FGF21 gene therapy as treatment for obesity and insulin resistance

Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.This work was supported by grants from Ministerio de Economía y Competi- tividad (MINECO) and FEDER, Plan Nacional I+D+I (SAF2014-54866R), andGeneralitat de Catalunya (2014SGR1669and ICREA Academia Award to F.B.), Spain, from the European Commission (MYOCURE, PHC-14-2015 667751) and the European Foundation for the Study of Diabetes (EFSD/MSD European Research Programme on Novel Therapies for Type 2 Diabetes,2013). V.J. was recipient of a post-doctoral research fellowship from EFSD/ Lilly. E.C., V.S., and C.M. received a predoctoral fellowship from Ministerio de Educación, Cultura y Deporte, and J.R. from Ministerio de Economía y Competitividad, Spain. The authors thank Marta Moya and Maria Molas for technical assistance.S

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement

Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.We thank A. Arbos, S. Turon, M. Morro, J. Barrero, L. Hernandez, a. Vazquez, V. Melgarejo, and L. Noya for technical assistance. This work was supported by grants from the Ministerio de Ciencia, Innovacion y Universidades, Plan Nacional I+D+I and the European Union through Regional Development Funds (ERDF) (SAF2017-86166-R), Generalitat de Catalunya (2017SGR1508 and ICREA Academia Award to F.B.) and MPS Espana Foundation. This work is part of a public-private partnership on gene therapy between UAB and ESTEVE Pharmaceuticals, Spain. V.S. and G.E. received a predoctoral fellowship from the Generalitat de Catalunya, Spain.S

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement

Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC

Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches. Summary: A new animal model of the severe neurodegenerative lysosomal disorder mucopolysaccharidosis IIIC recapitulates the human disease, with progressive CNS and somatic lysosomal pathology, and shortened lifespan

Desenvolupament d’una estratègia de teràpia gènica pel tractament de la patologia neurològica i somàtica de la MPSIIIA

La Mucopolisacaridosi tipus IIIA (MPSIIIA) o Síndrome de Sanfilippo és una malaltia d’acumulació lisosòmica (o Lysosomal Storage Disease, LSD) d’herència autosòmica recessiva, causada per la deficiència de l’enzim sulfamidasa (Sgsh). Aquesta sulfatasa està involucrada en la degradació del glicosaminoglicà (GAG) heparan sulfat, el qual s’acumula als lisosomes de les cèl·lules. Els signes i símptomes clínics de la MPSIIIA es caracteritzen per una severa neurodegeneració juntament amb unes alteracions somàtiques més lleugeres que provoquen la mort durant l’adolescència. Actualment no hi ha cap teràpia efectiva aprovada pel tractament d’aquesta malaltia. En primer lloc, es va dur a terme una sèrie d’estudis per tal de determinar l’eficàcia terapèutica de l’administració a dins la cisterna magna d’un virus adenoassociat (o Adenoassociated Vector, AAV) de serotip 9 codificant per a la sulfamidasa en un model murí de la malaltia, el ratolí MPSIIIA. L’administració del vector va resultar en un increment de l’activitat sulfamidasa a tot l’encèfal, que va ser al voltant d’un 40% de l’activitat present al cervell d’un animal sa. Aquest increment de sulfamidasa va portar a una normalització del contingut de GAGs i de la patologia lisosòmica a tot el cervell. Cal destacar especialment la completa correcció de la neuroinflamació, característica d’aquest model animal i de la MPSIIIA humana. D’altra banda, es va verificar un augment de l’activitat sulfamidasa al fetge i al sèrum dels animals tractats, augment relacionat amb el fet que els vectors drenen des del Líquid Cefaloraquidi (LCR) cap a la sang i arriben a transduir el fetge. Aquest augment de la sulfamidasa circulant va resultar en la reducció de l’acumulació de GAGs fins a nivells normals a la majoria dels teixits analitzats. Finalment, el tractament va aconseguir corregir els dèficits de comportament dels animals MPSIIIA i va perllongar considerablement la seva supervivència, que va ser similar a la d’animals sans. A més a més d’aquest estudis, es va realitzar un exhaustiu estudi de dosi-resposta per tal de determinar la mínima dosi terapèutica necessària per contrarestar la malaltia, i així com també la màxima edat de tractament que permet assolir eficàcia terapèutica abans que la malaltia no provoqui danys irreversibles. Els resultats d’aquesta part han constituït la base de l’atorgament l’any 2011 de la condició de medicament orfe per part de l’Agència Europea del Medicament i la Food and Drug Administration a l’AAV9-sulfamidasa. La segona part de l’estudi es va centrar en demostrar l’escalabilitat de l’aproximació a models animals grans, pas fonamental per a la translació d’aquesta teràpia cap a la clínica en pacients. Així doncs, es va avaluar en gossos la distribució del vector a tot el Sistema Nirviós Central (SNC), Sistema Nerviós Perifèric (SNP) i en òrgans somàtics. A més a més, es va avaluar l’efecte sobre l’eficiència de transducció del vector segons la velocitat d’infusió i la ruta d’administració. Finalment, es va demostrar l’eficient producció i secreció de sulfamidasa al LCR dels animals tractats amb vector codificant per a l’enzim, així com la seguretat del tractament desprès d’un seguiment de >16 mesos. Els anticossos neutralitzants (o neutralyzing antibodies, NAbs) dirigits contra el vector viral suposen la principal limitació per a l’eficàcia de la transferència gènica. Per tant, l’última part d’aquesta tesi va avaluar l’impacte de la immunitat humoral anti-AAV en l’eficiència de transducció dels vectors AAV9 quan són administrats directament al LCR. Primer es va dur a terme un estudi per analitzar la distribució dels NAbs a través de la barrera hemato-encefàlica en individus sans i afectats per la MPSIIIA, així com també en tots el gossos tractats. Així es va confirmar la distribució asimètrica dels anticossos, presents a títols molt més baixos al LCR respecte el sèrum. Aquests resultats van concordar amb l’observació de l’eficient transducció del SNC i del PNS en gossos amb immunitat anti-AAV prèvia quan se’ls administrava el vector directament al LCR, tot i que, com caldria esperar, es va perdre l’eficàcia en teixits perifèrics. Tenint en compte que la MPSIIIA és una malaltia predominantment neurodegenerativa, aquest resultats indiquen que es podrien tractar pacients amb anticossos neutralitzants. Tots aquests resultats constitueixen la base preclínica per a la translació cap a la clínica de l’administració al líquid cefaloraquidi d’AAV9-sulfamidasa com a tractament per a la MPSIIIA, com també per altres LSDs amb afectació, principalment, del SNC.Mucopolysaccharidosis Type IIIA (MPSIIIA) or Sanfilippo Syndrome is an autonomic recessive lysosomal storage disease (LSD) caused by the deficiency in the enzyme sulfamidase (SGSH). This sulfatase is involved in the sptepwise degradation of the glycosaminoglycan (GAG) heparan sulphate (HS), and its deficiency results in the accumulation of HS inside the lysosomes of cells. The disease is characterized by severe neurodegeneration, with mild somatic pathology, that leads to the death of most patients during adolescence. Currently, there is no approved therapy for the treatment of MPSIIIA. In the first part of this work a series of studies were performed aimed at demonstrating the therapeutic efficacy of the intracisternal administration of adeno-associated (AAV) vectors of serotype 9 (AAV9) coding for the enzyme sulfamidase to a mouse model of the disease, the MPSIIIA mouse. Vector delivery resulted in an increase in sulfamidase activity throughout the encephalon, with levels that were approximately 40% of those observed in healthy subjects. This restoration of sulfamidase activity led to the normalization of the content of GAGs and the lysosomal pathology in the whole brain. Noticeably, the neuroinflammation that characterizes the MPSIIIA disease in humans and in this animal model was completely reversed. On the other hand, an increase in sulfamidase activity was documented in the liver and serum of treated animals, and this correlated with the drainage of vectors from the cerebrospinal fluid (CSF) into the circulation, and transduction of the liver. This increase in circulating sulfamidase resulted in a reduction to normal levels in the accumulation of GAGs in the vast majority of tissues analysed. Finally, the treatment managed to correct the behavioural deficits of MPSIIIA mice and prolonged their survival, allowing treated MPSIIIA mice to live as long as their healthy littermates. In addition, several other studies were performed to try and identify the minimum therapeutic dose necessary to counteract the disease, as well as the maximum age at treatment that allows the achievement of therapeutic efficacy before the disease causes irreversible damage. The results of the present work have constituted the basis for the granting, in 2011, of the Orphan Drug Status to AAV9-sulfamidase by the European Medicines Agency (EU) and the Food and Drug Administration (USA). The second part of this work was focused on demonstrating the scalability of the approach to a large animal model, a crucial step for the translation of this therapy to the clinic. In this regard, the biodistribution following administration of vectors to the CSF of Beagle dogs was analysed in the central and peripheral nervous systems and in somatic organs. In addition, studies were conducted to evaluate the effects on transduction efficacy of the rate of vector infusion or the route of administration to the CSF. Finally, the efficient production of sulfamidase and secretion to the CSF was demonstrated in all treated dogs, as well as the safety of the treatment after a follow-up of more than 16 months. Neutralizing antibodies (NAbs) against the viral vector represent the main limitation to the efficacy of gene transfer. Therefore, the final part of this thesis work was dedicated to the evaluation of the impact of anti-AAV humoral immunity on the efficiency of transduction of vectors when they are delivered directly to the CSF. First, a study was performed to analyse the distribution of NAbs across the blood-brain barrier in healthy and MPSIIIA-affected individuals, as well as in all treated dogs, confirming the asymmetrical distribution of NAbs, which had much lower titers in CSF than in serum. These results agreed with the observation of efficient CNS and PNS transduction following the intra-CSF delivery of AAV9 vectors to dogs with pre-existing immunity against the vector, although, as expected, transduction of peripheral organs was completely abolished. Taking into account that MPSIIIA is primarily a neurodegenerative disease, these studies suggest that it would be feasible to treat patients’ bearers of neutralizing antibodies. Altogether these results constitute the preclinical base for the clinical translation of the intra-CSF administration of AAV9-sulfamidase for the treatment of MPSIIIA, as well as for other LSD that course with neurodegeneration

Desenvolupament d'una estratègia de teràpia gènica pel tractament de la patologia neurològica i somàtica de la MPSIIIA

La Mucopolisacaridosi tipus IIIA (MPSIIIA) o Síndrome de Sanfilippo és una malaltia d'acumulació lisosòmica (o Lysosomal Storage Disease, LSD) d'herència autosòmica recessiva, causada per la deficiència de l'enzim sulfamidasa (Sgsh). Aquesta sulfatasa està involucrada en la degradació del glicosaminoglicà (GAG) heparan sulfat, el qual s'acumula als lisosomes de les cèl·lules. Els signes i símptomes clínics de la MPSIIIA es caracteritzen per una severa neurodegeneració juntament amb unes alteracions somàtiques més lleugeres que provoquen la mort durant l'adolescència. Actualment no hi ha cap teràpia efectiva aprovada pel tractament d'aquesta malaltia. En primer lloc, es va dur a terme una sèrie d'estudis per tal de determinar l'eficàcia terapèutica de l'administració a dins la cisterna magna d'un virus adenoassociat (o Adenoassociated Vector, AAV) de serotip 9 codificant per a la sulfamidasa en un model murí de la malaltia, el ratolí MPSIIIA. L'administració del vector va resultar en un increment de l'activitat sulfamidasa a tot l'encèfal, que va ser al voltant d'un 40% de l'activitat present al cervell d'un animal sa. Aquest increment de sulfamidasa va portar a una normalització del contingut de GAGs i de la patologia lisosòmica a tot el cervell. Cal destacar especialment la completa correcció de la neuroinflamació, característica d'aquest model animal i de la MPSIIIA humana. D'altra banda, es va verificar un augment de l'activitat sulfamidasa al fetge i al sèrum dels animals tractats, augment relacionat amb el fet que els vectors drenen des del Líquid Cefaloraquidi (LCR) cap a la sang i arriben a transduir el fetge. Aquest augment de la sulfamidasa circulant va resultar en la reducció de l'acumulació de GAGs fins a nivells normals a la majoria dels teixits analitzats. Finalment, el tractament va aconseguir corregir els dèficits de comportament dels animals MPSIIIA i va perllongar considerablement la seva supervivència, que va ser similar a la d'animals sans. A més a més d'aquest estudis, es va realitzar un exhaustiu estudi de dosi-resposta per tal de determinar la mínima dosi terapèutica necessària per contrarestar la malaltia, i així com també la màxima edat de tractament que permet assolir eficàcia terapèutica abans que la malaltia no provoqui danys irreversibles. Els resultats d'aquesta part han constituït la base de l'atorgament l'any 2011 de la condició de medicament orfe per part de l'Agència Europea del Medicament i la Food and Drug Administration a l'AAV9-sulfamidasa. 16 mesos. Els anticossos neutralitzants (o neutralyzing antibodies, NAbs) dirigits contra el vector viral suposen la principal limitació per a l'eficàcia de la transferència gènica. Per tant, l'última part d'aquesta tesi va avaluar l'impacte de la immunitat humoral anti-AAV en l'eficiència de transducció dels vectors AAV9 quan són administrats directament al LCR. Primer es va dur a terme un estudi per analitzar la distribució dels NAbs a través de la barrera hemato-encefàlica en individus sans i afectats per la MPSIIIA, així com també en tots el gossos tractats. Així es va confirmar la distribució asimètrica dels anticossos, presents a títols molt més baixos al LCR respecte el sèrum. Aquests resultats van concordar amb l'observació de l'eficient transducció del SNC i del PNS en gossos amb immunitat anti-AAV prèvia quan se'ls administrava el vector directament al LCR, tot i que, com caldria esperar, es va perdre l'eficàcia en teixits perifèrics. Tenint en compte que la MPSIIIA és una malaltia predominantment neurodegenerativa, aquest resultats indiquen que es podrien tractar pacients amb anticossos neutralitzants. Tots aquests resultats constitueixen la base preclínica per a la translació cap a la clínica de l'administració al líquid cefaloraquidi d'AAV9-sulfamidasa com a tractament per a la MPSIIIA, com també per altres LSDs amb afectació, principalment, del SNC.Mucopolysaccharidosis Type IIIA (MPSIIIA) or Sanfilippo Syndrome is an autonomic recessive lysosomal storage disease (LSD) caused by the deficiency in the enzyme sulfamidase (SGSH). This sulfatase is involved in the sptepwise degradation of the glycosaminoglycan (GAG) heparan sulphate (HS), and its deficiency results in the accumulation of HS inside the lysosomes of cells. The disease is characterized by severe neurodegeneration, with mild somatic pathology, that leads to the death of most patients during adolescence. Currently, there is no approved therapy for the treatment of MPSIIIA. In the first part of this work a series of studies were performed aimed at demonstrating the therapeutic efficacy of the intracisternal administration of adeno-associated (AAV) vectors of serotype 9 (AAV9) coding for the enzyme sulfamidase to a mouse model of the disease, the MPSIIIA mouse. Vector delivery resulted in an increase in sulfamidase activity throughout the encephalon, with levels that were approximately 40% of those observed in healthy subjects. This restoration of sulfamidase activity led to the normalization of the content of GAGs and the lysosomal pathology in the whole brain. Noticeably, the neuroinflammation that characterizes the MPSIIIA disease in humans and in this animal model was completely reversed. On the other hand, an increase in sulfamidase activity was documented in the liver and serum of treated animals, and this correlated with the drainage of vectors from the cerebrospinal fluid (CSF) into the circulation, and transduction of the liver. This increase in circulating sulfamidase resulted in a reduction to normal levels in the accumulation of GAGs in the vast majority of tissues analysed. Finally, the treatment managed to correct the behavioural deficits of MPSIIIA mice and prolonged their survival, allowing treated MPSIIIA mice to live as long as their healthy littermates. In addition, several other studies were performed to try and identify the minimum therapeutic dose necessary to counteract the disease, as well as the maximum age at treatment that allows the achievement of therapeutic efficacy before the disease causes irreversible damage. The results of the present work have constituted the basis for the granting, in 2011, of the Orphan Drug Status to AAV9-sulfamidase by the European Medicines Agency (EU) and the Food and Drug Administration (USA). The second part of this work was focused on demonstrating the scalability of the approach to a large animal model, a crucial step for the translation of this therapy to the clinic. In this regard, the biodistribution following administration of vectors to the CSF of Beagle dogs was analysed in the central and peripheral nervous systems and in somatic organs. In addition, studies were conducted to evaluate the effects on transduction efficacy of the rate of vector infusion or the route of administration to the CSF. Finally, the efficient production of sulfamidase and secretion to the CSF was demonstrated in all treated dogs, as well as the safety of the treatment after a follow-up of more than 16 months. Neutralizing antibodies (NAbs) against the viral vector represent the main limitation to the efficacy of gene transfer. Therefore, the final part of this thesis work was dedicated to the evaluation of the impact of anti-AAV humoral immunity on the efficiency of transduction of vectors when they are delivered directly to the CSF. First, a study was performed to analyse the distribution of NAbs across the blood-brain barrier in healthy and MPSIIIA-affected individuals, as well as in all treated dogs, confirming the asymmetrical distribution of NAbs, which had much lower titers in CSF than in serum. These results agreed with the observation of efficient CNS and PNS transduction following the intra-CSF delivery of AAV9 vectors to dogs with pre-existing immunity against the vector, although, as expected, transduction of peripheral organs was completely abolished. Taking into account that MPSIIIA is primarily a neurodegenerative disease, these studies suggest that it would be feasible to treat patients' bearers of neutralizing antibodies. Altogether these results constitute the preclinical base for the clinical translation of the intra-CSF administration of AAV9-sulfamidase for the treatment of MPSIIIA, as well as for other LSD that course with neurodegeneration

Emotional salience enhances intelligibility in adverse acoustic conditions

Introduction: Emotion facilitates word recognition under adverse acoustic conditions. We use an auditory emotional paradigm to evaluate the ability to distinguish words from irrelevant random stimuli, elucidating its neural correlates. Secondarily, we evaluate the impact of schizotypy traits on this capacity. Methods: 25 participants, undertook an fMRI task, indicating whether they recognized words, through a response box. 20 audio files of emotionally negative words and 20 neutral words were presented. Word intelligibility was manipulated merging the audio files with white noise at varying signal-to-noise ratios (SNR), resulting in 3 levels (high, medium, and low). We measured schizotypy with the O-LIFE scale. Results: A 2x3 factorial ANOVA was performed with emotion (neutral or negative) and intelligibility (high, medium, and low) as factors. There was an interaction between emotion and intelligibility [F(2,44) = 23.89,p<0.001]. Post hoc t-test demonstrated that, in medium and low intelligibility, negative words were more recognized than neutral ones. Negative words minus neutral, activated the right anterior cingulate cortex (rACC), right dorsolateral prefrontal cortex (rDLPFC), and right orbitofrontal cortex (rOFC). Low compared to high intelligibility, activated the left medial temporal gyrus (lMTG), left supramarginal gyrus (lSMG), and left angular gyrus (lAG). Medium compared with high intelligibility, activated the left temporal pole (lTP) and the lMTG. There were correlations between schizotypy and rACC, lMTG, and rOFC activations. Discussion: Negative emotional salience improves intelligibility, possibly by recruiting selective attention. Less intelligible stimuli activated temporo-parietal regions related to speech processing in adverse acoustic conditions, while emotionally negative stimuli activated areas associated with emotional processing (rACC and rOFC) and selective attention (rDLPFC). High schizotypy correlated with greater responses in rACC, lMTG, and rOFC, during low intelligibility. Irrelevant emotionally salient stimuli would capture automatic attention activating rACC and rOFC, enhancing speech comprehension through additional recruitment of lMTG, which could derive in false word recognition.Fil: Olano, María A.. Universidad Austral. Facultad de Ciencias Biomédicas; ArgentinaFil: Elizalde Acevedo, Bautista. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Chambeau, Nahuel. Universidad de Buenos Aires. Facultad de Psicología; ArgentinaFil: Acuña, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Marcó, Mariano. Universidad Nacional Arturo Jauretche; ArgentinaFil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Alba Ferrara, Lucia M. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas; Argentin