Search

Your search keyword '"Comi, Giacomo"' showing total 1,839 results
Start Over Author "Comi, Giacomo"
1,839 results on '"Comi, Giacomo"'

6. A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy

Author

Ronchi, Dario, Garbellini, Manuela, Magri, Francesca, Menni, Francesca, Meneri, Megi, Bedeschi, Maria Francesca, Dilena, Robertino, Cecchetti, Valeria, Picciolli, Irene, Furlan, Francesca, Polimeni, Valentina, Salani, Sabrina, Pezzoli, Laura, Fortunato, Francesco, Bellini, Matteo, Piga, Daniela, Ripolone, Michela, Zanotti, Simona, Napoli, Laura, Ciscato, Patrizia, Sciacco, Monica, Mangili, Giovanna, Mosca, Fabio, Corti, Stefania, Iascone, Maria, and Comi, Giacomo Pietro

Published
2023
Full Text
View/download PDF

8. Genetic modifiers of upper limb function in Duchenne muscular dystrophy.

Author

Sabbatini, Daniele, Fusto, Aurora, Vianello, Sara, Villa, Matteo, Janik, Joanna, DAngelo, Grazia, Diella, Eleonora, Magri, Francesca, Comi, Giacomo, Panicucci, Chiara, Bruno, Claudio, DAmico, Adele, Bertini, Enrico, Astrea, Guja, Battini, Roberta, Politano, Luisa, Masson, Riccardo, Baranello, Giovanni, Previtali, Stefano, Messina, Sonia, Vita, Gianluca, Berardinelli, Angela, Mongini, Tiziana, Pini, Antonella, Pane, Marika, Mercuri, Eugenio, Hoffman, Eric, Morgenroth, Lauren, Gordish-Dressman, Heather, Duong, Tina, Bello, Luca, Pegoraro, Elena, and McDonald, Craig

Subjects
CD40, Duchenne muscular dystrophy, Genetic modifiers, SPP1–osteopontin, Upper limb function, Actinin, Cohort Studies, Genotype, Humans, Muscular Dystrophy, Duchenne, Quality of Life, Upper Extremity
Abstract

Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.

Published
2022

9. Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot–Marie–Tooth type 2A

Author

Rizzo, Federica, Bono, Silvia, Ruepp, Marc David, Salani, Sabrina, Ottoboni, Linda, Abati, Elena, Melzi, Valentina, Cordiglieri, Chiara, Pagliarani, Serena, De Gioia, Roberta, Anastasia, Alessia, Taiana, Michela, Garbellini, Manuela, Lodato, Simona, Kunderfranco, Paolo, Cazzato, Daniele, Cartelli, Daniele, Lonati, Caterina, Bresolin, Nereo, Comi, Giacomo, Nizzardo, Monica, and Corti, Stefania

Published
2023
Full Text
View/download PDF

12. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

Acsadi, Gyula, Baranello, Giovanni, Blaschek, Astrid, Brandsema, John, Brogna, Claudia, Bruno, Claudio, Connolly, Anne, de Groot, Imelda, De Waele, Liesbeth, Finanger, Erika, Finkel, Richard, Gidaro, Teresa, Guglieri, Michaela, Harper, Amy, Lopez Lobato, Mercedes, Madruga Garrido, Marcos, Magri, Francesca, Manousakis, Georgios, Masson, Riccardo, Monduy, Migvis, Muelas Gomez, Nuria, Munell, Francina, Nascimento, Andres, Nevo, Yoram, Pereon, Yann, Phan, Han, Sansone, Valeria, Scoto, Mariacristina, Vucinic, Dragana, Willis, Tracey, Mercuri, Eugenio, Vilchez, Juan J, Boespflug-Tanguy, Odile, Zaidman, Craig M, Mah, Jean K, Goemans, Nathalie, Müller-Felber, Wolfgang, Niks, Erik H, Schara-Schmidt, Ulrike, Bertini, Enrico, Comi, Giacomo P, Mathews, Katherine D, Servais, Laurent, Vandenborne, Krista, Johannsen, Jessika, Messina, Sonia, Spinty, Stefan, McAdam, Laura, Selby, Kathryn, Byrne, Barry, Laverty, Chamindra G, Carroll, Kevin, Zardi, Giulia, Cazzaniga, Sara, Coceani, Nicoletta, Bettica, Paolo, and McDonald, Craig M

