptoms, such as extensive dry eyes and dry mouth, and parotid enlargement. Other serious complications include profound fatigue, chronic pain, major organ involvement, neuropathies and lymphomas. Current treatments only focus on relieving symptoms and do not target the origin of the disease, which is largely unknown. The question we addressed here was whether some defects exist in autophagy processes in Sjögren's syndrome and if they can be corrected or minimized using an appropriate mechanism-driven treatment targeting this central survival pathway. Using a recognized murine model of secondary Sjögren's syndrome, we identified molecular alterations of autophagy occurring in the salivary glands of MRL/lpr mice, and discovered that opposite (up- or down-regulated) autophagy events can arise in distinct organs of the same mouse strain, here in lymphoid organs and salivary glands. We showed further that the therapeutic P140 peptide, known to directly act on chaperone-mediated autophagy, rescued MRL/lpr mice from cellular infiltration and autophagy defects occurring in salivary glands. Our findings provide a proof-of-concept that targeting autophagy might represent a promising therapeutic strategy for treating patients with Sjögren's syndrome.

Topics: Animals; Autophagy; Cells, Cultured; Disease Models, Animal; Female; Humans; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Peptide Fragments; Salivary Glands; Sjogren's Syndrome

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nerves evolving with diffuse sensory and motor symptoms. Although it is claimed that in neurodegenerative pathologies, a common feature is the failure of proteolytic systems to adequately eliminate aggregated or misfolded proteins, it has not been addressed whether autophagy, a central "clearance" system delivering damaged intracellular components to lysosomes, is affected in CIDP. The focus of the present investigation was therefore to determine if some defects exist in autophagy processes in this setting and if they can be corrected or minimized using an appropriate treatment targeting this survival pathway. Experiments were performed using a rat model mimicking human CIDP, also known as chronic experimental autoimmune neuritis (c-EAN), the disease establishment and development of which was followed at both the clinical and biological levels (indices of disease severity, histopathological alteration, cytokines and antibodies rates). Based on immunofluorescence and western immunoblotting experiments on sciatic nerves and spleen cells from c-EAN rats, we demonstrate that both, macroautophagy and chaperone-mediated autophagy (CMA), are significantly altered in non-neuronal cells of the peripheral nervous system. We show further that a 21-mer synthetic phosphopeptide called P140, known to target CMA and successfully used in pathological settings where CMA markers are overexpressed, considerably ameliorates the clinical and biological course of the disease in c-EAN rats. P140 displayed prophylactic and therapeutic effects, both in terms of disease intensity and chronicity, and preserved sciatic nerves from disease-related damages. Our findings uncover new disrupted molecular pathways in a c-EAN model and provide a proof-of-concept that targeting CMA might represent a promising therapeutic strategy for treating inflammatory neuropathies for which no disease-specific treatment is currently available.

Topics: Animals; Autophagy; Biological Products; Disease Models, Animal; Disease Progression; Humans; Male; Motor Activity; Neuritis, Autoimmune, Experimental; Peptide Fragments; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Proteostasis Deficiencies; Rats; Rats, Inbred Lew; Sciatic Nerve