CNRS patent portfolio related to Rare and Genetic Diseases

Transcription

1 CNRS patent portfolio related to Rare and Genetic Diseases V - 02/07/2013

2 Patents list for licensing opportunities Our Reference : Main Inventor : BRIAULT Title : Use of a BKCa opener as a treatment of Fragile X-Syndrome and KCNMA-1 related autism MASCHAT New therapeutic peptide for Huntington s Disease LUGNIER Use of Adenine-derived compounds for the treatment of Systemic Lupus Erythematous (SLE) BERTOLOTTI Use of Guanabenz derivatives for the treatment of Huntington s Disease POTIER DODD LEFEBVRE New Treatment of Cognitive Impairment in Down Syndrom UPCOMING TECHNOLOGY Novel DYRK1A inhibitors for the treatment of Alzheimer s Disease or Down Syndrom UPCOMING TECHNOLOGY Use of Calcium Channel Blockers for the Treatment of Spinal Muscular Atrophy BECQ Treatment of Cystic Fibrosis with Paullone Derivatives LEFEBVRE Peptide for its use in the treatment of Motor Neuropathies MARI Use of mir-199a-5p, targets and/or inhibitors thereof for the diagnosis, prognosis and treatment of fibroproliferative disorders BLONDEL Compounds for the treatment of mitochondrial diseases V - 02/07/2013

3 Use of a BKCa opener as a treatment of Fragile X-Syndrome CONTEXT Fragile X-Syndrome (FXS) is the most common cause of inherited mental retardation and affects 1 in every 2000 men and 1 in every 4000 women, together representing nearly 500,000 persons in Europe and USA. This disease is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X-chromosome, and results in a failure to express the protein coded by the FMR1 (Fragility Mental Retardation 1) gene. In normal individuals, FMR1 is a RNA-binding protein that is believed to regulate the transcription and translation of a substantial population of mrna, and it plays important roles in learning and memory. It also appears to be required for normal neural development since it is involved in development of axons, formation of synapses, and the wiring and development of neural circuits. Its mutation leads to its silencing, and results in a spectrum of characteristic physical and intellectual limitations, as well as emotional and behavioral features which range from severe to mild in manifestation. To date, there is no cure for the Fragile X-Syndrome and current therapeutic strategies rely on behavioral therapy, special education, and when necessary, treatment of physical abnormalities. TECHNICAL DESCRIPTION It has recently been shown that the silencing of FMR1 is leading to a 50% reduction of the level of KCNMA1, the sub-unit of the large-conductance Ca2+ and voltage-activated K+ (BKCa) channel (Liao et al., PNAS 2008). BKCa channels have a tetrameric structure, each monomer of the channel-forming alpha subunit being the product of the Kcnma1 gene, and this reduced level of KCNMA1 protein results in a fonctional impairment of the channel activity. BKCa channels are expressed in almost every tissue in our body and participate in many critical functions such as neuronal excitability, determination of action potential duration and frequency, neurotransmitter release and vascular tone regulation. BMS Our Reference N DI Keywords Fragile X syndrome, BKCa, mental retardation, fluoro-oxindole Status of Patent Priority patent application n EP filed on June 27, 2011 entitled " Compositions for the treatment of the Fragile X syndrome " PCT/EP/ filed on June 27,2012 Inventors Sylvain BRIAULT, MD, PhD Olivier PERCHE, PhD Commercial Status Collaborative agreement, Exclusive license, Option Laboratory Laboratory of Molecular Immunology and Embryology, a CNRS- Université d Orléans laboratory (UMR6218) in Orléans, France. Using the BKCa channel opener BMS204352, the inventors have been able to restore a normal BKCa channel activity in a FXS patient cell culture in a similar manner than what they observed in lymphoblastoid cultures of an autistic patient with a de novo 9q23/10q22 translocation (Laumonnier et al. Am J Psychiatry 2006). In addition, they showed that BMS restores dendritic spines maturation of Fmr1 KO neurons (4h treatment). Working with fmr1-ko mice, the FXS animal model, Dr Briault and Dr Perche have now shown that BMS allows behavioral recovery in a surprisingly efficient manner when administered in 1 injection i.p 2mg/kg: - Direct social interaction test showed a wild-type social interaction phenotype, - Social preference test showed a wild-type social preference phenotype, - Elevated plus-maze test showed a wild-type level of anxiety, V - 02/07/2013

4 - Y-maze test a wild-type spatial recognition (work memory). The quantification of cerebral metabolites (hippo/cortex) using Magnetic Resonance Spectroscopy (MRS) demonstrated that BMS (1 injection i.p 2mg/kg) restores the normal synaptic function. DEVELOPMENT STAGE Interestingly, BMS has been clinically developed by Bristol-Myers Squibb up to Phase III before it failed to improve stroke s issue, and therefore has an excellent ADMET profile (the whole regulatory package, results and samples have been obtained from BMS). The molecule is now free to operate. The research team is now strengthening preclinical data and setting up a clinical trial. As a medical geneticist, Dr Briault has established close relationships with hospitals and with French and international patient associations that are active in the field of Fragile-X syndrome research and support and/or collaborate to his action. An orphan drug designation filing is ongoing. CNRS is willing to collaborate with and license this patent to a pharmaceutical company, preferably experienced in the clinical development and marketing of rare disease treatment, to achieve the development of this drug. Indeed more than 1,5 million people may receive this life-long treatment, with a possible indication extension to all mental retardation associated with BKCa anomaly. V - 02/07/2013

5 New therapeutic peptide for Huntington s Disease CONTEXT Huntington's disease (HD) is a neurodegenerative genetic disorder that usually becomes noticeable in middle age. It affects muscle coordination and provokes cognitive decline and dementia. HD is caused by an autosomal dominant mutation of a gene called Huntingtin (Htt) leading to an abnormal repeat number of the amino acid Glutamine (Q) in the protein (PolyQ-Htt). This mutant form of the protein has altered activities and is prone to form protein aggregates. It is toxic to certain types of cells, especially in the brain where neurons are particularly affected. There is at the present time no cure for HD, and the available treatments aim at reducing the severity of some of its symptoms. TECHNICAL DESCRIPTION One therapeutic strategy that is explored is the prevention of aggregates caused by the polyq domain in mutant Huntingtin. The invention is based on the discovery published in 2008 that the aggregation of PolyQ-Htt may be prevented by its wild-type counterpart. Considering the size of the wild-type protein, around 600 amino acids, the inventors have looked for smaller but still active peptides isolated from Htt. One of them, pep42, turned out to be particularly interesting. BENEFITS The small size of the peptide is more appropriate for a use as a therapeutic compound than the Htt whole protein, while it retains its full anti-aggregates activity. Wild-type HD Model (-) (+ pep42) Phenotype rescue in a Drosophila HD model Our Reference Keywords Huntington s Disease, Peptide, Gene therapy Status of Patent Priority patent application n FR filed on April 12, 2011 entitled "Composés thérapeutiques contre la chorée de Huntington" Inventors Florence MASCHAT, Marie-Laure PARMENTIER, Nathalie BONNEAUD, Yoan ARRIBAT Commercial Status Exclusive or nonexclusive licenses, Option agreement, Collaborative agreement Laboratory Institut de génomique fonctionnelle, a CNRS laboratory (UMR 5203) in Montpellier, France. Institut de génétique humaine, a CNRS laboratory (UPR 1142) in Montpellier, France. INDUSTRIAL APPLICATIONS This peptide may be used as a treatment of HD, alone or in combination with other strategies, and administered as a peptide alone or integrated in a lentivirus allowing its expression. DEVELOPMENT STAGE In vitro and in vivo data have been obtained and are still in progress. Vectorisation strategies for the peptide are studied. In particular, its fusion with the TAT penetrating sequence has been very efficient to allow its tranbsport trough the blood-brain barrier. This work is financially supported by the programme Emergence of high potential products or services of the Agence Nationale pour la Recherche. V - 02/07/2013

6 PUBLICATION A huntingtin peptide inhibits polyq-huntingtin associated defects. Arribat Y, Bonneaud N, Talmat-Amar Y, Layalle S, Parmentier ML, Maschat F. PLoS One Jul 4;8(7):e V - 02/07/2013 For further Information please contact: FIST SA 83, Bd Exelmans PARIS France Tel: +33 (0) Fax: +33 (0) frinnov@frinnov.fr

7 USE OF ADENINE-DERIVED COMPOUNDS FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) RARE DISEASE CONTEXT Since the eighties, we have been collaborating with JJ Bourguignon (University of Strasbourg) performing structure-activity relationships on purified PDE1 to PDE5 (based on rolipram and trequinsin structures) to conceive specific PDE4 inhibitors (>1000 original compounds) and we have studied PDE implications in intracellular signalling in cardiovascular function and more recently in angiogenesis. Some findings were patented by Neuro3D/CNRS/University and lastly sold to Via Pharmaceuticals Inc., San Francisco, U.S.A. Among the not patented and optimized PDE4 inhibitors compounds, we have studied NCS 613 and its analogues as anti-inflammatory drugs. Therefore, in collaboration with Sylviane Muller, we established adenine analogues, and in particular NCS 613, as promising treatment for systemic lupus erythematosus (SLE) a rare diseases. Our latest results have shown encouraging in vivo effects on a mouse model. TECHNICAL DESCRIPTION SLE is a rare disease with a high polymorphism and multiple origins. The invention relates to the use of adenine-derived compounds, for the treatment of SLE. These original compounds are specific and potent inhibitors of the PDE4 family enzymes which are implicated in inflammation. They can also be used in combination with a non steroid antiinflammatory compound, a synthetic antimalarial compound, a corticoid compound or an immunosupressor. BENEFITS NCS 613 is an adenine-derived molecule of low molecular weight (pka<1.7, Log D7.4=3.78±0.03) that is active in vivo per os. This compound, given i. p. (30 µg/mouse, i.e. 1.5 mg/kg), protects mice from lupus disease progression (PlosOne 2012,) by decreasing proteinuria, anti-double stranded DNA antibodies and TNFα secretions and protecting kidney from nephropathy in which renal PDE4 activity is significantly increased when compared with control animals. Consequently, NCS 613 increases significantly the survival rate of MRL/lpr mice (SLE model) (p<0.005, in comparison with non treated mice). Furthermore, this compound decreases ex vivo basal and LPS-induced TNFα secretions from SLE and rheumatoid arthritis (RA) patient PBMCs. INDUSTRIAL APPLICATIONS The application of this invention concerns a drug for the treatment of SLE. The etiology remains elusive and the manisfestations are polymorphic classifying each form in the categoty of rare diseases. Currently, no specific treatment exists. An average of out of people is affected by SLE each year among northern Europeans to more than 200 cases per 1,000,000 people among black people (Compared to an average of out of 100,000 people is affected by RA). Further, our results and patented technology broadens the use of our adenine analogues for the treatment of auto-immune diseases. V - 02/07/2013 Our Reference Keywords Lupus, adenine, drug in vivo Status of Patent French patent application N FR filed on March 6th, 2006 and entitled "Traitement du lupus érythémateux disséminé (LED) par les inhibiteurs de PDE4 published on September 7th 2007 under N WO published on September 13th, 2007 EP (granted) US (granted) CA (pending) JP (pending) Inventors Claire LUGNIER, Fanny MONNEAUX, Sylviane MULLER and Jacques BOURGUIGNON Commercial Status Exclusive or nonexclusive licenses Laboratory Biophotonique et Pharmacologie (second Research Unit), CNRS and University of Strasbourg (UMR7213), in Illkirch, France. For further Information please contact: FIST SA 83, Bd Exelmans PARIS France Tel: +33 (0) Fax: +33 (0) frinnov@frinnov.fr

8 DEVELOPMENT STAGE: Conceptual/ Pre-clinical data Clinical data Laboratory samples X In vitro assays : - NCS 613 is 12,380 fold more active than theophylline, 3214 fold more active than pentoxifylline and 18 fold more active than denbufylline as PDE4 inhibitor with an IC50 of µm toward camp degradation by vascular purified PDE4. - When compared to their effects on PDE5 activity (specific for cgmp and target for Viagra ), NCS 613 is 112 fold selective for PDE4, whereas theophylline similarly inhibits PDE4 and PDE5, pentoxifylline is 2 fold less potent on PDE4 and denbufylline is only 7 fold selective for PDE4. - NCS 613 is specific for PDE4C subtype 14 fold relatively to PDE4D, 30 fold relatively to PDE4A and 36 fold relatively to PDE4B. - NCS 613 is more than 100 fold less effective than rolipram on 3 H rolipram binding High Affinity Rolipram Binding Site (HARBS), indicating that this compound might have few adverse emetic effects. - NCS 613 (10 µm) inhibits by 70% antigen-induced histamine release by rat peritoneal mast cells, whereas rolipram (10 µm) decreases it only by 30%. - NCS 613 inhibits fmlp-stimulated arachidonate acid (IC50= 1.99 µm) and LPSstimulated TNF (IC50= µm) releases from human mononuclear cells. - NCS 613 (10 µm) decreases ex vivo basal and LPS-induced TNFα secretions from SLE, and RA and Sjörgren syndrom (SS) patient PBMCs. - NCS 613 (10 µm) exhibits anti-inflammatrory effects on PBMCs from lupus patients by inhibiting p38 MAPK and NFk-B signalling pathway while reducing proinflammatory cytokine production (Can J Physiol Pharmac 2013,91: ) In vivo assays : (efficacy assays (pre-clinical POC): ongoing tests lead optimization).. - NCS 613 dose dependently (1, 10 and 30 mg/kg per os) inhibits the recruitment of neutrophils in the bronchoalveolar lavage fluid of mice exposed to endotoxin via aerosol and inhibits antigen-induced broncho constriction in guinea pig (0.1, 1 and 10 mg/kg per os) with an ED50 of 0.23 mg/kg being 100 fold more potent than theophylline. - NCS 613 at 30 mg/kg i.v. in rat, in opposite to RP 73401, does not increase basal acid neither pentagastrin-stimulated acid secretion, suggesting that NCS 613 may produce fewer gastrointestinal side effects than second-generation PDE4 inhibitors. - NCS 613 given 3 times every 2 weeks and the last time 4 weeks later to 5 week-old MRL/lpr mice (at 30 µg/mouse i.e. 1.5 mg/kg i.v.) significantly protects against SLE disease progression by decreasing proteinuria, anti-double stranded DNA antibodies and TNFα secretion and potently increases the mouse survival rate (at 30 weeks, 50% of NCS 613 treated mice were still alive, p<0.005) in comparison with non treated mice, whereas the survival rate of mice treated with pentoxifylline (100 µg/mouse) or denbufylline (100 µg/mouse) was not significantly changed. Toxicity data : NCS 613 given by i.v. at 1 µg or 10 µg, 3 times every 2 weeks, to BALB/c mice which were observed for 40 days, did not induced either weight changes or lung, kidney, liver and V - 02/07/2013

9 spleen alterations. Next development steps : - Rat LD50 and pharmacokinetics - Emetic test on ferret, PK and ADM in primates (Centre de Primatologie de Strasbourg) V - 02/07/2013

10 Use of Guanabenz Derivatives for the Treatment of Huntington s disease CONTEXT The prevalence of Huntington s disease (HD) is estimated to 3-7 per 100,000 people in western Europe. HD is caused by a faulty gene on chromosome 4. This gene produces a protein called Huntingtin and leads to a damage of the striatal neurons. The progressive degeneration of these neurons causes gradual physical, mental and emotional changes. At this time, there is no way to stop or to reverse the course of HD. HD is characterized by expansion of CAG codons translated in polyglutamine (polyq) and causes aggregation of the affected protein. The aim of the invention concerns non toxic compounds capable of treating polyglutamine expansion associated diseases. TECHNICAL DESCRIPTION The present invention relates to chlorine Guanabenz derivatives (inhibitors of aggregated proteins) for treating Huntington s disease and other polyglutamine expansion associated diseases. More specifically, it relates to the use of the molecule of formula (I) wherein R=H or Cl and the phenyl group is at least substituted twice, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating polyglutamine expansion associated diseases. Guanabenz and Chloroguanabenz specifically reduce accumulation of a pathogenic fragment of Huntingtin in a transiently transfected cellular model of HD. Our Reference Keywords Chlorine Guanabenz derivatives; polyglutamine expansion associated diseases; Huntington s disease Status of Patent Priority patent application EP filed on October 4th, 2006 entitled «Use of chlorine Guanabenz derivatives for treating polyglutamine expansion associated diseases» International patent : WO published on April 10, 2008 Extended to EP, US, CA and JP Inventors Anne BERTOLOTTI and Marc BLONDEL Commercial Status Exclusive or non exclusive licenses BENEFITS Formula I Guanabenz is a drug already in clinic to treat hypertension. This invention makes it possible to develop a new application of the chlorine Guanabenz derivatives. Guanabenz is a novel drug candidate for Huntington s disease treatment. INDUSTRIAL APPLICATIONS The Guanabenz derivatives described in this invention promote clearance of mutant Huntingtin and this opens new applications in preventing or treating pathological of polyglutamine expansion associated diseases such as HD. Furthermore this invention will be more generally applicable to all protein misfolding diseases. The commercial applications and potential markets in such therapeutics are huge. DEVELOPMENT STAGE Information about the molecular mechanism by which Guanabenz enhances clearance of misfolded proteins is a prerequisite for clinical development. The inventors are exploring the pathway by which the Guanabenz increases the cellular capacity to degrade aggregation-prone proteins. Laboratory «Régulation de l expression génétique», UMR8541, Paris, France 23/04/2014

11 New Treatment for Cognitive Impairment in Down Syndrom CONTEXT Trisomy 21 (T21), or Down Syndrome (DS), is the most common form of intellectual disability in human. We consider that a population of about 1 million people in Europe and in the United States is concerned by this pathology. Currently in Europe the number of conceptions of children with DS increases with later age of motherhood, but less than 1/1000 child are born with DS, thanks to prenatal diagnosis. DS is characterized by variable degrees of cognitive impairment - including deficits in memory, learning capacity or both. While advances in teaching methods and a trend toward educational mainstreaming has led to an improvement in cognitive development in those who have DS, there remain constitutive impairments that cannot be fully addressed through pedagogic methodology alone. TECHNICAL DESCRIPTION Initially developed by Merck Sharp & Dohme for the treatment of Alzheimer s disease, GABA alpha5 inverse agonists are very promising for the treatment of Down Syndrom-related cognitive impairment. DEVELOPMENT STAGE The development is ongoing with MSD GABA alpha 5 inverse agonist. PUBLICATIONS Chronic Treatment with a Promnesiant GABA-A α5-selective Inverse Agonist Increases Immediate Early Genes Expression during Memory Processing in Mice and Rectifies Their Expression Levels in a Down Syndrome Mouse Model. Braudeau J et al. Adv Pharmacol Sci. 2011;2011: Epub 2011 Oct 19. Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice. Braudeau J et al. J Psychopharmacol Aug;25(8): Epub 2011 Jun 21. Our Reference N DI Keywords Down syndrom, GABA R inverse agonist, Cognitive Impairment Status of Patent Priority patent application n US A61/236,625 and EP Composition and method for treating cognitive impairments in Down syndrome subjects filed on August 25, 2009 Inventors MC POTIER R DODD B DELATOUR J BRAUDEAU Y HERAULT Commercial Status Collaborative agreement, Exclusive license, Option Laboratory Centre de Recherches de l Institut du Cerveau et de la Moelle (CRICM) a CNRS laboratory (UMR7225) at the Pitié- Salpêtrière Hospital in Paris, France. 23/04/2014

12 Novel DYRK1A inhibitors for the treatment of Down Syndrome UPCOMING TECHNOLOGY CONTEXT Down syndrome (DS) is the most common genetic disorder with a frequency of 1 in 700 live births worldwide, and it is associated with an increased risk of Alzheimer s disease. DYRK1A is considered a pathogenic factor in Down syndrome and has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease brain. TECHNICAL DESCRIPTION The inventors have designed new azaindole-based Dirk1A inhibitors that demonstrate potent inhibitory activity against Dyrk1A and high affinity in ATP-binding site. In vitro evaluation and computer-guided molecular design were used to select the appropriate candidates. No cytotoxicity has been detected, and primary data obtained on wild-type and Down Syndrom model mice are very promising. This work is financially supported by the programme Emergence of high potential products or services of the Agence Nationale pour la Recherche. Our Reference Keywords Down s syndrome, Alzheimers, Kinase inhibitors, CNS Status of Patent French priority patent application to be filed in November 2012 Inventors Robert DODD Jean DELABAR Commercial Status Exclusive or nonexclusive licenses Laboratories Institut de Chimie des Substances Naturelles, a CNRS laboratory in Gifsur-Yvette, France. UMR4413, a Université Paris Diderot laboratory in Paris, France. 23/04/2014

13 Use of Calcium Channel Blockers for the Treatment of Spinal Muscular Atrophy CONTEXT Spinal muscular atrophy (SMA) refers to inherited neuromuscular disorders that are characterized by degeneration of spinal motor neurons leading to muscular weakness and atrophy. SMA is incurable to date and existing treatment remain unsatisfactory, thus although it occurs with a frequency of 1:10,000, it remains the most common fatal autosomal disease in infants. TECHNICAL DESCRIPTION Using a screening test based on the monitoring of SMN accumulation in Cajal Bodies of SMA fibroblasts, the inventors have shown that calcium channel blockers of the type phenylalkylamines were very efficient. In particular, flunarizine exhibited very promising results. This molecule is also known as SIBELIUM and is currently used for the treatment of pediatric migraine. DEVELOPMENT STAGE Flunarizine is currently tested on a mouse model of SMA. The results are expected on 2014 Q1. Our Reference Keywords SMA, Calcic Antagonist, Gene therapy Status of Patent Priority patent application n FR filed on September 19, 2012 entitled "Traitement des Neuropathies Motrices" Inventors Suzie LEFEBVRE, Kevinee KOOHBARRY Philippe BURLET Commercial Status Exclusive or nonexclusive licenses, Option agreement, Collaborative agreement Laboratory Institut de génomique fonctionnelle, a CNRS laboratory (UMR 5203) in Montpellier, France. Institut de génétique humaine, a CNRS laboratory (UPR 1142) in Montpellier, France. 23/04/2014

14 Treatment of Cystic Fibrosis with Paullone Derivatives CONTEXT Cystic fibrosis (CF) is a major inherited disorder affecting most critically the lungs, but also the pancreas, liver, and intestine. The disease affects arounf 70,000 people in the world, mostly of european anscestry. Several treatment exists but the lifetime of the patients remains shortened. Cystic fibrosis (CF) involves abnormalities of fluid and chloride and sodium electrolytes transport through epithelia due to mutation leading to abnormal function of cystic fibrosis transmembrane conductance regulator (CFTR) protein. Although there are over 1,000 mutations of CFTR proteins, the most common is delf508 that affects 70% of patients and causes the deletion of a phenylalanine at position 508. This mutation alters the folding of the protein. Therefore, although the delf508 CFTR could still be active as a chloride ion channel, it is no longer able to reach the membrane and is rapidly degraded. TECHNICAL DESCRIPTION The invention relates to the use of paullone derivatives for the treatment of cystic fibrosis, a family of compounds acting as CDK inhibitors and exhibiting antiproliferative activity. The inventors have shown that some paullone derivatives, especially kenpaullones, could act as activators of wild-type and mutant CFTR, and could induce the relocation of delf508 mutated CFTR to the plasma membrane in CF epithelial cells, thereby restoring its electrolyte transmembrane transport capacity. DEVELOPMENT STAGE A in vitro screening of paullone derivatives is ongoing and retained candidates will be validated on mice models of cystic fibrosis. Our Reference Keywords Cystic Fibrosis; paullone Status of Patent Priority patent of invention n FR filed in October 15, 2004, entitled: "Utilisation de dérivés de paullones pour la fabrication de médicaments pour le traitement de la mucoviscidose et de maladies liées à un défaut d adressage des proteines dans les cellules" PCT: WO National Phases: EP granted, US2008/ and CA Inventors Frédéric BECQ, Laurent MEIJER and Conrad KUNICK Commercial Status Exclusive or nonexclusive licenses Laboratory Institut de physiologie et biologie cellulaires (UMR6187), Poitiers, France. 23/04/2014

15 OTHER TECHNOLOGIES: 1- Dr MARI s invention, ref /BS: Use of mir-199a-5p, targets and/or inhibitors thereof for the diagnosis, prognosis and treatment of fibroproliferative disorders Cette invention concerne le domaine des pathologies fibroprolifératives, notamment la fibrose pulmonaire idiopathique (FPI) et à l implication des mirna dans le processus de fibrose tissulaire. Plus particulièrement, elle décrit l utilisation de mirna, en particulier du mir-199a-5p, de leurs cibles et/ou inhibiteurs pour le diagnostic, le pronostic et le traitement des pathologies fibroprolifératives, notamment la fibrose pulmonaire idiopathique (maladie pulmonaire chronique caractérisée par une cicatrisation excessive des tissus sains au niveau des poumons). L aspect thérapeutique de la FPI a pu être développé davantage par le lancement de travaux complémentaires portant en particulier sur la détermination d inhibiteurs potentiels du mir-199a-5p. Cela est rendu possible grâce notamment à un partenariat avec la une société de biotechnologies spécialisée en services et design des microrna et qui a apporté sa contribution dans le design et la chimie des molécules LNA (Locked Nucleic Acids) et de nucléotides spécifiques (Target side nucleotides) dotés d une meilleure vectorisation leur permettant d inhiber très spécifiquement la cible. Des résultats préliminaires très encourageants sont obtenus in vitro depuis octobre 2012 et les premiers résultats in vivo sont également obtenus récemment. Brevet prioritaire ref. FR est déposé le 06/02/2012 (pas encore publié). 2- Dr BLONDEL s invention, ref /VA: Compounds for the treatment of mitochondrial diseases L invention concerne des molécules (dont l une d entre elles a été reproduite ci-dessus) capables d améliorer la croissance respiratoire d un modèle levure pour la maladie mitochondriale humaine NARP (neuropathie, Ataxie, rétinite Pigmentaire). Il s agit de syndromes liés à des mutations bien caractérisées dans le gène mitochondrial ATP6 et conduisant à un déficit de production d ATP par l ATP synthase F1F0. O O N + O Cl O Molécule L134H07 O Brevet prioritaire ref. EP déposé le 17/04/2009; PCT: WO Extensions : EP, US, CA, JP 23/04/2014

16 UPCOMING OPPORTUNITIES (Confidential - Further information upon request) - Dr LEFEBVRE s invention, Ref /CL: «Peptide pour son utilisation dans le traitement des neuronopathies motrices» Patent: Priority patent n FR 2013/ filed on January 04, 2013 naming as inventor Suzie LEFEBVRE. 23/04/2014

17 FIST SA in figures FIST SA is the acronym of France Innovation Scientifique et Transfert (France Scientific Innovation and Transfer). It was created in Paris in 1992 as a private company in order to focus on the transfer of innovative patents from French government-funded research organization (CNRS) to industry. Today, it represents 4.2 millions of sales. Shareholders 30% 70% CNRS Oséo A professional and specialized team With the benefit of a large range of technical competences, our team comes along from the protection of the invention to its licensing contract. The team (Total 45) Licensing Managers Lawyers Administratives Partner Search Project Manager EU Project Assistant IP Marketing Managers Portfolio Managers Assistants Foreign Client Project Manager A range of services The different services proposed by FIST SA are also available for private and start-up companies: - Intellectual property and valorization strategies - Partners research and negotiations - Patent portfolio management - Patent mapping/ Intellectual property landscape

18 Technology Transfer Success: examples Taxotere : Sanofi Aventis Chemotherapy drug approved in treatment of breast cancer, non-small cell lung cancer, advanced stomach cancer, head and neck cancer and metastatic prostate cancer. Sales in 2008: EUR 2,033 million Lupuzor : ImmuPharma / Cephalon Inc Drug that specifically modulates the immune system of Lupus patients. Lupuzor has successfully completed phase I, Phase IIa and Phase IIb studies. Sublicense to Cephalon inc. by ImmuPharma in Selectiose : PFDC - AVENE Sélectiose, amphiphilic derivative of Rhamnose reduces skin hypersensitivity and irritation and controls skin inflammation response. Marketed in cosmetic product line (Trixera+) in 2008 by AVENE. A collaboration success story: CENTRON C1S Fifteen years ago, a collaboration between a laboratory affiliated to the CNRS, the «Groupe d'etudes des Semi-conducteurs», and RMS, a division of the Schlumberger Company now integrated to the Itron/Actaris group, developed semi conductive straight structure III-V showing a magnetic field high sensibility and a low thermal drift. The magnetic sensor then developed allowed the manufacture of a new generation of residential electricity meter, the CENTRON C1S. This technology was enlarged to all the meters product range by ITRON. At the moment, 30 millions of meters have been fixed up in the USA and other countries. 5 millions of meters are yearly produced. CNRS in figures Budget for 2012 Euros 3.3 billion of which Euros 677 million come from revenues generated by CNRS Personnel 34,530 permanent employees 11,450 researchers 14,180 engineers and technical staff Organisation 10 institutes (3 of which have the status of national institutes) 19 regional offices, ensuring decentralized direct management of laboratories 1,100 research units (95 % are joint research laboratories with universities and industry) 40 International Associated Laboratories (LEA+LIA)

19 FIST SA always seeks industrial partners to develop and commercialize technologies held by CNRS within the framework of licenses or research agreements. We look forward to discussing any opportunity with you. Initiate the future For further Information please contact: FIST SA 83, Bd Exelmans PARIS France Tel: +33 (0) Fax: +33 (0)