Published
2024
Full Text
View/download PDF

14. Multi-omics profiling of CSF from spinal muscular atrophy type 3 patients after nusinersen treatment: a 2-year follow-up multicenter retrospective study

Author

Faravelli, Irene, Gagliardi, Delia, Abati, Elena, Meneri, Megi, Ongaro, Jessica, Magri, Francesca, Parente, Valeria, Petrozzi, Lucia, Ricci, Giulia, Farè, Fiorenza, Garrone, Giulia, Fontana, Manuela, Caruso, Donatella, Siciliano, Gabriele, Comi, Giacomo Pietro, Govoni, Alessandra, Corti, Stefania, and Ottoboni, Linda

Published
2023
Full Text
View/download PDF

16. Respiratory function in a large cohort of treatment-naïve adult spinal muscular atrophy patients: a cross-sectional study

Author

Vicino, Alex, Bello, Luca, Bonanno, Silvia, Govoni, Alessandra, Cerri, Federica, Ferraro, Manfredi, Capece, Giuliana, Gadaleta, Giulio, Meneri, Megi, Vacchiano, Veria, Ricci, Giulia, D'Errico, Eustachio, Tramacere, Irene, Banfi, Paolo, Bortolani, Sara, Zanin, Riccardo, Maioli, Maria Antonietta, Silvestrini, Mauro, Previtali, Stefano Carlo, Berardinelli, Angela, Turri, Mara, Coccia, Michela, Mantegazza, Renato, Liguori, Rocco, Filosto, Massimiliano, Siciliano, Gabriele, Simone, Isabella Laura, Mongini, Tiziana, Comi, Giacomo, Pegoraro, Elena, and Maggi, Lorenzo

Published
2023
Full Text
View/download PDF

17. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A, Stein, Thor D, Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S, Portley, Makayla K, Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, FNU, Keagle, Pamela, Rossi, Giacomina, Caroppo, Paola, Tagliavini, Fabrizio, Waldo, Maria L, Johansson, Per M, Nilsson, Christer F, Rowe, James B, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Jabbari, Edwin, Viollet, Coralie, Glass, Jonathan D, Singleton, Andrew B, Silani, Vincenzo, Ross, Owen A, Ryten, Mina, Torkamani, Ali, Tanaka, Toshiko, Ferrucci, Luigi, Resnick, Susan M, Pickering-Brown, Stuart, Brady, Christopher B, Kowal, Neil, Hardy, John A, Van Deerlin, Vivianna, Vonsattel, Jean Paul, Harms, Matt, Morris, Christopher M, Ferrari, Raffaele, Landers, John E, Chiò, Adriano, Gibbs, Jesse Raphael, Dalgard, Clifton L, Scholz, Sonja W, Traynor, Bryan J, Adeleye, Adelani, Alba, Camille, Bacikova, Dagmar, Hupalo, Daniel N, Martinez, Elisa McGrath, Pollard, Harvey B, Sukumar, Gauthaman, Soltis, Anthony R, Tuck, Meila, Zhang, Xijun, Wilkerson, Matthew D, Smith, Bradley N, Ticozzi, Nicola, Fallini, Claudia, Gkazi, Athina Soragia, Topp, Simon D, Kost, Jason, Scotter, Emma L, Kenna, Kevin P, Miller, Jack W, Tiloca, Cinzia, Vance, Caroline, Danielson, Eric W, Troakes, Claire, Colombrita, Claudia, Al-Sarraj, Safa, Lewis, Elizabeth A, King, Andrew, Calini, Daniela, Pensato, Viviana, Castellotti, Barbara, de Belleroche, Jacqueline, Baas, Frank, Asbroek, Anneloor LMA ten, Sapp, Peter C, McKenna-Yasek, Diane, McLaughlin, Russell L, Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Muñoz-Blanco, José Luis, Stevic, Zorica, D’Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P, Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, and van Rheenen, Wouter

Subjects
Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Neurodegenerative, Acquired Cognitive Impairment, Dementia, Frontotemporal Dementia (FTD), Alzheimer's Disease Related Dementias (ADRD), ALS, Rare Diseases, Brain Disorders, Neurosciences, Huntington's Disease, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, DNA Repeat Expansion, Frontotemporal Dementia, Humans, Huntingtin Protein, Mutation, Whole Genome Sequencing, American Genome Center, FALS Sequencing Consortium, Genomics England Research Consortium, International ALS/FTD Genomics Consortium, International FTD Genetics Consortium, International LBD Genomics Consortium, NYGC ALS Consortium, PROSPECT Consortium, amyotrophic lateral sclerosis, frontotemporal dementia, huntingtin, repeat expansions, whole-genome sequencing, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2021

19. Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

Author

Bello, Luca, DAngelo, Grazia, Villa, Matteo, Fusto, Aurora, Vianello, Sara, Merlo, Beatrice, Sabbatini, Daniele, Barp, Andrea, Gandossini, Sandra, Magri, Francesca, Comi, Giacomo, Pedemonte, Marina, Tacchetti, Paola, Lanzillotta, Valentina, Trucco, Federica, DAmico, Adele, Bertini, Enrico, Astrea, Guja, Politano, Luisa, Masson, Riccardo, Baranello, Giovanni, Albamonte, Emilio, De Mattia, Elisa, Rao, Fabrizio, Sansone, Valeria, Previtali, Stefano, Messina, Sonia, Vita, Gian, Berardinelli, Angela, Mongini, Tiziana, Pini, Antonella, Pane, Marika, Mercuri, Eugenio, Vianello, Andrea, Bruno, Claudio, Hoffman, Eric, Morgenroth, Lauren, Gordish-Dressman, Heather, Pegoraro, Elena, and McDonald, Craig

Subjects
Adolescent, Adult, CD40 Antigens, Child, Child, Preschool, Dystrophin, Follow-Up Studies, Glucocorticoids, Humans, Male, Muscular Dystrophy, Duchenne, Osteopontin, Respiratory Function Tests, Respiratory Insufficiency, Retrospective Studies, Vital Capacity, Young Adult
Abstract

OBJECTIVE: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). METHODS AND RESULTS: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3 of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. INTERPRETATION: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

Published
2020

20. Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial

Author

Abete Fornara, Giorgia, Agnelli, Nicolò M., Albanese, Alessio, Awad, Issam, Bagnati, Renzo, Balconi, Giovanna, Ballabio, Elena, Beghi, Ettore, Bernasconi, Roberto, Bertani, Giulio A., Besana, Silvia, Blanda, Adriana, Bossi, Chiara, Bresolin, Nereo, Buratti, Maria G., Calabrese, Roberta, Carriero, Maria R., Castori, Marco, Ciceri, Elisa F., Ciurleo, Rossella, Comi, Giacomo P., Contarino, Valeria, Conte, Giorgio, D'Agruma, Leonardo, D'Alessandris, Giorgio Q., de Grazia, Ugo, Di Bonaventura, Rina, d'Orio, Piergiorgio, Farago', Giuseppe, Foresta, Andreana, Fusco, Carmela, Gaudino, Chiara, Lampugnani, Maria G., Lanno, Alessia, Lazzaroni, Francesca, Lee, Cornelia, Locatelli, Marco, Maggioni, Aldo P., Magnusson, Peetra, Malinverno, Matteo, Mangiavacchi, Maurizio, Mangraviti, Antonella, Marino, Silvia, Mazzola, Selene, Nicolis, Enrico B., Novelli, Deborah, Ojeda Fernandez, Maria L., Petracca, Antonio, Pignotti, Fabrizio, Pogliani, Simona, Poloni, Marco, Prelle, Alessandro, Raggi, Pamela, Raucci, Franca, Regna-Gladin, Caroline, Ronchi, Dario, Scelzo, Emma, Seyfried, Salim, Simeone, Anna, Sturiale, Carmelo L., Tassi, Laura, Tettamanti, Mauro, Torri, Valter, Tournier-Lasserve, Elisabeth, Treglia, Rita, Triulzi, Fabio M., Ungaro, Celeste, Ursi, Elison, Valcamonica, Gloria, Vasami', Antonella, Zarino, Barbara, Lanfranconi, Silvia, Scola, Elisa, Meessen, Jennifer M T A, Pallini, Roberto, Bertani, Giulio A, Al-Shahi Salman, Rustam, Dejana, Elisabetta, and Latini, Roberto

Published
2023
Full Text
View/download PDF

23. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial

Author

Volpe, Joseph J, Posner, John, Kellner, Ulrich, Quinlivan, Rosaline, Gerber, Marianne, Khwaja, Omar, Scalco, Renata S, Seabrook, Timothy, Koch, Armin, Balikova, Irina, Joniau, Inge, Accou, Geraldine, Tahon, Valentine, Wittevrongel, Sylvia, De Vos, Elke, de Holanda Mendonça, Rodrigo, Matsui Jr, Ciro, Fornazieri Darcie, Ana Letícia, Machado, Cleide, Kiyoko Oyamada, Maria, Martini, Joyce, Polido, Graziela, Rodrigues Iannicelli, Juliana, Caires de Oliveira Achili Ferreira, Juliana, Hu, Chaoping, Zhu, Xiaomei, Qian, Chen, Shen, Li, Li, Hui, Shi, Yiyun, Zhou, Shuizhen, Xiao, Ying, Zhou, Zhenxuan, Wang, Sujuan, Sang, Tian, Wei, Cuijie, Dong, Hui, Cao, Yiwen, Wen, Jing, Li, Wenzhu, Qin, Lun, Barisic, Nina, Celovec, Ivan, Galiot Delic, Martina, Ivkic, Petra Kristina, Vukojevic, Nenad, Kern, Ivana, Najdanovic, Boris, Skugor, Marin, Tomas, Josipa, Boespflug-Tanguy, Odile, De Lucia, Silvana, Seferian, Andrea, Barreau, Emmanuel, Mnafek, Nabila, Peche, Helene, Grange, Allison, Trang Nguyen, Diem, Milascevic, Darko, Tachibana, Shotaro, Pagliano, Emanuela, Bianchi Marzoli, Stefania, Santarsiero, Diletta, Garcia Sierra, Myriam, Tremolada, Gemma, Arnoldi, Maria Teresa, Vigano, Marta, Dosi, Claudia, Zanin, Riccardo, Schembri, Veronica, Brolatti, Noemi, Rao, Giuseppe, Tassara, Elisa, Morando, Simone, Tacchetti, Paola, Pedemonte, Marina, Priolo, Enrico, Sposetti, Lorenza, Comi, Giacomo Pietro, Govoni, Alessandra, Osnaghi, Silvia Gabriella, Minorini, Valeria, Abbati, Francesca, Fassini, Federica, Foa, Michaela, Lopopolo, Amalia, Pane, Marika, Palermo, Concetta, Pera, Maria Carmela, Amorelli, Giulia Maria, Barresi, Costanza, D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Leone, Daniela, Laura, Antonaci, De Sanctis, Roberto, Berti, Beatrice, Kimura, Naoki, Takeshima, Yasuhiro, Shimomura, Hideki, Lee, Tomoko, Gomi, Fumi, Morimatsu, Takanobu, Furukawa, Toru, Stodolska-Koberda, Urszula, Waskowska, Agnieszka, Kolendo, Jagoda, Sobierajska-Rek, Agnieszka, Modrzejewska, Sandra, Lemska, Anna, Melnik, Evgenia, Artemyeva, Svetlana, Leppenen, Natalya, Yupatova, Nataliya, Monakhova, Anastasya, Papina, Yulia, Shidlovsckaia, Olga, Litvinova, Elena, Enzmann, Cornelia, Galiart, Elea, Gugleta, Konstantin, Wondrusch Haschke, Christine, Topaloglu, Haluk, Oncel, Ibrahim, Ertugrul, Nesibe Eroglu, Konuskan, Bahadir, Eldem, Bora, Kadayifçilar, Sibel, Alemdaroglu, Ipek, Sari, Seher, Bilgin, Neslihan, Karaduman, Aynur Ayse, Sarikaya, Fatma Gokcem Yildiz, Graham, Robert J, Ghosh, Partha, Casavant, David, Levine, Alexis, Titus, Rachael, Engelbrekt, Amanda, Ambrosio, Lucia, Fulton, Anne, Baglieri, Anna Maria, Dias, Courtney, Maczek, Elizabeth, Pasternak, Amy, Beres, Shannon, Duong, Tina, Gee, Richard, Young, Sally, Masson, Riccardo, Mazurkiewicz-Bełdzińska, Maria, Rose, Kristy, Servais, Laurent, Xiong, Hui, Zanoteli, Edmar, Baranello, Giovanni, Bruno, Claudio, Day, John W, Deconinck, Nicolas, Klein, Andrea, Mercuri, Eugenio, Vlodavets, Dmitry, Wang, Yi, Dodman, Angela, El-Khairi, Muna, Gorni, Ksenija, Jaber, Birgit, Kletzl, Heidemarie, Gaki, Eleni, Fontoura, Paulo, and Darras, Basil T

Published
2022
Full Text
View/download PDF

24. Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson’s disease

Author

Riboldi, Giulietta Maria, Vialle, Ricardo A., Navarro, Elisa, Udine, Evan, de Paiva Lopes, Katia, Humphrey, Jack, Allan, Amanda, Parks, Madison, Henderson, Brooklyn, Astudillo, Kelly, Argyrou, Charalambos, Zhuang, Maojuan, Sikder, Tamjeed, Oriol Narcis, J., Kumar, Shilpa Dilip, Janssen, William, Sowa, Allison, Comi, Giacomo P., Di Fonzo, Alessio, Crary, John F., Frucht, Steven J., and Raj, Towfique

Published
2022
Full Text
View/download PDF

28. Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study

Author

Fusto, Aurora, Cassandrini, Denise, Fiorillo, Chiara, Codemo, Valentina, Astrea, Guja, D’Amico, Adele, Maggi, Lorenzo, Magri, Francesca, Pane, Marika, Tasca, Giorgio, Sabbatini, Daniele, Bello, Luca, Battini, Roberta, Bernasconi, Pia, Fattori, Fabiana, Bertini, Enrico Silvio, Comi, Giacomo, Messina, Sonia, Mongini, Tiziana, Moroni, Isabella, Panicucci, Chiara, Berardinelli, Angela, Donati, Alice, Nigro, Vincenzo, Pini, Antonella, Giannotta, Melania, Dosi, Claudia, Ricci, Enzo, Mercuri, Eugenio, Minervini, Giovanni, Tosatto, Silvio, Santorelli, Filippo, Bruno, Claudio, and Pegoraro, Elena

Published
2022
Full Text
View/download PDF

31. Unleashing the potential of mRNA therapeutics for inherited neurological diseases.

Author

Monfrini, Edoardo, Baso, Giacomo, Ronchi, Dario, Meneri, Megi, Gagliardi, Delia, Quetti, Lorenzo, Verde, Federico, Ticozzi, Nicola, Ratti, Antonia, Fonzo, Alessio Di, Comi, Giacomo P, Ottoboni, Linda, and Corti, Stefania

Subjects
DRUG side effects, COVID-19, THERAPEUTIC use of proteins, GENETIC variation, DRUG toxicity
Abstract

Neurological monogenic loss-of-function diseases are hereditary disorders resulting from gene mutations that decrease or abolish the normal function of the encoded protein. These conditions pose significant therapeutic challenges, which may be resolved through the development of innovative therapeutic strategies. RNA-based technologies, such as mRNA replacement therapy, have emerged as promising and increasingly viable treatments. Notably, mRNA therapy exhibits significant potential as a mutation-agnostic approach that can address virtually any monogenic loss-of-function disease. Therapeutic mRNA carries the information for a healthy copy of the defective protein, bypassing the problem of targeting specific genetic variants. Moreover, unlike conventional gene therapy, mRNA-based drugs are delivered through a simplified process that requires only transfer to the cytoplasm, thereby reducing the mutagenic risks related to DNA integration. Additionally, mRNA therapy exerts a transient effect on target cells, minimizing the risk of long-term unintended consequences. The remarkable success of mRNA technology for developing coronavirus disease 2019 vaccines has rekindled interest in mRNA as a cost-effective method for delivering therapeutic proteins. However, further optimization is required to enhance mRNA delivery, particularly to the CNS, while minimizing adverse drug reactions and toxicity. In this comprehensive review, we delve into past, present and ongoing applications of mRNA therapy for neurological monogenic loss-of-function diseases. We also discuss the promises and potential challenges presented by mRNA therapeutics in this rapidly advancing field. Ultimately, we underscore the full potential of mRNA therapy as a game-changing therapeutic approach for neurological disorders. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

32. TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models

Author

Longo, Miriam, Meroni, Marica, Paolini, Erika, Erconi, Veronica, Carli, Fabrizia, Fortunato, Francesco, Ronchi, Dario, Piciotti, Roberto, Sabatini, Silvia, Macchi, Chiara, Alisi, Anna, Miele, Luca, Soardo, Giorgio, Comi, Giacomo Pietro, Valenti, Luca, Ruscica, Massimiliano, Fracanzani, Anna L., Gastaldelli, Amalia, and Dongiovanni, Paola

Published
2022
Full Text
View/download PDF

33. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Volpe, Joseph J., Posner, John, Kellner, Ulrich, Quinlivan, Rosaline, Daron, Aurore, Delstanche, Stéphanie, Bruninx, Romain, Dal Farra, Fabian, Schneider, Olivier, Deconinck, Nicolas, Balikova, Irina, Delbeke, Patricia, Joniau, Inge, Tahon, Valentine, Wittevrongel, Sylvia, De Vos, Elke, Goemans, Nathalie, Casteels, Ingele, De Waele, Liesbeth, Cassiman, Catherine, Prové, Lies, Kinoo, David, Vancampenhout, Lisa, Van Den Hauwe, Marleen, Van Impe, Annelies, Prufer de Queiroz Campos Araujo, Alexandra, Chacon Pereira, Aline, Nardes, Flávia, Haefeli, Lorena, Rossetto, Julia, Ferreira Rebel, Marcos, Almeida Pereira, Jaqueline, Campbell, Craig, Sharan, Sapna, McDonald, Wendy, Scholtes, Cheryl, Mah, Jean, Sframeli, Maria, Chiu, Angela, Hagel, Jane, Oskoui, Maryam, Beneish, Raquel, Cariou-Palmer, Gaela, Pham, Connie, Toffoli, Daniela, Arpin, Stephanie, Turgeon Desilets, Sarah, Wang, Yi, Hu, Chaoping, Huan, Jianfeng, Qian, Chen, Shen, Li, Xiao, Ying, Zhou, Zhenxuan, Li, Hui, Wang, Sujuan, Xiong, Hui, Chang, Xingzhi, Dong, Hui, Liu, Ying, Sang, Tian, Wei, Cuijie, Wen, Jing, Cao, Yiwen, Ly, Xingyao, Zhao, Jingjing, Li, Wenzhu, Qin, Lun, Barisic, Nina, Galiot Delic, Martina, Ivkic, Petra Kristina, Vukojevic, Nenad, Kern, Ivana, Najdanovic, Boris, Skugor, Marin, Servais, Laurent, Boespflug-Tanguy, Odile, Gidaro, Teresa, Seferian, Andreea, De Lucia, Silvana, Barreau, Emmanuel, Mnafek, Nabila, Momtchilova, Marta Milkova, Peche, Helene, Valherie, Carole, Grange, Allison, Lilien, Charlotte, