Methods for the treatment of type 2-mediated diseases

Abstract

Augmenting the portfolio of therapeutics for type 2-driven diseases is crucial to address unmet clinical needs and to design personalized treatment schemes. An attractive therapy for such diseases would consist in targeting the recruitment of T helper 2 (Th2) lymphocytes to inflammatory sites. In the present study, the Inventors unraveled the degradation of filamins (FLN) A and B by the ASB2α E3 ubiquitin ligase as a mechanism sustaining Th2 lymphocyte functions. They showed that low levels of FLNa and FLNb confer an elongated shape to Th2 lymphocytes associated with efficient αVβ3 integrin-dependent cell migration. Genes encoding the αVβ3 integrin and ASB2α belong to the core of Th2-specific genes. Using genetically modified mice and the small molecule thiostrepton, they found that increasing the levels of FLNa and FLNb in Th2 lymphocytes reduces airway inflammation. Collectively, their results highlight ASB2α and its substrates FLNa and FLNb to rewire Th2 lymphocyte mediated responses.

Description

[0001]METHODS FOR THE TREATMENT OF TYPE 2-MEDIATED DISEASES FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular immunology. BACKGROUND OF THE INVENTION: Adaptive immunity relies on the recognition of antigens, development of immunologic memory and acquisition of tolerance to self-antigens. Key mediators of adaptive immune responses are T helper (Th) lymphocytes that, via the secretion of distinct cytokine combinations, orchestrate immune responses against foreign antigens, neo-antigens and self- antigens, respectively in the context of infection, cancer and auto-immunity. The understanding of the molecular mechanisms involved in the regulation of specific Th lymphocyte properties and functions will pave the way to the development of new approaches to tackle immune system-mediated diseases. Asthma is a chronic inflammatory disease of the lower airways that affects near 400 million people worldwide. Despite high diversity of endotypes characteristic of this pathology, half of asthmatic patients present a high type-2 inflammation initiated by the release of type 2 cytokines. Th2 lymphocytes represent a major source of type 2 cytokines and are key drivers of asthma pathogenesis because of their myriad effects on both structural and inflammatory cells in the airways1,2. Several E3 ubiquitin ligases (E3s) are known to regulate differentiation and functions of Th2 lymphocytes3,4. Among them, ASB2α is the specificity subunit of a multimeric E3 of the Cullin 5 RING Ligase family5up-regulated during Th2 differentiation of naive CD4+ T lymphocytes6–8. Importantly, loss of ASB2 diminished Th2 lymphocyte function, promoted a type 1 anti-tumor immune response and attenuated colitis- associated tumorigenesis in mice8. These results position ASB2α as a prominent pharmacological target to mitigate Type 2 responses in Th2-driven pathologies such as asthma. ASB2α triggers ubiquitylation and proteasomal degradation of filamins (FLN) A and B, thereby regulating actin cytoskeleton remodeling and cell motility in different cell types9–14, yet the role and mechanisms of action of ASB2α in Th2 lymphocytes are not well-defined. SUMMARY OF THE INVENTION: The invention is defined by the claims. In particular, the present invention relates to a method of treating a Type 2-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a modulator of the ASB2- FLNA / B axis, wherein the modulator of the ASB2-FLNA / B axis is an ASB2 inhibitor or a FLNA / B enhancer. DETAILED DESCRIPTION OF THE INVENTION: In the present study, the Inventors asked whether ASB2α-mediated degradation of FLNA and FLNBis a mechanism sustaining Th2 lymphocyte functions and investigated whether targeting the ASB2α-FLNA / B axis may represent a potential therapeutic opportunity in asthma using mouse models of airway inflammation and allergic asthma. They showed that low levels of FLNAand FLNBconfer specific morphological features and migratory properties to Th2 lymphocytes. Using two experimental strategies, genetically modified mice and the small molecule thiostrepton, they found that increasing the levels of FLNA and FLNB proteins in Th2 lymphocytes attenuates airway inflammation. Collectively, their results highlight original targets to rewire Th2 lymphocyte mediated responses. In a first aspect, the present invention relates to a method of treating a Type 2-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a modulator of the ASB2-FLNA / B axis. In some embodiments, the modulator of the ASB2-FLNA / B axis is an ASB2 inhibitor. In some embodiments, the ASB2 inhibitor is an ASB2αinhibitor. In some embodiments, the modulator of the ASB2-FLNA / Baxis is a FLNA / B enhancer. In some embodiments, the modulator of the ASB2-FLNA / B axis is an ASB2 inhibitor and / or a FLNA / B enhancer. As used herein, the term “subject” denotes a mammal, such as a rodent, a feline, a canine, and a primate. Particularly, the subject according to the invention is a human. In some embodiments, the subject suffers from airway inflammation. In some embodiments, the subject is allergic to an allergen. In some embodiments, the allergen is ovalbumin or house dust mite. In some embodiments, the subject suffers from respiratory allergy. In some embodiments, the subject suffers from allergic asthma. As used herein, the term “Type 2-mediated disease” denotes a disease which is characterized by the overproduction of IL-4, IL-5 and / or IL-13. Both Th2 cells and ILC2 cells secrete these cytokines. The term “Th2” refers to T helper 2 cells. The term “ILC2” refers to group 2 innate lymphoid cells. Thus, the term “Type 2-mediated disease” includes both Th2- mediated diseases and ILC2-mediated diseases. Such diseases are well-known and include, for example, allergic disorders such as respiratory allergy, food allergy or skin allergy, asthma, bronchitis, rhinitis, sinusitis, pollinosis, conjunctivitis, dermatitis, atopic dermatitis, eczema, urticaria, inflammatory bowel syndrome, inflammatory bowel disease, ulcerative colitis, anaphylactic hypersensitivity, eosophageal eosinophilia, exacerbation of infection with infectious diseases (e.g., Leishmania major, Mycobacterium leprae, Candida albicans, Toxoplasma gondii, respiratory syncytial virus, human immunodeficiency virus, coronaviruses), nasal polyposis, immunodeficiency diseases (e.g. Omenn’s Syndrome), graft immune diseases (e.g. chronic graft vs host disease), autoimmune diseases (e.g. scleroderma) or chronic obstructive pulmonary disease (COPD). In some embodiments, the Type 2-mediated disease is a respiratory disease, a skin disease or a food allergy. In some embodiments, the Type 2-mediated disease is respiratory allergy. In some embodiments, the Type 2-mediated disease is asthma. In some embodiments, the Type 2-mediated disease is atopic dermatitis. In some embodiments, the Type 2-mediated disease is induced by Type 2-mediated inflammation. As used herein, the term “allergic disorders” or “allergy” refers to a reaction of immune system, particularly of specific IgE antibodies. Typically, the IgE antibodies and antigen bind to the membrane receptors of mast cells and granulocytes, the antigen-antibody reaction releases inflammatory mediators, and cause vasodilation, capillary permeability hyperactivity and leading to tissue infiltration of inflammatory cells. For example, allergic disorders may be characterized by, but are not limited to, rhinitis, dermatitis, urticaria, asthma, conjunctivitis, gastrointestinal inflammation or anaphylaxis. In another aspect, the present invention relates to a method of treating a Type 2-mediated inflammation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a modulator of the ASB2-FLNA / Baxis. In some embodiments, the modulator of the ASB2-FLNA / Baxis is an ASB2 inhibitor. In some embodiments, the ASB2 inhibitor is an ASB2α inhibitor. In some embodiments, the modulator of the ASB2-FLNA / B axis is a FLNA / B enhancer. In some embodiments, the modulator of the ASB2-FLNA / Baxis is an ASB2 inhibitor and / or a FLNA / Benhancer. As used herein, the term “Type 2-mediated inflammation” denotes an inflammation induced by overproduction of Type 2 cytokines. As example, Type 2 cytokines include IL-4, IL-5 and IL-13. Type 2-mediated inflammation is typically characterized by the presence of eosinophils and basophils and extensive mast cell degranulation. More particularly, Type 2 inflammatory immune responses involve IgE production and eosinophilic infiltration as a result of the actions of IL-4, IL-5 and IL-13. In some embodiments, the Type 2-mediated inflammation is a Type 2-mediated airways inflammation. In order to detect an airways inflammation, markers of airways inflammation can be measured. A bronchial biopsy or a bronchoalveolar lavage can be performed for these purposes. Noninvasive methods are also suitable such as examination of sputum and blood. In some embodiments, the Type 2-mediated airways inflammation causes asthma. As used herein, the term “asthma” is a chronic disease that involves inflammation of the pulmonary airways and bronchial hyper-responsiveness leading to reversible obstruction of the lower airways. Symptoms includes cough, wheeze, shortness of breath, chest tightness and itchy throat. A lack of therapeutic management can lead to sleep disturbance, tiredness and poor concentration and in the most severe cases, can lead to death. In some embodiments, asthma is allergic asthma. Allergic asthma occurs when the subject’s airways are extra sensitive to certain allergens. In some embodiments, the allergen is ovalbumin. In some embodiments, the allergen is house dust mite. In some embodiments, asthma is non-allergic asthma. As used herein, the terms “treating”, “treatment” or “therapy” refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. In some embodiments, the term “treatment” particularly refers to the preventive treatment of the Type 2-mediated disease and / or Type 2-mediated inflammation and / or asthma. The treatment may be administered to a subject having a medical disorder or a subject likely to suffer from the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]). As used herein the terms "administering" or "administration" refer to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g. a modulator of the ASB2-FLNA / B axis, an ASB2 inhibitor or a FLNA / B enhancer) into the subject, such as by mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery and / or any other method of physical delivery described herein or known in the art. In some embodiments, the administration is intranasal. In some embodiments, the modulator of the ASB2-FLNA / B axis is administrated by inhalation. When a disease, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof. When a disease or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease or symptoms thereof. As used herein, the term “efficient” denotes a state wherein the administration of one or more drugs to a subject permit to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or to prolong the survival of a subject beyond that expected in the absence of such treatment. A "therapeutically effective amount" is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject. For example, a "therapeutically effective amount" to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Modulators of the ASB2-FLNA / Baxis In another aspect, the present invention relates to a method of treating a Type 2-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a modulator of the ASB2-FLNA / Baxis, wherein the modulator of the ASB2- FLNA / B axis is: - An ASB2 inhibitor; or - A FLNA / Benhancer; As used herein the term “modulator of the ASB2-FLNA / Baxis” refers to a molecule or compound that totally or partially enhances or inhibits (i.e. modulates) the expression of ASB2 (e.g. ASB2α or ASB2β), FLNA and / or FLNB, or that partially or totally enhances or inhibits their biological activity. ASB2 ubiquitin ligase activity drives proteasome-mediated degradation of the actin-binding proteins FLNAand FLNB. Preferentially, the modulator of the ASB2-FLNA / Baxis is an ASB2 inhibitor, a FLNAenhancer, a FLNBenhancer, a FLNAand FLNB enhancer, an ASB2 inhibitor and a FLNA enhancer, an ASB2 inhibitor and a FLNB enhancer or an ASB2 inhibitor and FLNAand FLNBenhancer. In some embodiments, the ASB2 inhibitor is an ASB2α inhibitor. Thus, in some embodiments, the modulator of the ASB2- FLNA / B axis is an ASB2α inhibitor. ASB2 inhibitors As used herein, the term “ASB2” or “Ankyrin Repeat And SOCS Box Containing 2” refers to a protein encoded by the ASB2 gene (Entrez: 51676; Ensembl: ENSG00000100628). The ASB2 gene encodes two isoforms, ASB2α and ASB2β. ASB2α targets both FLNAand FLNBfor proteasomal degradation while ASB2β targets FLNBfor proteasomal degradation (Bello NF, Cell death and differentiation 2009; Heuzé ML, Blood 2008). As used herein, the term “ASB2 inhibitors” denotes a molecule that partially or totally inhibits the biological activity (e.g. ubiquitin ligase activity) or expression of ASB2. In some embodiments, the ASB2 inhibitor is an ASB2α inhibitor. In some embodiments, the ASB2 inhibitor is an ASB2β inhibitor. In some embodiments, the ASB2 inhibitor interacts directly with ASB2. In some embodiments, the ASB2 inhibitor inhibits the interaction between ASB2 and FLNA / B. In some embodiments, the ASB2 inhibitor according to the invention is an inhibitor of ASB2 gene expression (i.e., ASB2 gene). In some embodiments, the ASB2 inhibitor is an inhibitor of ASB2 gene expression selected from the list consisting of antisense oligonucleotide, nuclease, siRNA, shRNA or ribozyme. In some embodiments, the inhibitor of ASB2 gene expression is a siRNA directed against ASB2 gene. In some embodiments, the inhibitor of ASB2 gene expression is a shRNA directed against ASB2 gene. Thus, in some embodiments, the inhibitor of ASB2 gene expression is a siRNA or a shRNA directed against ASB2 gene. ASB2 gene expression can be reduced by contacting a subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that ASB2 gene expression is specifically inhibited (i.e. RNA interference or RNAi). Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see for example Tuschl, T. et al. (1999); Elbashir, S. M. et al. (2001); Hannon, GJ. (2002); McManus, MT. et al. (2002); Brummelkamp, TR. et al. (2002); U.S. Pat. Nos.6,573,099 and 6,506,559; and International Patent Publication Nos. WO 01 / 36646, WO 99 / 32619, and WO 01 / 68836). In some embodiments, the ASB2 inhibitor is an antisense oligonucleotide. As used herein, the term "antisense oligonucleotide (AON)" refers to an oligonucleotide capable of interacting with and / or hybridizing to a pre-mRNA or an mRNA having a complementary nucleotide sequence thereby modifying gene expression. Typically, the antisense oligonucleotide is complementary to the nucleic acid sequence that is necessary for preventing splicing of the targeted exon including cryptic exon, supplementary exon, pseudo-exon or intron sequence retained after splicing. In a more particular embodiment, the ASB2 inhibitor is an antisense oligonucleotide directed against ASB2. In some embodiments, the antisense oligonucleotide is an ASB2 antisense oligonucleotide. Ribozymes can also function as inhibitors of ASB2 gene expression in the present invention. Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of ASB2 mRNA sequences are thereby useful within the scope of the present invention. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays. Both antisense oligonucleotides and ribozymes useful as inhibitors of ASB2 gene expression can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis. Alternatively, anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life. Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and / or 3' ends of the molecule, or the use of phosphorothioate or 2'-O-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone. Antisense oligonucleotides, siRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector. In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide siRNA or ribozyme nucleic acid to the cells and, in particular, to the cells expressing ASB2. In the scope of the present invention, the vector is particularly able to facilitate the transfer of the oligonucleotide siRNA or ribozyme nucleic acid to Th2 cells or to ILC2 cells. Particularly, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA or ribozyme nucleic acid sequences. Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus; SV40- type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus. One can readily employ other vectors not named but known to the art. Preferred viral vectors are based on non-cytopathic eukaryotic viruses in which non-essential genes have been replaced with the gene of interest. Non- cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo. Standard protocols for producing replication-deficient retroviruses (including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided in Kriegler, 1990 and in Murry, 1991. Preferred viruses for certain applications are the adenoviruses and adeno-associated viruses, which are double-stranded DNA viruses that have already been approved for human use in gene therapy. The adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hematopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions. Reportedly, the adeno- associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection. In addition, wild-type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event. The adeno-associated virus can also function in an extrachromosomal fashion. Other vectors include plasmid vectors. Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g. Sambrook et al., 1989. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen-encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors. These plasmids, however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid. Some commonly used plasmids are well known to those of ordinary skill in the art. Additionally, plasmids may be custom designed using restriction enzymes and ligation reactions to remove and add specific fragments of DNA. Plasmids may be delivered by a variety of parenteral, mucosal and topical routes. For example, the DNA plasmid can be injected by intramuscular, eye, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally. In some embodiments, the DNA plasmid is administered by intranasal spray. In some embodiments, the DNA plasmid is administered by inhalation. It may also be administered into the epidermis or a mucosal surface using a gene-gun. The plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation. In a particular embodiment, the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequence is under the control of a heterologous regulatory region, e.g., a heterologous promoter. The promoter can be, e.g., a viral promoter, such as CMV promoter or any synthetic promoters. In some embodiments, an endonuclease can be used to abolish the expression of ASB2. As an alternative to, as example, cDNA overexpression or downregulation by RNA interference, more recent technologies provide means to manipulate the genome. The mechanism behind endonuclease-based genome inactivating generally requires a first step of DNA single or double strand break, which can then trigger two distinct cellular mechanisms for DNA repair, which can be exploited for DNA inactivating: the error prone non homologous end-joining (NHEJ) and the high-fidelity homology-directed repair (HDR). In a particular embodiment, the endonuclease is CRISPR-cas. As used herein, the term “CRISPR-cas” has its general meaning in the art and refers to clustered regularly interspaced short palindromic repeats associated which are the segments of prokaryotic DNA containing short repetitions of base sequences. In some embodiment, the endonuclease is CRISPR-cas9 which is from Streptococcus pyogenes. The CRISPR / Cas9 system has been described in US 8697359 B1 and US 2014 / 0068797. Originally an adaptive immune system in prokaryotes (Barrangou and Marraffini, 2014), CRISPR has been engineered into a new powerful tool for genome editing. It has already been successfully used to target important genes in many cell lines and organisms, including human (Mali et al., 2013, Science, Vol.339 : 823–826), bacteria (Fabre et al., 2014, PLoS Negl. Trop. Dis., Vol. 8:e2671.), zebrafish (Hwang et al., 2013, PLoS One, Vol. 8:e68708.), C. elegans (Hai et al., 2014 Cell Res. doi: 10.1038 / cr.2014.11.), bacteria (Fabre et al., 2014, PLoS Negl. Trop. Dis., Vol.8:e2671.), plants (Mali et al., 2013, Science, Vol.339 : 823–826), Xenopus tropicalis (Guo et al., 2014, Development, Vol. 141 : 707–714.), yeast (DiCarlo et al., 2013, Nucleic Acids Res., Vol.41 : 4336–4343.), Drosophila (Gratz et al., 2014 Genetics, doi:10.1534 / genetics.113.160713), monkeys (Niu et al., 2014, Cell, Vol.156 : 836– 843.), rabbits (Yang et al., 2014, J. Mol. Cell Biol., Vol.6 : 97-99.), pigs (Hai et al., 2014, Cell Res. doi: 10.1038 / cr.2014.11.), rats (Ma et al., 2014, Cell Res., Vol. 24 : 122–125.) and mice (Mashiko et al., 2014, Dev. Growth Differ. Vol.56 : 122–129.). Several groups have now taken advantage of this method to introduce single point mutations (deletions or insertions) in a particular target gene, via a single gRNA. Using a pair of gRNA-directed Cas9 nucleases instead, it is also possible to induce large deletions or genomic rearrangements, such as inversions or translocations. A recent exciting development is the use of the dCas9 version of the CRISPR / Cas9 system to target protein domains for transcriptional regulation, epigenetic modification, and microscopic visualization of specific genome loci. In some embodiment, the endonuclease is CRISPR-Cpf1 which is CRISPR from Provotella and Francisella 1 (Cpf1) in Zetsche et al. (“Cpf1 is a Single RNA-guided Endonuclease of a Class 2 CRISPR-Cas System (2015); Cell; 163, 1-13). In some embodiments, the ASB2 inhibitor according to the invention may be a low molecular weight compound, e. g. a small organic molecule (natural or not). The term "small organic molecule" refers to a molecule (natural or not) of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e. g., proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to about 10000 Da, more preferably up to 5000 Da, more preferably up to 2000 Da and most preferably up to about 1000 Da. In some embodiments, the ASB2 inhibitor is a PROTAC. The term PROTAC or PROteolysis TArgeting Chimera refers to a heterobifunctional molecule composed of two active domains and a linker, capable of removing specific unwanted proteins by inducing selective intracellular proteolysis. PROTACs are typically constituted of two covalently linked protein-binding molecules, the first one capable of engaging an E3 ubiquitin ligase and the second one that binds to a target protein meant for degradation. The recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome. PROTAC strategies are described as example in Schneekloth A.R. et al. (Ashley R. Schneekloth et al. “Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics” Bioorganic & Medicinal Chemistry Letters, Volume 18, Issue 22, 2008, Pages 5904-5908), Jia X. et al. (Xiaojuan Jia et am. “Targeting androgen receptor degradation with PROTACs from bench to bedside”, Biomedicine & Pharmacotherapy, Volume 158, 2023, 114112) or Sakamoto KM et al. (Sakamoto K.M. et al. “Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation”. Proc Natl Acad Sci U S A. 2001;98(15):8554-8559. doi:10.1073 / pnas.141230798). In some embodiment, the ASB2 inhibitor according to the invention is an antibody directed against ASB2. Antibodies directed against ASB2 can be raised according to known methods by administering the appropriate antigen or epitope to a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others. Various adjuvants known in the art can be used to enhance antibody production. Although antibodies useful in practicing the invention can be polyclonal, monoclonal antibodies are preferred. Monoclonal antibodies against ASB2 can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture. Techniques for production and isolation include but are not limited to the hybridoma technique originally described by Kohler and Milstein (1975); the human B-cell hybridoma technique (Cote et al., 1983); and the EBV-hybridoma technique (Cole et al. 1985). Alternatively, techniques described for the production of single chain antibodies (see e.g., U.S. Pat. No. 4,946,778) can be adapted to produce anti-ASB2 single chain antibodies. Compounds useful in practicing the present invention also include anti-ASB2 antibody fragments including but not limited to F(ab')2 fragments, which can be generated by pepsin digestion of an intact antibody molecule, and Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab')2 fragments. Alternatively, Fab and / or scFv expression libraries can be constructed to allow rapid identification of fragments having the desired specificity to ASB2. Humanized anti-ASB2 antibodies and antibody fragments therefrom can also be prepared according to known techniques. "Humanized antibodies" are forms of non-human (e.g., rodent) chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (CDRs) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Methods for making humanized antibodies are described, for example, by Winter (U.S. Pat. No.5,225,539) and Boss (Celltech, U.S. Pat. No.4,816,397). Then, for this invention, neutralizing antibodies of ASB2 are selected. In another embodiment, the antibody according to the invention is a single domain antibody directed against ASB2. The term “single domain antibody” (sdAb) or "VHH" refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals, which are naturally devoid of light chains. Such VHH are also called “nanobody®”. According to the invention, sdAb can particularly be llama sdAb. The term “VHH” refers to the single heavy chain having 3 complementarity determining regions (CDRs): CDR1, CDR2 and CDR3. The term “complementarity determining region” or “CDR” refers to the hypervariable amino acid sequences, which define the binding affinity and specificity of the VHH. The VHH according to the invention can readily be prepared by an ordinarily skilled artisan using routine experimentation. The VHH variants and modified form thereof may be produced under any known technique in the art such as in-vitro maturation. VHHs or sdAbs are usually generated by PCR cloning of the V-domain repertoire from blood, lymph node, or spleen cDNA obtained from immunized animals into a phage display vector, such as pHEN2. Antigen-specific VHHs are commonly selected by panning phage libraries on immobilized antigen, e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells. However, such VHHs often show lower affinities for their antigen than VHHs derived from animals that have received several immunizations. The high affinity of VHHs from immune libraries is attributed to the natural selection of variant VHHs during clonal expansion of B- cells in the lymphoid organs of immunized animals. The affinity of VHHs from non-immune libraries can often be improved by mimicking this strategy in vitro, i.e., by site directed mutagenesis of the CDR regions and further rounds of panning on immobilized antigen under conditions of increased stringency (higher temperature, high or low salt concentration, high or low pH, and low antigen concentrations). VHHs derived from camelid are readily expressed in and purified from the E. coli periplasm at much higher levels than the corresponding domains of conventional antibodies. VHHs generally display high solubility and stability and can also be readily produced in yeast, plant, and mammalian cells. For example, the “Hamers patents” describe methods and techniques for generating VHH against any desired target (see for example US 5,800,988; US 5,874, 541 and US 6,015,695). The “Hamers patents” more particularly describe production of VHHs in bacterial hosts such as E. coli (see for example US 6,765,087) and in lower eukaryotic hosts such as moulds (for example Aspergillus or Trichoderma) or in yeast (for example Saccharomyces, Kluyveromyces, Hansenula or Pichia) (see for example US 6,838,254). In some embodiments, the inhibitor according to the invention is an aptamer. Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity. Such ligands may be isolated through Systematic Evolution of Ligands by EXponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. and Gold L., 1990. The random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena S.D., 1999. Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996). In some embodiment, the ASB2 inhibitor is a polypeptide. In one embodiment, the polypeptide of the invention may be linked to a “cell-penetrating peptide” to allow the penetration of the polypeptide in the cell. The term “cell-penetrating peptides” are well known in the art and refers to cell permeable sequence or membranous penetrating sequence such as penetratin, TAT mitochondrial penetrating sequence and compounds (Bechara and Sagan, 2013; Jones and Sayers, 2012; Khafagy el and Morishita, 2012; Malhi and Murthy, 2012). The polypeptides of the invention may be produced by any suitable means, as will be apparent to those of skill in the art. In order to produce sufficient amounts of polypeptide or functional equivalents thereof for use in accordance with the present invention, expression may conveniently be achieved by culturing under appropriate conditions recombinant host cells containing the polypeptide of the invention. Particularly, the polypeptide is produced by recombinant means, by expression from an encoding nucleic acid molecule. Systems for cloning and expression of a polypeptide in a variety of different host cells are well known. When expressed in recombinant form, the polypeptide is particularly generated by expression from an encoding nucleic acid in a host cell. Any host cell may be used, depending upon the individual requirements of a particular system. Suitable host cells include bacteria mammalian cells, plant cells, yeast and baculovirus systems. Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary cells, HeLa cells, baby hamster kidney cells and many others. Bacteria are also preferred hosts for the production of recombinant proteins, due to the ease with which bacteria may be manipulated and grown. A common, preferred bacterial host is E coli. In specific embodiments, it is contemplated that polypeptides used in the therapeutic methods of the present invention may be modified in order to improve their therapeutic efficacy. Such modification of therapeutic compounds may be used to decrease toxicity, increase circulatory time, or modify biodistribution. For example, the toxicity of potentially important therapeutic compounds can be decreased significantly by combination with a variety of drug carrier vehicles that modify biodistribution. In example adding dipeptides can improve the penetration of a circulating agent in the eye through the blood retinal barrier by using endogenous transporters. A strategy for improving drug viability is the utilization of water-soluble polymers. Various water-soluble polymers have been shown to modify biodistribution, improve the mode of cellular uptake, change the permeability through physiological barriers; and modify the rate of clearance from the body. To achieve either a targeting or sustained-release effect, water-soluble polymers have been synthesized that contain drug moieties as terminal groups, as part of the backbone, or as pendent groups on the polymer chain. Polyethylene glycol (PEG) has been widely used as a drug carrier, given its high degree of biocompatibility and ease of modification. Attachment to various drugs, proteins, and liposomes has been shown to improve residence time and decrease toxicity. PEG can be coupled to active agents through the hydroxyl groups at the ends of the chain and via other chemical methods; however, PEG itself is limited to at most two active agents per molecule. In a different approach, copolymers of PEG and amino acids were explored as novel biomaterials which would retain the biocompatibility properties of PEG, but which would have the added advantage of numerous attachment points per molecule (providing greater drug loading), and which could be synthetically designed to suit a variety of applications. Those of skill in the art are aware of PEGylation techniques for the effective modification of drugs. For example, drug delivery polymers that consist of alternating polymers of PEG and tri-functional monomers such as lysine have been used by VectraMed (Plainsboro, N.J.). The PEG chains (typically 2000 daltons or less) are linked to the a- and e-amino groups of lysine through stable urethane linkages. Such copolymers retain the desirable properties of PEG, while providing reactive pendent groups (the carboxylic acid groups of lysine) at strictly controlled and predetermined intervals along the polymer chain. The reactive pendent groups can be used for derivatization, cross-linking, or conjugation with other molecules. These polymers are useful in producing stable, long- circulating pro-drugs by varying the molecular weight of the polymer, the molecular weight of the PEG segments, and the cleavable linkage between the drug and the polymer. The molecular weight of the PEG segments affects the spacing of the drug / linking group complex and the amount of drug per molecular weight of conjugate (smaller PEG segments provides greater drug loading). In general, increasing the overall molecular weight of the block co-polymer conjugate will increase the circulatory half-life of the conjugate. Nevertheless, the conjugate must either be readily degradable or have a molecular weight below the threshold-limiting glomular filtration (e.g., less than 60 kDa). In addition, to the polymer backbone being important in maintaining circulatory half-life, and biodistribution, linkers may be used to maintain the therapeutic agent in a pro-drug form until released from the backbone polymer by a specific trigger, typically enzyme activity in the targeted tissue. For example, this type of tissue activated drug delivery is particularly useful where delivery to a specific site of biodistribution is required and the therapeutic agent is released at or near the site of pathology. Linking group libraries for use in activated drug delivery are known to those of skill in the art and may be based on enzyme kinetics, prevalence of active enzyme, and cleavage specificity of the selected disease-specific enzymes. Such linkers may be used in modifying the protein or fragment of the protein described herein for therapeutic delivery. FLNA / Benhancers As used herein, the term “FLN” or “filamin” refers to a family of crosslinking filament proteins encoded by FLN genes. Filamins are typically involved in cell adhesion, spreading and migration. Filamin proteins include FLNA(Gene ID: 2316), FLNB(Gene ID: 2317) and FLNC (Gene ID: 2318). As used herein, the term “FLNA / B” encompasses FLNA, FLNB or both FLNA and FLNB. As used herein, the term “FLNA / Benhancer” denotes a molecule that partially or totally enhance FLNA / B biological activity or expression. An exemplary amino acid sequence for FLNA is shown as SEQ ID NO:1. SEQ ID NO:1 >sp|P21333|FLNA_HUMAN OS=Homo sapiens OX=9606 GN=FLNA PE=1 SV=4 MSSSHSRAGQSAAGAAPGGGVDTRDAEMPATEKDLAEDAPWKKIQQNTFTRWCNEHLKCVSKRIANLQTDLSDGL RLIALLEVLSQKKMHRKHNQRPTFRQMQLENVSVALEFLDRESIKLVSIDSKAIVDGNLKLILGLIWTLILHYSI SMPMWDEEEDEEAKKQTPKQRLLGWIQNKLPQLPITNFSRDWQSGRALGALVDSCAPGLCPDWDSWDASKPVTNA REAMQQADDWLGIPQVITPEEIVDPNVDEHSVMTYLSQFPKAKLKPGAPLRPKLNPKKARAYGPGIEPTGNMVKK RAEFTVETRSAGQGEVLVYVEDPAGHQEEAKVTANNDKNRTFSVWYVPEVTGTHKVTVLFAGQHIAKSPFEVYVD KSQGDASKVTAQGPGLEPSGNIANKTTYFEIFTAGAGTGEVEVVIQDPMGQKGTVEPQLEARGDSTYRCSYQPTM EGVHTVHVTFAGVPIPRSPYTVTVGQACNPSACRAVGRGLQPKGVRVKETADFKVYTKGAGSGELKVTVKGPKGE ERVKQKDLGDGVYGFEYYPMVPGTYIVTITWGGQNIGRSPFEVKVGTECGNQKVRAWGPGLEGGVVGKSADFVVE AIGDDVGTLGFSVEGPSQAKIECDDKGDGSCDVRYWPQEAGEYAVHVLCNSEDIRLSPFMADIRDAPQDFHPDRV KARGPGLEKTGVAVNKPAEFTVDAKHGGKAPLRVQVQDNEGCPVEALVKDNGNGTYSCSYVPRKPVKHTAMVSWG GVSIPNSPFRVNVGAGSHPNKVKVYGPGVAKTGLKAHEPTYFTVDCAEAGQGDVSIGIKCAPGVVGPAEADIDFD IIRNDNDTFTVKYTPRGAGSYTIMVLFADQATPTSPIRVKVEPSHDASKVKAEGPGLSRTGVELGKPTHFTVNAK AAGKGKLDVQFSGLTKGDAVRDVDIIDHHDNTYTVKYTPVQQGPVGVNVTYGGDPIPKSPFSVAVSPSLDLSKIK VSGLGEKVDVGKDQEFTVKSKGAGGQGKVASKIVGPSGAAVPCKVEPGLGADNSVVRFLPREEGPYEVEVTYDGV PVPGSPFPLEAVAPTKPSKVKAFGPGLQGGSAGSPARFTIDTKGAGTGGLGLTVEGPCEAQLECLDNGDGTCSVS YVPTEPGDYNINILFADTHIPGSPFKAHVVPCFDASKVKCSGPGLERATAGEVGQFQVDCSSAGSAELTIEICSE AGLPAEVYIQDHGDGTHTITYIPLCPGAYTVTIKYGGQPVPNFPSKLQVEPAVDTSGVQCYGPGIEGQGVFREAT TEFSVDARALTQTGGPHVKARVANPSGNLTETYVQDRGDGMYKVEYTPYEEGLHSVDVTYDGSPVPSSPFQVPVT EGCDPSRVRVHGPGIQSGTTNKPNKFTVETRGAGTGGLGLAVEGPSEAKMSCMDNKDGSCSVEYIPYEAGTYSLN VTYGGHQVPGSPFKVPVHDVTDASKVKCSGPGLSPGMVRANLPQSFQVDTSKAGVAPLQVKVQGPKGLVEPVDVV DNADGTQTVNYVPSREGPYSISVLYGDEEVPRSPFKVKVLPTHDASKVKASGPGLNTTGVPASLPVEFTIDAKDA GEGLLAVQITDPEGKPKKTHIQDNHDGTYTVAYVPDVTGRYTILIKYGGDEIPFSPYRVRAVPTGDASKCTVTVS IGGHGLGAGIGPTIQIGEETVITVDTKAAGKGKVTCTVCTPDGSEVDVDVVENEDGTFDIFYTAPQPGKYVICVR FGGEHVPNSPFQVTALAGDQPSVQPPLRSQQLAPQYTYAQGGQQTWAPERPLVGVNGLDVTSLRPFDLVIPFTIK KGEITGEVRMPSGKVAQPTITDNKDGTVTVRYAPSEAGLHEMDIRYDNMHIPGSPLQFYVDYVNCGHVTAYGPGL THGVVNKPATFTVNTKDAGEGGLSLAIEGPSKAEISCTDNQDGTCSVSYLPVLPGDYSILVKYNEQHVPGSPFTA RVTGDDSMRMSHLKVGSAADIPINISETDLSLLTATVVPPSGREEPCLLKRLRNGHVGISFVPKETGEHLVHVKK NGQHVASSPIPVVISQSEIGDASRVRVSGQGLHEGHTFEPAEFIIDTRDAGYGGLSLSIEGPSKVDINTEDLEDG TCRVTYCPTEPGNYIINIKFADQHVPGSPFSVKVTGEGRVKESITRRRRAPSVANVGSHCDLSLKIPEISIQDMT AQVTSPSGKTHEAEIVEGENHTYCIRFVPAEMGTHTVSVKYKGQHVPGSPFQFTVGPLGEGGAHKVRAGGPGLER AEAGVPAEFSIWTREAGAGGLAIAVEGPSKAEISFEDRKDGSCGVAYVVQEPGDYEVSVKFNEEHIPDSPFVVPV ASPSGDARRLTVSSLQESGLKVNQPASFAVSLNGAKGAIDAKVHSPSGALEECYVTEIDQDKYAVRFIPRENGVY LIDVKFNGTHIPGSPFKIRVGEPGHGGDPGLVSAYGAGLEGGVTGNPAEFVVNTSNAGAGALSVTIDGPSKVKMD CQECPEGYRVTYTPMAPGSYLISIKYGGPYHIGGSPFKAKVTGPRLVSNHSLHETSSVFVDSLTKATCAPQHGAP GPGPADASKVVAKGLGLSKAYVGQKSSFTVDCSKAGNNMLLVGVHGPRTPCEEILVKHVGSRLYSVSYLLKDKGE YTLVVKWGDEHIPGSPYRVVVP An exemplary amino acid sequence for FLNBis shown as SEQ ID NO:2. SEQ ID NO:2 >sp|O75369|FLNB_HUMAN OS=Homo sapiens OX=9606 GN=FLNB PE=1 SV=2 MPVTEKDLAEDAPWKKIQQNTFTRWCNEHLKCVNKRIGNLQTDLSDGLRLIALLEVLSQKRMYRKYHQRPTFRQM QLENVSVALEFLDRESIKLVSIDSKAIVDGNLKLILGLVWTLILHYSISMPVWEDEGDDDAKKQTPKQRLLGWIQ NKIPYLPITNFNQNWQDGKALGALVDSCAPGLCPDWESWDPQKPVDNAREAMQQADDWLGVPQVITPEEIIHPDV DEHSVMTYLSQFPKAKLKPGAPLKPKLNPKKARAYGRGIEPTGNMVKQPAKFTVDTISAGQGDVMVFVEDPEGNK EEAQVTPDSDKNKTYSVEYLPKVTGLHKVTVLFAGQHISKSPFEVSVDKAQGDASKVTAKGPGLEAVGNIANKPT YFDIYTAGAGVGDIGVEVEDPQGKNTVELLVEDKGNQVYRCVYKPMQPGPHVVKIFFAGDTIPKSPFVVQVGEAC NPNACRASGRGLQPKGVRIRETTDFKVDTKAAGSGELGVTMKGPKGLEELVKQKDFLDGVYAFEYYPSTPGRYSI AITWGGHHIPKSPFEVQVGPEAGMQKVRAWGPGLHGGIVGRSADFVVESIGSEVGSLGFAIEGPSQAKIEYNDQN DGSCDVKYWPKEPGEYAVHIMCDDEDIKDSPYMAFIHPATGGYNPDLVRAYGPGLEKSGCIVNNLAEFTVDPKDA GKAPLKIFAQDGEGQRIDIQMKNRMDGTYACSYTPVKAIKHTIAVVWGGVNIPHSPYRVNIGQGSHPQKVKVFGP GVERSGLKANEPTHFTVDCTEAGEGDVSVGIKCDARVLSEDEEDVDFDIIHNANDTFTVKYVPPAAGRYTIKVLF ASQEIPASPFRVKVDPSHDASKVKAEGPGLSKAGVENGKPTHFTVYTKGAGKAPLNVQFNSPLPGDAVKDLDIID NYDYSHTVKYTPTQQGNMQVLVTYGGDPIPKSPFTVGVAAPLDLSKIKLNGLENRVEVGKDQEFTVDTRGAGGQG KLDVTILSPSRKVVPCLVTPVTGRENSTAKFIPREEGLYAVDVTYDGHPVPGSPYTVEASLPPDPSKVKAHGPGL EGGLVGKPAEFTIDTKGAGTGGLGLTVEGPCEAKIECSDNGDGTCSVSYLPTKPGEYFVNILFEEVHIPGSPFKA DIEMPFDPSKVVASGPGLEHGKVGEAGLLSVDCSEAGPGALGLEAVSDSGTKAEVSIQNNKDGTYAVTYVPLTAG MYTLTMKYGGELVPHFPARVKVEPAVDTSRIKVFGPGIEGKDVFREATTDFTVDSRPLTQVGGDHIKAHIANPSG ASTECFVTDNADGTYQVEYTPFEKGLHVVEVTYDDVPIPNSPFKVAVTEGCQPSRVQAQGPGLKEAFTNKPNVFT VVTRGAGIGGLGITVEGPSESKINCRDNKDGSCSAEYIPFAPGDYDVNITYGGAHIPGSPFRVPVKDVVDPSKVK IAGPGLGSGVRARVLQSFTVDSSKAGLAPLEVRVLGPRGLVEPVNVVDNGDGTHTVTYTPSQEGPYMVSVKYADE EIPRSPFKVKVLPTYDASKVTASGPGLSSYGVPASLPVDFAIDARDAGEGLLAVQITDQEGKPKRAIVHDNKDGT YAVTYIPDKTGRYMIGVTYGGDDIPLSPYRIRATQTGDASKCLATGPGIASTVKTGEEVGFVVDAKTAGKGKVTC TVLTPDGTEAEADVIENEDGTYDIFYTAAKPGTYVIYVRFGGVDIPNSPFTVMATDGEVTAVEEAPVNACPPGFR PWVTEEAYVPVSDMNGLGFKPFDLVIPFAVRKGEITGEVHMPSGKTATPEIVDNKDGTVTVRYAPTEVGLHEMHI KYMGSHIPESPLQFYVNYPNSGSVSAYGPGLVYGVANKTATFTIVTEDAGEGGLDLAIEGPSKAEISCIDNKDGT CTVTYLPTLPGDYSILVKYNDKHIPGSPFTAKITDDSRRCSQVKLGSAADFLLDISETDLSSLTASIKAPSGRDE PCLLKRLPNNHIGISFIPREVGEHLVSIKKNGNHVANSPVSIMVVQSEIGDARRAKVYGRGLSEGRTFEMSDFIV DTRDAGYGGISLAVEGPSKVDIQTEDLEDGTCKVSYFPTVPGVYIVSTKFADEHVPGSPFTVKISGEGRVKESIT RTSRAPSVATVGSICDLNLKIPEINSSDMSAHVTSPSGRVTEAEIVPMGKNSHCVRFVPQEMGVHTVSVKYRGQH VTGSPFQFTVGPLGEGGAHKVRAGGPGLERGEAGVPAEFSIWTREAGAGGLSIAVEGPSKAEITFDDHKNGSCGV SYIAQEPGNYEVSIKFNDEHIPESPYLVPVIAPSDDARRLTVMSLQESGLKVNQPASFAIRLNGAKGKIDAKVHS PSGAVEECHVSELEPDKYAVRFIPHENGVHTIDVKFNGSHVVGSPFKVRVGEPGQAGNPALVSAYGTGLEGGTTG IQSEFFINTTRAGPGTLSVTIEGPSKVKMDCQETPEGYKVMYTPMAPGNYLISVKYGGPNHIVGSPFKAKVTGQR LVSPGSANETSSILVESVTRSSTETCYSAIPKASSDASKVTSKGAGLSKAFVGQKSSFLVDCSKAGSNMLLIGVH GPTTPCEEVSMKHVGNQQYNVTYVVKERGDYVLAVKWGEEHIPGSPFHVTVP In some embodiments, the FLNA / Benhancer according to the invention is a low molecular weight compound, e. g. a small organic molecule (natural or not). The term "small organic molecule" refers to a molecule (natural or not) of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e. g., proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to about 10000 Da, more preferably up to 5000 Da, more preferably up to 2000 Da and most preferably up to about 1000 Da. In some embodiments, the FLNA / Benhancer is selected from a list consisting in thiostrepton, spironolactone, griseofulvin, econazole nitrate, etoposide, ciclopirox ethanolamine, sertaconazole nitrate, oxfendazole, oxibendazole, irinotecan hydrochloride trihydrate, estramustine, carbazochrome sodium sulfonate, L-tryptophan, prosultiamine, flupirtine, tinoridine hydrochloride, riboflavin. In a preferred embodiment, the FLNA / Benhancer is thiostrepton. In some embodiments, the FLNA / Benhancer is a polypeptide encoding for FLNAand / or FLNB. In some embodiments, the FLNA / B enhancer is a polypeptide encoding for FLNA. In some embodiments, the FLNA / B enhancer is a polypeptide comprising an amino acid sequence as set forth in SEQ ID NO:1. In some embodiments, the FLNA / Benhancer is a polypeptide that comprises an amino acid sequence having at least 90% of identity with the amino acid sequence as set forth in SEQ ID NO:1. In some embodiments, the FLNA / Benhancer is a polypeptide encoding for FLNB. In some embodiments, the FLNA / B enhancer is a polypeptide comprising an amino acid sequence as set forth in SEQ ID NO:2. In some embodiments, the FLNA / B enhancer is a polypeptide that comprises an amino acid sequence having at least 90% of identity with the amino acid sequence as set forth in SEQ ID NO:2. In some embodiments, the FLNA / Benhancer is a polypeptide that comprises the amino acid sequence as set forth in SEQ ID NO:1 or a polypeptide that comprises the amino acid sequence as set forth in SEQ ID NO:2. As used herein, the “percent identity” between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described below. The percent identity between two amino acid sequences can be determined using the Needleman and Wunsch algorithm (Needleman, Saul B. & Wunsch, Christian D. (1970). "A general method applicable to the search for similarities in the amino acid sequence of two proteins". Journal of Molecular Biology.48 (3): 443–53.). The percent identity between two nucleotide or amino acid sequences may also be determined using for example algorithms such as EMBOSS Needle (pair wise alignment; available at www.ebi.ac.uk). For example, EMBOSS Needle may be used with a BLOSUM62 matrix, a “gap open penalty” of 10, a “gap extend penalty” of 0.5, a false “end gap penalty”, an “end gap open penalty” of 10 and an “end gap extend penalty” of 0.5. In general, the “percent identity” is a function of the number of matching positions divided by the number of positions compared and multiplied by 100. For instance, if 6 out of 10 sequence positions are identical between the two compared sequences after alignment, then the identity is 60%. The % identity is typically determined over the whole length of the query sequence on which the analysis is performed. Two molecules having the same primary amino acid sequence or nucleic acid sequence are identical irrespective of any chemical and / or biological modification. According to the invention a first amino acid sequence having at least 90% of identity with a second amino acid sequence means that the first sequence has 90; 91; 92; 93; 94; 95; 96; 97; 98; 99 or 100% of identity with the second amino acid sequence. In some embodiments, the FLNA / Benhancer is a polypeptide encoding for FLNAand FLNB. In some embodiments, the FLNA / B enhancer is a polypeptide comprising an amino acid sequence as set forth in SEQ ID NO:1 and SEQ ID NO:2. As used herein, the terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component. Polypeptides when discussed in the context of gene therapy refer to the respective intact polypeptide, or any fragment or genetically engineered derivative thereof, which retains the desired biochemical function of the intact protein. In some embodiments, the FLNA / B enhancer is a polynucleotide that encodes for a FLNA, FLNBor FLNAand FLNBpolypeptide according to the present invention. As used herein, the term “polynucleotide” refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, refers interchangeably to double- and single- stranded molecules. Unless otherwise specified or required, any embodiment of the invention described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double- stranded form. In some embodiments, the FLNA / Benhancer is a mutated FLNA / Bpolypeptide or a polynucleotide that encodes a mutated FLNA / Bpolypeptide. In some embodiments, the mutated FLNA / B polypeptide or the polynucleotide that encodes a mutated FLNA / B polypeptide has an impaired ability to interact with ASB2. As used herein, the term “mutation” has its general meaning in the art and refers to a substitution, deletion or insertion. In particular, the term "substitution" means that a specific amino acid residue at a specific position is removed and another amino acid residue is inserted into the same position. Within the specification, the mutation are references according to the standard mutation nomenclature. In some embodiments, it is contemplated that the polypeptides of the invention used in the therapeutic methods of the present invention may be modified in order to improve their therapeutic efficacy. Such modification of therapeutic compounds may be used to decrease toxicity, increase circulatory time, or modify biodistribution. For example, the toxicity of potentially important therapeutic compounds can be decreased significantly by combination with a variety of drug carrier vehicles that modify biodistribution. A strategy for improving drug viability is the utilization of water-soluble polymers. Various water-soluble polymers have been shown to modify biodistribution, improve the mode of cellular uptake, change the permeability through physiological barriers; and modify the rate of clearance from the body. To achieve either a targeting or sustained-release effect, water-soluble polymers have been synthesized that contain drug moieties as terminal groups, as part of the backbone, or as pendent groups on the polymer chain. Polyethylene glycol (PEG) has been widely used as a drug carrier, given its high degree of biocompatibility and ease of modification. Attachment to various drugs, proteins, and liposomes has been shown to improve residence time and decrease toxicity. PEG can be coupled to active agents through the hydroxyl groups at the ends of the chain and via other chemical methods; however, PEG itself is limited to at most two active agents per molecule. In a different approach, copolymers of PEG and amino acids were explored as novel biomaterials which would retain the biocompatibility properties of PEG, but which would have the added advantage of numerous attachment points per molecule (providing greater drug loading), and which could be synthetically designed to suit a variety of applications. In some embodiments, the polynucleotide of the present invention is included in a suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector. So, a further object of the invention relates to a vector comprising a nucleic acid encoding for a FLNA / B polypeptide according to the invention. Typically, the vector is a viral vector which is an adeno-associated virus (AAV), a retrovirus, bovine papilloma virus, an adenovirus vector, a lentiviral vector, a vaccinia virus, a polyoma virus, or an infective virus. In some embodiments, the vector is an AAV vector. As used herein, the term "AAV vector" means a vector derived from an adeno- associated virus serotype, including without limitation, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and mutated forms thereof. AAV vectors can have one or more of the AAV wild-type genes deleted in whole or part, preferably the rep and / or cap genes, but retain functional flanking ITR sequences. Retroviruses may be chosen as gene delivery vectors due to their ability to integrate their genes into the host genome, transferring a large amount of foreign genetic material, infecting a broad spectrum of species and cell types and for being packaged in special cell- lines. In order to construct a retroviral vector, a nucleic acid encoding a gene of interest is inserted into the viral genome in the place of certain viral sequences to produce a virus that is replication-defective. In order to produce virions, a packaging cell line is constructed containing the gag, pol, and / or env genes but without the LTR and / or packaging components. When a recombinant plasmid containing a cDNA, together with the retroviral LTR and packaging sequences is introduced into this cell line (by calcium phosphate precipitation for example), the packaging sequence allows the RNA transcript of the recombinant plasmid to be packaged into viral particles, which are then secreted into the culture media. The media containing the recombinant retroviruses is then collected, optionally concentrated, and used for gene transfer. Retroviral vectors are able to infect a broad variety of cell types. Lentiviruses are complex retroviruses, which, in addition to the common retroviral genes gag, pol, and env, contain other genes with regulatory or structural function. The higher complexity enables the virus to modulate its life cycle, as in the course of latent infection. Some examples of lentivirus include the Human Immunodeficiency Viruses (HIV 1, HIV 2) and the Simian Immunodeficiency Virus (SIV). Lentiviral vectors have been generated by multiply attenuating the HIV virulence genes, for example, the genes env, vif, vpr, vpu and nef are deleted making the vector biologically safe. Lentiviral vectors are known in the art, see, e.g.. U.S. Pat. Nos. 6,013,516 and 5,994,136, both of which are incorporated herein by reference. In general, the vectors are plasmid-based or virus-based, and are configured to carry the essential sequences for incorporating foreign nucleic acid, for selection and for transfer of the nucleic acid into a host cell. The gag, pol and env genes of the vectors of interest also are known in the art. Thus, the relevant genes are cloned into the selected vector and then used to transform the target cell of interest. Recombinant lentivirus capable of infecting a non-dividing cell wherein a suitable host cell is transfected with two or more vectors carrying the packaging functions, namely gag, pol and env, as well as rev and tat is described in U.S. Pat. No.5,994,136, incorporated herein by reference. This describes a first vector that can provide a nucleic acid encoding a viral gag and a pol gene and another vector that can provide a nucleic acid encoding a viral env to produce a packaging cell. Introducing a vector providing a heterologous gene into that packaging cell yields a producer cell which releases infectious viral particles carrying the foreign gene of interest. The env preferably is an amphotropic envelope protein which allows transduction of cells of human and other species. Typically, the polynucleotide or the vector of the present invention include "control sequences'", which refers collectively to promoter sequences, polyadenylation signals, transcription termination sequences, upstream regulatory domains, origins of replication, internal ribosome entry sites ("IRES"), enhancers, and the like, which collectively provide for the replication, transcription and translation of a coding sequence in a recipient cell. Not all of these control sequences need always be present so long as the selected coding sequence is capable of being replicated, transcribed and translated in an appropriate host cell. Another nucleic acid sequence, is a "promoter" sequence, which is used herein in its ordinary sense to refer to a nucleotide region comprising a DNA regulatory sequence, wherein the regulatory sequence is derived from a gene which is capable of binding RNA polymerase and initiating transcription of a downstream (3'-direction) coding sequence. Transcription promoters can include "inducible promoters" (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), "repressible promoters" (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), and "constitutive promoters”. In some embodiments, the FLNA / B enhancer is a host cell transformed with a polynucleotide encoding FLNA / B polypeptide. The term "transformation" means the introduction of a "foreign" (i.e. extrinsic or extracellular) gene, DNA or RNA sequence to a host cell, so that the host cell will express the introduced gene or sequence to produce a desired substance, typically a protein or enzyme coded by the introduced gene or sequence. A host cell that receives and expresses introduced DNA or RNA has been "transformed". In a particular embodiment, for expressing and producing the FLNA / Bpolypeptides of the present invention, prokaryotic cells, in particular E. coli cells, will be chosen. In some embodiments, it is not mandatory to produce the FLNA / B polypeptides of the present invention in a eukaryotic context that will favour post-translational modifications (e.g. glycosylation). Furthermore, prokaryotic cells have the advantages to produce protein in large amounts. If a eukaryotic context is needed, yeasts (e.g. saccharomyces strains) may be particularly suitable since they allow production of large amounts of proteins. Otherwise, typical eukaryotic cell lines such as CHO, BHK-21, COS- 7, C127, PER.C6, YB2 / 0 or HEK293 could be used, for their ability to process to the right post- translational modifications of the FLNA / B polypeptides of the present invention. The construction of expression vectors in accordance with the invention, and the transformation of the host cells can be carried out using conventional molecular biology techniques. The FLNA / Bpolypeptides of the invention, can, for example, be obtained by culturing genetically transformed cells in accordance with the invention and recovering the FLNA / B polypeptide expressed by said cell, from the culture. They may then, if necessary, be purified by conventional procedures, known in themselves to those skilled in the art, for example by fractional precipitation, in particular ammonium sulfate precipitation, electrophoresis, gel filtration, affinity chromatography, etc. In particular, conventional methods for preparing and purifying recombinant proteins may be used for producing the proteins in accordance with the invention. The FLNA / Bpolypeptides of the present invention and polynucleotides encoding thereof are typically used as medicament. In particular, the polynucleotides encoding FLNA / Baccording to the present invention (inserted or not into a vector) are particularly suitable for gene therapy. Therapeutic composition In another aspect, the present invention relates to a therapeutic composition comprising a modulator of the ASB2-FLNA / B axis for use in the treatment of a Type 2-mediated disease in a subject in need thereof. In some embodiments, the modulator of the ASB2-FLNA / Baxis is an ASB2 inhibitor. In some embodiments, the ASB2 inhibitor is an ASB2αinhibitor. In some embodiments, the modulator of the ASB2-FLNA / B axis is a FLNA / B enhancer. In some embodiments, the modulator of the ASB2-FLNA / B axis is an ASB2 inhibitor and / or a FLNA / B enhancer. In some embodiments, the Type 2-mediated disease is asthma. In some embodiments, asthma is allergic asthma. In another aspect, the present invention also relates to a therapeutic composition comprising a modulator of the ASB2-FLNA / Baxis for use in the treatment of Type 2-mediated inflammation in a subject in need thereof. In some embodiments, the Type 2-mediated inflammation is allergic inflammation. In some embodiments, the Type 2-mediated inflammation is a Type 2-mediated airway inflammation. In some embodiments, the Type 2- mediated airway inflammation causes asthma. Any therapeutic agent of the invention (i.e. modulator of the ASB2-FLNA / Baxis) may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions. "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The form of the therapeutic compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc. The therapeutic composition of the invention can be formulated for a topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular or subcutaneous administration and the like. In some embodiments, the therapeutic composition is formulated for intranasal administration. In some embodiments, the therapeutic composition is formulated for an administration by inhalation. The therapeutic compositions may also contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment. In addition, other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; time release capsules; and any other form currently can be used. Therapeutic compositions of the present invention may comprise at least one further therapeutic active agent. Thus, in some embodiments, the present invention relates to a therapeutic composition comprising a modulator of the ASB2-FLNA / Baxis and at least one further therapeutic active agent. The present invention also relates to a kit comprising a modulator of the ASB2-FLNA / Baxis according to the invention and at least one further therapeutic active agent. For example, the further therapeutic active agent may be an anti-histaminic. Antihistamines include but are not limited to promethazine, dexchlorpheniramine, cyproheptadine, cetirizine, levocetirizine, fexofenadine, sodium cromoglycate, loratadine, desloratadine, mizolastine, ebastine, mefenidramium, rupatadine, ligelizumab or omalizumab. Another example of further therapeutic active agents relates to anti-inflammatory agents. Anti- inflammatory agents include but are not limited to resveratrol, cortisone, corticoids, beclomethasone, budesonide, fluticasone, mometasone, tixocortol, dupilumab, pascolizumab, benralizumab, mepolizumab, reslizumab, lebrikizumab, tralokinumab or triamcinolone. Another example of further therapeutic active agents relates to anaesthetics. Anaesthetics include but are not limited to lidocaine, mepivacaine, bupivacaine, etidocaine, prilocaine, tetracaine, procaine or chloroprocaine. Another example of further therapeutic active agent relates to adrenalin. This further therapeutic active agent is particularly indicated when the subject suffers from anaphylactic shock. The ASB2 / FLNA / Bmodulator of the present invention and the further therapeutic agent may be used as a combined preparation for simultaneous, separate or sequential use in one of the methods of treating herein described. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURES: Figure 1. FLNa and FLNb are substrates of Asb2α in mouse Th2 lymphocytes. T effector lymphocytes were generated from naïve CD4+T lymphocytes of ctrl and ASB2 cKO mice. a, Relative expression of ASB2α transcripts during Th2 differentiation of naïve CD4+T lymphocytes of ctrl mice assessed by RT-qPCR. b, Expression of ASB2α transcripts in ctrl and ASB2 cKO Th2 lymphocytes assessed by RT-qPCR. c, Mass spectrometry quantitative analyses of protein abundance differences between cell extracts of ctrl and ASB2 cKO Th2 lymphocytes (n=9 replicates). The volcano plot (left) illustrates for each protein the statistical significance of the variation as a function of the amplitude of the abundance (log2) difference between the two conditions. Dashed lines indicate cut-off values corresponding respectively to a Student t- test p-value of 0.01 and a log2-transformed intensity difference of 0.5. Bar plots (right) show the intensities of ASB2, FLNa and FLNb in each condition based on the MS measurements. Full data are presented in Supplementary Table 1. d,e, Expression of FLNa and FLNb relative to GAPDH was analyzed by western blot (d) and by intracellular flow cytometry (e) in ctrl and ASB2 cKO Th2 lymphocytes. f, Cell extracts of ctrl and ASB2 cKO Th2 lymphocytes were immunoprecipitated with control (Ctrl IP) or anti-FLNa (FLNa IP) antibodies. Pre-cleared cell lysates (input), unbound and bound fractions were immunoblotted with antibodies to FLNa. After stripping, the blot was reprobed with antibodies to ubiquitylated proteins. g, Expression of FLNa was analyzed by intracellular flow cytometry in ctrl Th2 lymphocytes treated at day 5 with the PS-341 proteasome inhibitor at 4 nM. h,i, Expression of FLNa and FLNb was analyzed by western blot (h) and by intracellular flow cytometry (i) in naive CD4+ T cells, Th1, Th2, Th17 and Treg cells generated from naïve CD4 T lymphocytes of ctrl mice. j, Representative flow cytometry and quantification of FLNa expression in Th1 (CD4+CXCR3+CCR6-), Th2 (CD4+CXCR3-CCR6-CRTH2+) and Th17 (CD4+CXCR3-CCR6+) lymphocytes of human PBMCs. Data are mean ± s.e.m. p-values were calculated using the Mann Whitney t-test except in g and j where the Wilcoxon matched-pairs signed rank test was used (* p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001). Figure 2. ASB2α-mediated degradation of FLNa and FLNb confers specific migration properties to Th2 lymphocytes. ctrl and ASB2 cKO Th2 lymphocytes seeded onto vitronectin-coated slides were imaged by time-lapse microscopy. Representative images (left) and individual tracks (a), percentages of migrating cells (b), track length (c), mean scanned area (d), persistence coefficient (e), average velocities (f); left panel, all the cells; right panel, cells with a track length > 50 µm), elongation coefficient and average sphericity (g) are shown. h,i, Scatter plots showing correlation data for elongation coefficient and track length (h) or average velocity (i) of ctrl Th2 lymphocytes. Linear regression-fit curves are shown as red lines. Scale bar, 20 µm. In a-i, Data are mean ± SEM. p-values were calculated using the Mann Whitney t- test (* p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001). Figure 3. Deletion of ASB2 in hematopoietic cells attenuates airway inflammation in mice. Ctrl and ASB2 cKO mice were submitted to OVA-airway inflammation (OVA) as indicated. Ctrl mice treated with PBS were used as controls. a, Inflammation of the lungs assessed using hematoxylin and eosin (HE) staining of lung sections to analyze the infiltration of inflammatory cells (0- to 12-point scale), Masson’s trichrome (MT) staining of lung sections to visualize and quantify collagen deposits (µm2 / µm) (collagen area / bronchus perimeter), and periodic acid Schiff (PAS) staining to visualize and quantify mucus production. b, Data represents the numbers of CD45+cells in the lungs. c, Numbers of CD45+Siglec-F+CD11c- (eosinophils) and representative flow cytometry plots for CD11c and Siglec-F within a CD45+gated in the lungs. d, Relative expression of eotaxin 2 mRNA in the lung lysates assessed by RT-qPCR. e, Numbers of CD45+CD4+in the lungs. f. Percentage of ST2+cells in CD4+cells, representative flow cytometry plots for ST2 and CD4 within a CD4+gate and numbers of CD45+CD4+ST2+in the lungs. g. Data represents the percentage of CD4+in CD45+cells and the percentage of ST2+in CD4+cells in the BAL fluids. h, Relative expression of IL-4, IL-5 and IL-13 mRNA in the lung lysates. i, Data represents the percentage of IL-4+, IL-5+or IL-13+in CD4+cells and in ST2+CD4+cells in the lungs. j, Production of IL-4, IL-5 and IL-13 measured by ELISA after antigen restimulation (OVA) or not (-) of cells of the lung draining lymph nodes of mice submitted to OVA-induced airway inflammation. k, Expression of FLNa was analyzed by intracellular flow cytometry in CD45+CD4+ST2+cells from the lungs of ctrl or ASB2 cKO mice submitted to OVA-induced airway inflammation. l, Intensities of FLNa calculated using MaxQuant quantitative metrics in cell extracts of CD45+CD4+ST2+living cells sorted from the lungs of control or ASB2 cKO mice submitted to OVA-induced airway inflammation. Data are mean ± SEM. p-values were calculated using the Mann Whitney t-test (* p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001). Scale bar, 200 µm. Figure 4. Deletion of ASB2 in hematopoietic cells attenuates allergic asthma in mice. Ctrl and ASB2 cKO mice were submitted to HDM-allergic airway inflammation (HDM) as indicated. a, HE, MT and PAS staining of lung sections to analyze the infiltration of inflammatory cells and inflammatory scores. b, Data represents the numbers of CD45+cells in the lungs. c, Data represents the numbers and the percentages of Siglec-F+CD11c- in CD45+cells in the lungs. d, Data represents the percentages of Siglec-F+CD11c- in CD45+cells in the BAL fluids. e, Data represents the numbers of CD4+CD45+cells, the percentages of ST2+in CD4+cells and the numbers of ST2+CD4+CD45+cells in the lungs. f, Data represents the percentages of CD4+in CD45+cells and the percentages of ST2+in CD4+cells in the BAL fluids. g, Expression of FLNa was analyzed by intracellular flow cytometry in CD45+CD4+ST2+cells from the lungs of ctrl or ASB2 cKO mice submitted to HDM-induced allergic asthma. Data are mean ± SEM. p-values were calculated using the Mann Whitney t-test (* p<0.05; ** p<0.01; *** p<0.001). Scale bar, 200 µm. Figure 5. ASB2α expressed by Th2 lymphocytes is key to the mediation of airway inflammation. OVA-specific Th2 lymphocytes generated from control or ASB2 cKO OT2 mice were transferred to C57Bl / 6 recipients that were subsequently submitted to daily OVA inhalations to induce airway inflammation. Analysis was performed 24h after the 5th(a-h) or after the 1stOVA inhalation (i-j). a, HE staining of lung sections. b, MT staining of lung sections. c, PAS staining of lung sections. d, Data represents the numbers of CD45+in the lungs. e, Data represents the numbers and the percentages of Siglec-F+CD11c- in CD45+cells in the lungs. f, Data represents the percentages of Siglec-F+CD11c- in CD45+cells in the BAL fluids. g, Data represents the numbers of Vβ5+Vα2+CD4+CD45+cells in the lungs. h, Data represents the percentages of Vβ5+Vα2+in CD4+cells in the lungs and the BAL fluids. i, Data represents the numbers of Vβ5+Vα2+CD4+CD45+cells in the lungs. j, Data represents the percentages of Vβ5+Vα2+in CD4+cells in the lungs, BAL fluids and lung draining lymph nodes. Data are mean ± SEM. p-values were calculated using the Mann Whitney t-test (* p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001). Scale bar, 200 µm. Figure 6. Targeting the Asb2α-FLNa / b axis with small molecules reduces type 2 immune response. a, Validation of the functional assay. HeLa cells were transfected with a vector expressing DsRed-hASB2α (wt) or DsRed-hASB2αLA (LA) together with a vector expressing hFLNa-GFP as indicated. Ratios of GFP MFI measured by flow cytometry in DsRed+cells treated or not with the PS-341 proteasome inhibitor to those measured in DMSO- treated cells are shown. b, Endogenously expressed FLNa MFI in Th2 lymphocytes generated from naïve CD4+T lymphocytes of B6J mice and treated at day 5 with the PCL compounds or DMSO for 20 hours. d-h, Th2 lymphocytes were generated from naïve CD4+T lymphocytes of B6J mice and treated at day 5 with 3 µM P-522 (thiostrepton / TST) or DMSO for 20 hours. Percentages of alive Th2 lymphocytes. P-128, spironolactone; P-226, griseofulvin, P-304, econazole nitrate; P-396, etoposide; P-541, ciclopirox ethanolamine; P-522, thiostrepton; P- 1045, sertaconazole nitrate; P-1459, oxfendazole, P-1460, oxibendazole; P-1494, irinotecan hydrochloride trihydrate; P-1709, estramustine; P-1938 (carbazochrome sodium sulfonate), P- 1942, L-tryptophan; P-1952, prosultiamine; P-1989, flupirtine; P-2066, tinoridine hydrochloride; P-2096, riboflavin (c), Ki67 MFI (d) and GATA3 MFI (e) measured by flow cytometry in ctrl Th2 lymphocytes are shown. f, Expression of FLNa was analyzed and quantified by western blot. g, FLNa MFI measured by flow cytometry in Th2 lymphocytes after 20h-treatment of human PBMCS with 3 µM TST or DMSO. h-m. Airway inflammation induced by OT2 Th2 lymphocytes treated with 3 µM TST or DMSO before injection to recipient mice. HE, PAS and MT staining of lung sections (h), percentages of Siglec-F+CD11c- in CD45+cells and numbers of Siglec-F+CD11c-CD45+in the lungs (i), percentages of Siglec- F+CD11c- in CD45+cells in BALF (j), numbers of Vβ5+Vα2+CD4+CD45+cells in the lungs (k) and percentages of Vβ5+Vα2+in CD4+cells in the lungs, in BALF and LDLN (l) are shown. m, Data represent the concentrations of IL-4, IL-5 and IL-13 in the supernatants of LDLN cells measured by ELISA after antigen restimulation (OVA). Data are mean ± SEM. In i-m, each dot represents the mean measured in two recipient mice. p-values were calculated using the Wilcoxon matched-pairs signed rank test except in a and d where the Mann Whitney t-test was used (* p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001). Scale bar, 200 µm. EXAMPLE: Methods Reagent and antibodies PS-341 (Euromedex) was prepared in DMSO. The Prestwick Chemical Library was obtained from GreenPharma. Ciclopirox olamine, econazole nitrate, oxibendazole, riboflavin, spironolactone and thiostrepton were purchased from MedChemExpress and prepared in DMSO. Mice and models of airway allergic inflammation All mice were housed under specific pathogen-free conditions. Female Asb2fl / fl(control) and VE-cadherin (VEC) -Cre;Asb2fl / fl(ASB2 cKO) transgenic mice were generated as described previously9,14. TCR transgenic OT2 mice were crossed with VEC-Cre;Asb2fl / flto generate female OT2;VEC-Cre;Asb2fl / flor OT2;Asb2fl / flmice. Female C57BL / 6J mice were purchased from Charles River Laboratories or Janvier Labs. Mice studies were handled according to the Centre National de la Recherche Scientifique (CNRS) and the Institut national de la santé et de la recherche médicale (Inserm) ethical guidelines and approved by the French Ministry ethic committees (CEEA-122 & CEEA-001). Control or ASB2 cKO transgenic mice were immunized by intraperitoneal injection of 100 µg ovalbumin (OVA; Sigma-Aldrich) in alum (2 mg; Sigma- Aldrich) at day 0 and 7. From days 22 to 26, mice were subjected to five daily OVA inhalation (50 µg / day) and analyzed at day 28. Control or ASB2 cKO transgenic mice were subjected to HDM inhalation (10 µg) (Dermatophagoides pteronyssinus, Stallergenes Greer) at day 0. From days 7 to 11, mice were subjected to five daily HDM inhalation (10 µg / day) and analyzed at day 16. For Th2 lymphocyte adoptive transfer experiments, 3x106ASB2 cKO or ctrl OT2 Th2 lymphocytes were injected intravenously into C57Bl / 6J recipients. Recipient mice received intranasal OVA (50 µg) for 1 or 5 days. Twenty-four hours after the last OVA administration, serum, bronchoalveolar lavage fluid (BALF), lungs, and lung draining lymph nodes (LDLN) were collected and processed. Lungs were digested for 30 min at 37°C with 0.25 mg / ml Liberase (Sigma-Aldrich) and 0.5 mg / ml DNAse I (Roche). LDLN were digested for 25 min at 37°C with 2.5 mg / ml collagenase D (Roche). Single-cell suspensions were used after filtration through a 70-µm strainer. Histological analyses Lungs were fixed in 4 % paraformaldehyde (Electron Microscopy Sciences) at 4°C for 24 h, placed in 70 % ethanol and paraffin embedded. Sections (5 µm) were stained with hematoxylin and eosin (HE), Masson Trichrome (MT) or Periodic Acid Schiff (PAS). Histological disease scores from 0 to 3 were attributed based on the severity of peribronchial, perivascular, and interstitial immune cell infiltration, together with thickening of peribronchial epithelium, resulting in a maximum score of 12. Collagen deposit and PAS+bronchi were quantified using QuPath version 0.4.115. The algorithm was based on a pixel classifier and was trained on representative pictures with dedicated annotations. Bronchi were manually delineated and the respective total amount of detected collagen was obtained. The percentage of PAS+bronchi were calculated by comparing the percentage of PAS staining in manually detected respective bronchi. T lymphocyte culture In vitro differentiation of mouse Th1, Th2, Treg, and Th17 cells was performed as previously described8. Peripheral blood mononuclear cells (PBMC) were obtained from Etablissement Français du Sang, and all human participants provided written informed consent. Freshly thawed PBMCs were cultured in RPMI 1640 supplemented with 5% FBS, 1mM sodium pyruvate, 2 mM glutamine, 100 U / ml penicillin, 100 mg / ml streptomycin, 1mM HEPES and 1% NEAA medium for 24 hours before treatment with 3 µM TST or DMSO. ELISA Lung draining lymph node cells were seeded into 96-well flat-bottom plates (6x105cells per well) and stimulated with 200 µg / ml ovalbumin in complete medium (RPMI 1640 supplemented with 10% FBS, 1% pyruvate, 2 mM glutamine, 100 U / ml penicillin, 100 mg / ml streptomycin, and 50 µmol / l β-mercaptoethanol) for 72 hours, and cytokine production was quantified by ELISA according to the manufacturer (Invitrogen). RT-qPCR RNA isolation, cDNA synthesis, and real-time PCR with the SYBR Green mix were carried out as described previously8. Gene expression was determined using the ∆∆Ct method and data are presented as relative amounts of mRNA normalized to Rplp0 (ribosomal protein, large, P0) or YWHAZ for mouse or human cells, respectively. Micro-array and chromatin immunoprecipitation sequencing analysis Micro-array ASB2, ITGAV, ITGB3 expression data and ChIP-seq data showing global histone H3 lysine 27 acetylation (H3K27ac), H3 lysine 4 and lysine 27 trimethylation (H3K4me3 and H3K27me3) in the ASB2, ITGAV and ITGB3 loci in T lymphocytes cultured under Th1, Th2 and Th17 conditions were retrieved from the GSE144586 dataset16. Micro- array ASB2, ITGAV, ITGB3 expression data in OVA-induced airway inflammation and HDM- induced asthma were retrieved from the publicly available GSE10973717and GSE720018datasets, respectively. RNA-seq Total RNA was extracted with the Nuclespin RNA kit (Macherey-Nagel) and subsequently used to prepare the libraries using the Stranded Total RNA Prep, Ligation with Ribo-Zero Plus kit (Illumina). Quality controls of the libraries were performed using standard methods, including quantification with Qubit spectrophotometer and assessment of size distribution with TapeStation 4150 (Agilent). Samples were indexed and sequenced (paired- end reads of 150 bp) on the NovaSeq 6000 system (Illumina) from the Genomic and Transcriptomic Platform of the GeT core facility 414 (Toulouse, France). Raw sequencing reads were processed using nf-core / rnaseq pipeline v.3.12.0 developed with Nextflow. Briefly, this pipeline trims adapters and removes low-quality reads using Cutadapt v.3.4. It then aligns reads to the Ensemble GRCm39_v.107 genome using STAR v.2.7.9a. Finally, gene expression was quantified with Salmon v.1.10.1. Only samples with more than 10 M reads were kept for further analyses. Raw counts were normalized and differential expression analyses were performed using the R package DESeq2 v.1.38.3. Differentially expressed genes between activated and non-activated ctrl Th2 lymphocytes were identified as genes with an adjusted p-value below 0.5 and an absolute log2 fold change greater than 2. Gene Set Enrichment analyses were performed with ClusterProfiler v.4.6.2. Heatmap and boxplots were made using Th1 and Th2 gene sets extracted from Adoue V. et al (2019) and Th17 gene set extracted from the Harmonizome database v.3.0. RNA-seq data used in this study have been deposited at GEO under accession number GSE251847. Flow cytometry For flow cytometry analysis and cell sorting, cells were first incubated with Zombie viability dyes (BioLegend) for 15 min at room temperature and then incubated for 30 min a 4°C with the appropriate combination of antibodies. IL-4, IL-5 and IL-13 were measured by intracellular staining after stimulation for 5 hours with phorbol 12-myristate 13-acetate (50 ng / ml, Sigma-Aldrich) and ionomycin (500 ng / ml, Sigma-Aldrich). Cells were incubated with Monensin (BioLegend) during the last 4 hours of stimulation. Quantification of FLNa expression by FACS was performed as previously described19. Flow cytometry analysis was performed with LSRII or Fortessa X20 Cytometers (BD Biosciences) and cell sorting on a FACS ARIA II Cytometer (BD Biosciences). Analyses of flow cytometry data were performed using FlowJo (TreeStar). High Content imaging, image acquisition and processing CellCarrier Ultra tissue culture treated 384-well plates (Perkin Elmer) were coated with 1 µg / ml vitronectin (BioLegend) or 1 µg / ml of VCAM-1 (BioLegend).10,000 Th1, ctrl Th2, ASB2 cKO Th2, Treg or Th17 cells were seeded per well and incubated 25 min at 37°C to adhere in RPMI 1640 supplemented with 10 % FBS, 2 mM glutamine, 100 U / mL penicillin and 100 mg / mL streptomycin and then fixed with 4% paraformaldehyde, 60 mM sucrose (Sigma- Aldrich). After fixation, cells were washed and stained with anti-FLNa, anti-FLNb and phalloidin. Nuclei were stained with 50 ng / ml of DAPI. Images were acquired on an automated Opera Phenix confocal HCS device (Perkin Elmer) with a 40x 1.1 NA Plan Apochromat water immersion objective and a SCMOS camera.13 non-adjacent fields and 3 stacks per field (1 µm step) were acquired per well. Stacks of images were combined, then assembled in sets of images per field of view corresponding to DAPI, phalloidin, FLNa and / or FLNb. These datasets were processed, and measurements were made using the Harmony software. Time-lapse Imaging and Analyses 6 channel µ-slide VI 0.4 (Ibidi) were coated overnight with 1 µg / ml of vitronectin (BioLegend). Control and ASB2 cKO Th2 lymphocytes were labelled 15 min at 37°C with 0.6 µM CellTraker Green (CTG) CMFDA (Invitrogen). Labelling reactions were stopped by addition of PBS.8 x 105cells were seeded per well and migration was initiated by the addition of 10% FBS. When indicated Th2 lymphocytes were treated with 0.5 mM MnCl2and a combination of 0.2µg / mL of antibodies against mouse CD51 (Clone RMV-7) or the corresponding isotypic controls (Clone HTK888), and 0.2 µg / mL of antibodies against mouse CD61 (Clone 2C9.G2) or the corresponding isotypic controls (Clone HTK888). The microscope environmental chamber was maintained and monitored at 37°C and 5% CO2. Images were acquired by spinning disk confocal microscopy (Yogokawa head, Hamamatsu CMOS Flash4 camera, 20X objective NA 0.75) using the Metamorph 7.10.1.161 software. Images were acquired every minute for both transmitted light and 491 nm CTG associated fluorescence. Multiple parameters measurements of images were performed via IMARIS 9.5 software (Oxford Instruments). Distance and directionality data were obtained using spot function. Shape description data were obtained using surface function. Spider plots were obtained using the MatLab algorithm on track distance data. Western blot For immunoblot analysis, cells were pelleted, washed in PBS and lysed using in whole- cell extract buffer containing 50 mM Tris-HCl (pH 7.9), 150 mM NaCl, 1 mM EDTA, 0.1% Igepal CA-630, 10% glycerol, 1 mM dithiothreitol, 1 mM Na3VO4, 50 mM NaF, 25 mM β glycerophosphate, 2 mM Na pyrophosphate and 1% protease inhibitor cocktail (P8340; Sigma- Aldrich). After three freeze–thaw cycle in liquid nitrogen, the resulting cell lysates were cleared by a 20 min 20,000 g centrifugation at 4 °C. The lysates were boiled with Laemmli buffer, resolved by SDS–polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes and the proteins visualized by standard immunoblotting procedures. Signal acquisition was conducted using the Bio-Rad ChemiDoc apparatus and quantification of the immunoblot signal was performed with the Bio-Rad Image Lab software. Protein quantifications were normalized to the levels of the GAPDH protein. Immunoprecipitation ctrl and ASB2 cKO Th2 lymphocytes generated in vitro from naïve CD4+ T lymphocytes were washed twice in ice-cold PBS, and lysed in Triton X100 lysis buffer containing 20 mM Tris-HCl, pH 8, 137 mM NaCl, 10% glycerol and 1% Triton X100 and supplemented with 1% protease inhibitor cocktail (Sigma-Aldrich), 1 mM DTT, 1 mM Na3VO4, 50 mM NaF, 2mM sodium pyrophosphate and 25 mM β-glycerophosphate. After a 30 min incubation on ice, cell lysates were cleared by a 20-min 20000 X g centrifugation at 4°C.100 μg ctrl or ASB2 cKO Th2 lymphocyte extracts was precleared by incubating 30 minutes in the presence of protein A-Sepharose beads (GE Healthcare) in a binding buffer containing 20 mM Tris-HCl pH 8, 250 mM NaCl, 10% glycerol and 0.1% Igepal CA-630 at 4°C. Anti-rabbit FLNa serum or rabbit pre-immune serum was added to the precleared cell extracts. After 16 hours of incubation, immunocomplexes were recovered with protein A-Sepharose. After 3 washes with binding buffer, proteins were eluted with boiling Laemmli’s buffer, fractionated by SDS- polyacrylamide gel electrophoresis (SDS-PAGE) and analyzed by immunoblotting with anti- FLNa. After incubation with the Restore western blot stripping buffer (Fisher Scientific), proteins were probed with antibodies to ubiquitylated proteins. Proteome Analysis Ctrl and ASB2 cKO Th2 lymphocytes generated in vitro from naïve CD4+T lymphocytes and CD45+CD4+ST2+living cells sorted from the lungs of control or ASB2 cKO mice submitted to OVA-induced airway inflammation were lysed in 5% SDS, 50mM ammonium bicarbonate and sonicated on a Bioruptor (Diagenode). Proteins were digested on S-trap devices (Protifi) and 50 ng of the resulting peptides were analyzed by nanoLC-MS / MS using an UltiMate 3000 RS nanoLC system (ThermoFisher Scientific) coupled to a TIMS-TOF SCP mass spectrometer (Bruker). Peptides were separated on a C18 Aurora column (25 cm x 75 µm ID, IonOpticks) using a gradient ramping from 2% to 20% of B in 30 min, then to 37% of B in 3 min and to 85% of B in 2min (solvent A: 0.1% FA in H2O; solvent B 0.1% FA in acetonitrile), with a flow rate of 150 nl / min. MS acquisition was performed in DIA-PASEF mode on the precursor mass range [400-1000] m / z and ion mobility 1 / K0 [0.64-1.37]. The acquisition scheme was composed of 8 consecutive TIMS ramps using an accumulation time of 100 ms, with 3 MS / MS acquisition windows of 25 Th for each of them. The resulting cycle time was 0.96 s. The collision energy was ramped linearly as a function of the ion mobility from 59 eV at 1 / K0=1.6 Vs.cm−2to 20 eV at 1 / K0=0.6Vs.cm−2. Nine independent replicate samples for each condition (ctrl or ASB2 cKO), obtained from 2 different cell culture experiments, were analyzed in total. The raw data (18 files) was searched and quantified with DIA-NN 1.8.1, using a predicted library generated by the software from the Uniprot mouse reference proteome. Validation was performed at 1% precursor and protein FDR, with a peptide length range set at 7–30 and precursor charge range set at 2–3. MS intensities measured by DIA-NN for each peptide ions (precursor matrix) were processed using the Proline software20for calculation of protein intensities (peptide-to-protein inference and summarization of peptide intensities) and normalization. Only proteins detected and quantified in more than 2 replicates from at least one of the conditions (ctrl or ASB2 cKO), and quantified based on more than 2 peptides, were kept for statistical analysis. Normalized abundance values were log2- transformed, and missing values were imputed with a low-intensity value reflecting the noise background, defined for each analytical run as the lowest 1% percentile value of the total protein intensity distribution. A student t-test (bilateral, equal variance) was calculated based on the 9 replicates to evaluate statistical significance of the protein abundance variation between the two conditions. Cell lines and culture conditions HeLa cells were grown in Dulbecco modified Eagle medium (DMEM) containing 4.5 g / l glucose (Invitrogen), 10% fetal bovine serum (FBS; Biowest) and penicillin–streptomycin (Invitrogen). HeLa cells were transfected using the Jet PEI reagent (Polyplus transfection) as recommended by the manufacturer. Plasmid constructs The pDsRED-monomerC1-hASB2α and pDsRED-monomerC1-hASB2αLA were as described10. The pcDNA3-FLNa-GFP21and pCl-puro-FLNb-GFP22expression constructs have been used previously. High-throughput screen for drugs increasing FLNa levels HeLa cells were co-transfected with pDsRED-monomerC1-hASB2α and pcDNA3- FLNa-GFP. After 6 h, cells were seeded into 96-well-plates (3X104cells per well) and treated with compounds from the Prestwick Chemical Library at 10 µM or DMSO. Eighteen hours later, GFP MFI of FLNa-GFP in DsRed+cells was assessed by flow cytometry. Statistical Analyses All p-values were calculated using the nonparametric Mann-Whitney t-test except in Figure 1j and Figure 8c,e-n where the Wilcoxon’s test was used. For the proteome analyses, the Student t-test was used in the statistical analysis. Differences were considered significant at p<0.05. ****p<0.0001; ***p<0.001; **p<0.01; *p<0.05; ns, not significant. Results The actin-binding protein FLNa and FLNb are substrates of ASB2α in Th2 lymphocytes. To elucidate the roles of ASB2α in Th2 lymphocytes, we first evaluated its expression upon Th2 differentiation of naïve CD4+T lymphocytes in vitro. ASB2α transcripts are highly expressed after 5 days of culture of naïve CD4+lymphocytes from ctrl mice in Th2 polarizing conditions (Figure 1a) and are almost undetectable in Th2 lymphocytes generated from ASB2 cKO mice (Figure 1b). Because E3 ubiquitin ligases often ubiquitylate several substrates, we used an unbiased and broad mass spectrometry approach to identify ASB2α substrates in Th2 lymphocytes generated from naïve CD4+T lymphocytes of ctrl or ASB2 cKO mice. As expected, ASB2 peptides were barely detected in ASB2α-deficient Th2 lymphocytes (Figure 1c). Deletion of ASB2 had no impact on the expression of the master transcription factors of the Th2 lineage STAT6, GATA3 and c-MAF (data not shown), suggesting no role of ASB2α in the generation of Th2 lymphocytes. Out of the > 6400 quantified proteins in MS experiments, FLNa and FLNb stood out as the only proteins being more abundantly expressed in ASB2α-deficient vs ctrl Th2 lymphocytes (Figure 1a and data not shown), pointing to the selectivity of ASB2α in controlling FLNa / FLNb levels. Enhanced expression of FLNa and FLNb at the protein levels in ASB2α-deficient Th2 lymphocytes was confirmed by western blot (Figure 1d) and intracellular flow cytometry (Figure 1e). In contrast, levels of FLNa and FLNb transcripts were similar in ctrl and ASB2 cKO Th2 lymphocytes (data not shown). Furthermore, we showed that FLNa was conjugated to ubiquitin chains in ctrl but not in ASB2 cKO Th2 lymphocytes (Figure 1f) and that FLNa degradation in ctrl Th2 lymphocytes was proteasome-dependent (Figure 1g). Altogether, these results demonstrate that the FLNa and FLNb proteins are continuously degraded in Th2 lymphocytes expressing ASB2α. Notably, lower levels of FLNa and FLNb in Th2 lymphocytes compared to naïve CD4+T lymphocytes or to other T effector lymphocytes were observed by western blot (Figure 1h and data not shown) and by intracellular flow cytometry (Figure 1i), while the levels of FLNa and FLNb transcripts were similar in Th1, Th2, Th17 and Treg lymphocytes (data not shown). In agreement with the low levels of ASB2α transcripts previously measured in naive CD4+ T lymphocytes, Th1 and Th17 lymphocytes, loss of ASB2α had no impact on the abundance of FLNa and FLNb in these cells (data not shown). Protein levels of FLNa were also lower in Th2 lymphocytes than in Th1 or Th17 lymphocytes of human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors (Figure 1j). ASB2α transcript and protein are also induced during the in vitro Th2 differentiation of naive human CD4+ T lymphocytes (data not shown). Moreover, FLNa degradation in human Th2 lymphocytes is proteasome-dependent as evidenced by increased levels of FLNa after proteasome inhibition (data not shown). Altogether, these results demonstrate that the FLNa and FLNb proteins are continuously and selectively degraded by ASB2α in mouse Th2 lymphocytes and suggest that this mechanism is conserved in humans. Loss of ASB2α has no impact on the transcriptomic program of Th2 lymphocytes. Because ASB2α-mediated degradation of FLNa and FLNb could be involved in the modulation of Th2 lymphocyte signaling and thus in the regulation of Th2-specific genes, the transcriptomic signatures of ctrl and ASB2α-deficient Th2 lymphocytes were established by RNA-seq (data not shown). Our analyses failed to detect differentially expressed genes between ctrl and ASB2 cKO Th2 lymphocytes (data not shown). In fact, Th2-specific genes exhibited similar expression patterns in ctrl and ASB2 cKO Th2 lymphocytes, while Th1 and Th17 gene signatures were not deregulated in the absence of ASB2α (data not shown). Collectively, these analyses strongly support that ASB2α does not play a role in regulating the expression of Th genes. We next tested whether ASB2α-deficiency could nevertheless affect the transcriptional program in Th2 lymphocytes upon T-cell stimulation. Once again, our RNA- seq data did not reveal any significant difference between ctrl and ASB2 cKO Th2 lymphocytes (data not shown). Altogether, these data indicate that ASB2α does not shape Th2 lymphocyte identity at the transcriptional level. ASB2α-mediated degradation of filamins A and B in Th2 lymphocytes correlates with specific morphological features. Because FLNa has a dual role in controlling the architecture and the mechanics of the actin cytoskeleton23, we examined whether the lower levels of FLNa and FLNb in mouse Th2 lymphocytes impact cell morphology using high- content imaging. We demonstrated that lower levels of FLNa and FLNb correlated with increased cell area and perimeter, as well as an elongated shape in Th2 lymphocytes compared to Th1, Th17 or Treg lymphocytes (data not shown). In accordance with these observations, higher levels of FLNa and FLNb in ASB2α-deficient Th2 lymphocytes correlated with reduced cell area and perimeter, and a rounded shape of these cells compared to ctrl Th2 lymphocytes (data not shown). In addition, low levels of FLNa in human Th2 lymphocytes are associated with increased cell area and perimeter, and an elongated shape compared to naive human CD4+ T lymphocytes (data not shown). These results suggest that the low levels of FLNa and FLNb due to their degradation driven by ASB2α confer specific morphological features to Th2 lymphocytes. ASB2, ITGAV and ITGB3 belong to the core set of Th2-specific genes. Because FLNa is also a gatekeeper to integrin activation23, we next examined the expression of α and β integrin subunits in Th2 lymphocytes by semi-quantitative MS. We demonstrated that the ⍺Vβ3integrin together with the leukocyte-specific ⍺Lβ2integrin are the main integrin proteins expressed in Th2 lymphocytes and ASB2 deficiency has no impact on their abundance (data not shown). Given that transcriptional specificity is largely controlled by chromatin-based regulations in differentiating Th cells, we hypothesized that the genes encoding the ⍺V (ITGAV) and β3(ITGB3) integrin subunits and the ASB2⍺ protein might be controlled by epigenetic regulatory pathways in different Th cell lineages. We first conducted expression profiling of genes encoding the α and β subunits of integrins in naive, Th1, Th2 and Th17 lymphocytes using our previously published transcriptomic data16. ASB2, ITGAV and ITGB3 transcripts are more expressed in Th2 lymphocytes compared to in naive, Th1 and Th17 lymphocytes (data not shown). Global mapping of RNApol II, and active (H3K27ac, H3K4me1) and repressive (H3K27me3) histone marks in naive, Th1, Th2 and Th17 lymphocytes indicated that ASB2, ITGAV and ITGB3 gene harbor cis-regulatory regions that are specifically active in Th2 lymphocytes. These latter are either poised or repressed through H3K23m3-dependent silencing mechanisms in the other lineages (data not shown). This indicates that chromatin remodeling machineries maintain these enhancers in their respective active and silent states implying that these three genes play an important role in Th2 lymphocyte identity and / or function. All these data imply that ASB2, ITGAV and ITGB3 belong to the core of Th2-specific genes. We then wondered whether the expression of ASB2, ITGAV and ITGB3 transcripts were upregulated in Th2 lymphocyte-dependent pathological settings. Analyses of transcriptomic data17,18showed that ASB2, ITGAV and ITGB3 transcripts are upregulated in both ovalbumin (OVA)- induced airway inflammation and house dust mite (HDM)-induced asthma (data not shown). Importantly, cell surface expression of αvand β3 integrin subunits was also higher in human Th2 lymphocytes compared to naïve CD4+T lymphocytes or Th1, Th17 and Treg lymphocytes of human PBMCs (data not shown), and in vitro generated human Th2 lymphocytes compared to naïve human CD4+ T lymphocytes. Overall, these results suggest a coordinated regulation of ASB2α and the αVβ3integrin in Th2 lymphocytes to build an efficient Th2 lymphocyte response. ASB2α-mediated degradation of FLNa and FLNb regulates migration properties of Th2 lymphocytes. FLNa restrains integrins in a resting state by preventing the binding of Talin24,25. We therefore speculated that degradation of FLNa and FLNb triggered by ASB2α in Th2 lymphocytes favors fast αVβ3 integrin-dependent migration within inflamed tissues via a bypass of the inside-out signal. We first verified that ASB2α loss has no effect on the total amount and cell surface expression of αVand β3 integrins (data not shown). We then use live imaging to study the dynamics of ctrl and ASB2 cKO Th2 lymphocytes seeded onto vitronectin- coated slides (data not shown). Single-cell analysis revealed marked differences in the dynamic motility patterns of ctrl and ASB2 cKO Th2 lymphocytes (Figure 2a,b,c,d,e,f). ASB2α-deficient Th2 lymphocytes exhibited a diminished track displacement length (Figure 2a,b,c), a diminished mean scanned area and persistence (Figure 2a and 2d,e), associated with a reduced cell velocity compared to ctrl Th2 lymphocytes (Figure 2f). This reduced cell velocity is not due to a defect in the initiation of the migration since cells that have a track length > of 50µm present also a reduced velocity in the absence of ASB2 (data not shown). Our results demonstrated that ASB2α-deficient Th2 lymphocytes are less motile, indicating that loss of ASB2α impacted the dynamic behavior of Th2 lymphocytes. As previously observed with fixed cells, live imaging showed that ASB2α-deficient Th2 lymphocytes have a rounded shape compared to ctrl Th2 lymphocytes (Figure 2g). We also observed a positive correlation between the elongated shape and the track displacement length or the average velocity of ctrl Th2 lymphocytes but not ASB2α-deficient Th2 lymphocytes (Figure 2h,i). Taken together, our data indicate the low levels of FLNa and FLNb due to their degradation driven by ASB2α confer specific migratory properties to Th2 lymphocytes. Accumulation of FLNa and FLNb inhibits integrin-dependent migration of ASB2α-deficient Th2 lymphocytes by enhancing integrin activation. To understand how FLNa and FLNb accumulation in ASB2α-deficient Th2 lymphocytes inhibits cell migration, we challenged the two models linking FLNa to inhibition of integrin-dependent cell motility. In the first model, FLNa maintains integrins in an inactive state. In a second model, FLNa promotes integrin outside-in signaling leading to inhibition of dynamic cell movement. We first studied by live imaging the dynamics of ctrl and ASB2 cKO Th2 lymphocytes treated with MnCl2 to activate integrins and allowed to migrate onto vitronectin-coated slides (data not shown). Compared to untreated ctrl Th2 lymphocytes, MnCl2-treated ctrl Th2 lymphocytes exhibited a diminished track displacement length and a reduced cell velocity that were similar to those measured in untreated or in MnCl2-treated ASB2 cKO Th2 lymphocytes (data not shown), suggesting that integrins are more activated in ASB2α-deficient Th2 lymphocytes than in ctrl Th2 lymphocytes. We then assessed the dynamics of ctrl and ASB2 cKO Th2 lymphocytes treated with a combination of anti-αVand anti-β3integrin blocking antibodies to inhibit integrins. As expected, following αVβ3 integrin inhibition, ctrl Th2 lymphocytes showed decreased track displacement length and decreased cell velocity compared to untreated cells in agreement with the role of the αVβ3integrin in Th2 lymphocyte migration cells (data not shown). In contrast, following αVβ3integrin inhibition, ASB2 cKO Th2 lymphocytes exhibited an enhanced track displacement length and an increased cell velocity compared to untreated cells (data not shown), reinforcing the view that increased levels of FLNa and FLNb in ASB2 cKO Th2 lymphocytes leads to abnormal αVβ3integrin dependent cell migration. Deletion of ASB2 in hematopoietic cells attenuates OVA-induced airway inflammation and HDM-induced asthma. We next investigated the specific role of ASB2α in Th2 lymphocytes in a mouse model of airway inflammation. Compared to ctrl mice, induction of airway inflammation with OVA injection and challenge in ASB2 cKO mice resulted in: (i) decreased cell infiltration, mucus secretion and remodeling of the airways (Figure 3a); (ii) reduced numbers of leukocytes in the lungs (Figure 3b); (iii) similar numbers of alveolar macrophages, (iv) less eosinophil recruitment in the lungs (Figure 3c) in agreement with the reduced expression of eotaxin 2 mRNA in lung lysates (Figure 3d); (v) reduced numbers of CD4+cells and Th2 lymphocytes in the lungs (Figure 3e, f) and in the bronchoalveolar lavage fluids (BALF; Figure 3g); (vi) decreased mRNA levels of IL-4, IL-5 and IL-13 in lung lysates (Figure 3h); (vii) reduced percentages of IL-4+, IL-5+or IL-13+in CD4+cells in the lungs and reduced percentages of IL-4+, IL-5+or IL-13+in ST2+CD4+cells in the lungs (Figure 3i); and (viii) reduced IL-4, IL-5 and IL-13 secretion by LDLN cells after OVA-antigen restimulation (Figure 3j). In contrast, numbers and percentages of Th1 lymphocytes in the lungs as well as mRNA levels of TBX21 and IFNG were similar in ctrl and ASB2 cKO mice submitted to OVA-induced inflammation (data not shown). FLNa is substrate of ASB2α in Th2 lymphocytes from the lungs of mice submitted to OVA-airway inflammation as evidenced by increased FLNa intensity in ASB2 cKO mice measured by intracellular flow cytometry (Figure 3k) or mass spectrometry (Figure 3l). Although an experimental toolbox to dissect molecular mechanisms governing complex pathologies, the OVA model of asthma is artificial. We therefore focused on a more clinically-relevant asthma model based on repeated exposures to HDM inhalation. As shown in Figure 4, loss of ASB2α resulted in: (i) decreased inflammation and mucus production (Figure 4a); (ii) decreased recruitment of leukocytes in the inflamed lungs (Figure 4b); (iii) decreased recruitment of eosinophils in the lungs (Figure 4c) and in BALF (Figure 4d); (iv) decreased recruitment of CD4+cells and Th2 lymphocytes in the lungs (Figure 4e); and (v) reduced percentages of CD4+cells in leukocytes and of ST2+cells in T lymphocytes in the BALF (Figure 4f). Furthermore, FLNa is substrate of ASB2α in Th2 lymphocytes from the lungs of mice submitted to HDM-asthma as evidenced by increased FLNa intensity in Th2 lymphocytes of the inflamed lungs of ASB2 cKO mice (Figure 4g). Collectively, our work showed that loss of ASB2α in hematopoietic cells attenuates airway inflammation in both models. ASB2α expressed by Th2 lymphocytes is key to the mediation of airway inflammation. To evaluate whether ASB2α in Th2 lymphocytes plays important roles in airway inflammation, we used a mouse model of adoptive transfer that relies on the injection of OVA-specific Th2 lymphocytes from ctrl or ASB2 cKO OT2 mice to C57Bl / 6 recipients followed by OVA inhalation. Deletion of ASB2 attenuated decreased cell infiltration, mucus secretion and remodeling of the airways (Figure 5a,b,c). Compared to mice that received ctrl OT2 Th2 lymphocytes, mice that received ASB2 cKO OT2 Th2 lymphocytes showed: (i) reduced leukocyte infiltration in the lungs (Figure 5d); (ii) reduced frequencies and reduced numbers of eosinophils (CD45+Siglec-F+CD11c-) in the lungs (Figure 5e); (iii) reduced frequencies of eosinophils in the BALF (Figure 5f); (iii) reduced numbers of Vβ5+Vα2+CD4+CD45+cells in the lungs (Figure 5g); (iv) reduced frequencies of OT2 Th2 lymphocytes in the lungs and BALF (Figure 5h). Altogether, our results indicate that ASB2α expressed by Th2 lymphocytes is key to the mediation of airway inflammation and points to ASB2α-mediated degradation of FLNa and FLNb as a molecular mechanism sustaining Th2 lymphocyte functions. To further elucidate how ASB2α loss and subsequent accumulation of FLNa and FLNb alters Th2 lymphocyte functions leading to attenuated airway inflammation, we analyzed the recruitment of transferred OT2 Th2 lymphocytes into the lungs 24 hours after the first OVA-inhalation. The numbers of ASB2 cKO OT2 Th2 lymphocytes in the lungs (Figure 5i) and their frequencies in the lungs and BALF (Figure 5j) were lower compared to those of ctrl Th2 lymphocytes, suggesting decreased recruitment of ASB2α-deficient Th2 lymphocytes in the inflamed area. Taken together, our results indicate that loss of ASB2α in Th2 lymphocytes reduces cell mobility and attenuates the recruitment of Th2 lymphocytes in inflamed areas, suggesting that increasing levels of FLNa and FLNb in Th2 lymphocytes might mitigate pathogenic type 2 immune responses. Targeting the ASB2α-FLNa / b axis with thiostrepton (TST) attenuates airway inflammation. We evaluated the therapeutic value of targeting the ASB2α-FLNa / b axis in type 2 diseases. We performed a functional screen of the 1520 FDA, EMA and / or JAN-approved bioactive molecules contained in the Prestwick Chemical Library to identify compounds that increase FLNa and FLNb levels in ASB2α-expressing cells. In this assay, human FLNa is fused to the green fluorescent protein (GFP) while human ASB2α is fused to the DsRed protein to facilitate monitoring FLNa levels in ASB2α-expressing cells by flow cytometry. As a validation of this approach, we first showed that the levels of FLNa are higher in ASB2α-expressing cells treated with the PS-341 proteasome inhibitor than in untreated cells, and are comparable to the levels measured in cells expressing an ASB2α E3 ubiquitin ligase defective mutant (Figure 6a). We next identified 17 compounds that significantly increase the levels of FLNa-GFP in ASB2α-expressing cells (data not shown). Among them, 13 also increase the levels of FLNb- GFP (data not shown). Five of these compounds increase the levels of endogenously expressed FLNa in mouse Th2 lymphocytes (Figure 6b). We then focused on one of these drugs, TST (P- 522), to evaluate its ability to inhibit the Type 2 response and assess the therapeutic value of targeting the ASB2α-FLNa / b axis in a mouse model of airway inflammation. We first verified that TST has no effect on Th2 lymphocyte viability and proliferation nor on Th2 differentiation (Figure 6c,d,e). As shown by immunoblotting (Figure 6f), TST increased the levels of FLNa proteins in Th2 lymphocytes. In addition, treatment of human PBMCs of healthy donors with TST increased FLNa levels in Th2 lymphocytes (Figure 6g). Similarly to ASB2α-deficient Th2 lymphocytes and in contrast to ctrl Th2 lymphocytes treated or not with DMSO, TST-treated ctrl Th2 lymphocytes are less motile (data not shown). Indeed, they exhibited: (i) a diminished track displacement length, a diminished mean scanned area, a reduced cell velocity and a less elongated shape (data not shown). Using the passive asthma model, we next showed that airway inflammation was attenuated in mice receiving OVA-specific Th2 cells treated with TST before injection, as evidenced by: (i) HE, MT and PAS staining (Figure 6h); (ii) decreased recruitment of eosinophils in the lungs (Figure 6i); (iii) decreased percentages of eosinophils in the BALF (Figure 6j); (iv) decreased numbers of Vβ5+Vα2+CD4+cells in the lungs (Figure 6k); (v) decreased percentages of Vβ5+Vα2+CD4+cells in the lungs, the BALF and the LDLN (Figure 6l). In addition, reduced IL-4, IL-5 and IL-13 secretion by LDLN cells of mice that received TST-treated OT2 lymphocytes after OVA-antigen restimulation was measured (Figure 6m). Taken together, our results indicate that increasing the levels of FLNa and FLNb axis with TST in Th2 lymphocytes attenuated Type 2 response in a mouse model of airway inflammation. CONCLUSION In this study, we highlighted original targets to rewire Th2 lymphocyte mediated responses. We revealed an unexpected role for ASB2α-mediated degradation of FLNa and FLNb in Th2 lymphocyte specific functions and properties, and therefore in airway inflammation. Using genetically modified mice and the small molecule TST, we found that increasing the levels of FLNa and FLNb in Th2 lymphocytes attenuates airway inflammation. Collectively, our results highlight the ASB2α-FLNa / b axis as a novel therapeutic opportunity to rewire Th2 lymphocyte mediated responses. REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. 1. Muehling, L. M., Lawrence, M. G. & Woodfolk, J. A. Pathogenic CD4(+) T cells in patients with asthma. J. Allergy Clin. Immunol.140, 1523–1540 (2017). 2. Vieira Braga, F. A. et al. A cellular census of human lungs identifies novel cell states in health and in asthma. Nat. 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The E3 Ubiquitin Ligase Asb2alpha in T Helper 2 Cells Negatively Regulates Antitumor Immunity in Colorectal Cancer. Cancer Immunol Res 7, 1332– 1344 (2019). 9. Métais, A. et al. Asb2α-filamin A axis is essential for actin cytoskeleton remodeling during heart development. Circ. Res.122, e34 (2018). 10. Heuzé, M. L. et al. ASB2 targets filamins A and B to proteasomal degradation. Blood 112, 5130–5140 (2008). 11. Burande, C. F. et al. A label-free quantitative proteomics strategy to identify E3 ubiquitin ligase substrates targeted to proteasome degradation. Mol. Cell. Proteomics 8, 1719– 1727 (2009). 12. Baldassarre, M. et al. Filamins regulate cell spreading and initiation of cell migration. PLoS One 4, e7830 (2009). 13. Lamsoul, I. et al. Functional and structural insights into ASB2α, a novel regulator of integrin-dependent adhesion of hematopoietic cells. J. Biol. Chem. 286, 30571– 30581 (2011). 14. Lamsoul, I. et al. ASB2α regulates migration of immature dendritic cells. Blood 122, 533–541 (2013). 15. Bankhead, P. et al. QuPath: Open source software for digital pathology image analysis. Sci. Rep.7, 1–7 (2017). 16. Maqbool, M. A. et al. Alternative Enhancer Usage and Targeted Polycomb Marking Hallmark Promoter Choice during T Cell Differentiation. Cell Rep.32, 108048 (2020). 17. Kilic, A. et al. A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation. JCI Insight 3, e97503 (2018). 18. Coquet, J. M. et al. Interleukin-21-Producing CD4(+) T Cells Promote Type 2 Immunity to House Dust Mites. Immunity 43, 318–330 (2015). 19. Spinner, C. A. et al. Substrates of the ASB2alpha E3 ubiquitin ligase in dendritic cells. Sci Rep 5, 16269 (2015). 20. Bouyssié, D. et al. Proline: An efficient and user-friendly software suite for large-scale proteomics. Bioinformatics 36, 3148–3155 (2020). 21. Lad, Y. et al. Structure of three tandem filamin domains reveals auto-inhibition of ligand binding. Embo J 26, 3993–4004 (2007). 22. 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Claims

CLAIMS:

1. A method of treating a Type 2-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a modulator of the ASB2-FLNA / B axis, wherein the modulator of the ASB2-FLNA / B axis is: - An ASB2 inhibitor; or - A FLNA / B enhancer.

2. The method according to claim 1, wherein the ASB2 inhibitor is an inhibitor of ASB2 gene expression selected from the list consisting of antisense oligonucleotide, nuclease, siRNA, shRNA or ribozyme.

3. The method according to any of claims 1 or 2, wherein the ASB2 inhibitor is an ASB2α inhibitor.

4. The method according to claim 1, wherein the FLNA / B enhancer is selected from a list consisting in thiostrepton, spironolactone, griseofulvin, econazole nitrate, etoposide, ciclopirox ethanolamine, sertaconazole nitrate, oxfendazole, oxibendazole, irinotecan hydrochloride trihydrate, estramustine, carbazochrome sodium sulfonate, L- tryptophan, prosultiamine, flupirtine, tinoridine hydrochloride, riboflavin.

5. The method according to any of claim 1 or 4, wherein the FLNA / Benhancer is thiostrepton.

6. The method according to claim 1, wherein the FLNA / Benhancer is a polypeptide that comprises the amino acid sequence as set forth in SEQ ID NO:1 or a polypeptide that comprises the amino acid sequence as set forth in SEQ ID NO:

2.

7. The method according to claim 1, wherein the FLNA / B enhancer is a polynucleotide encoding a polypeptide that comprises the amino acid sequence as set forth in SEQ ID NO:1 or a polypeptide that comprises the amino acid sequence as set forth in SEQ ID NO:2.

8. The method according to any of claims 1 to 7, wherein the Type 2-mediated disease is induced by a Type 2-mediated inflammation.

9. The method according to claim 8, wherein the Type 2-mediated inflammation is a Type 2-mediated airways inflammation.

10. The method according to any of claim 1 to 9, wherein the Type 2-mediated disease is atopic dermatitis.

11. The method according to any of claim 1 to 9, wherein the Type 2-mediated disease is asthma.

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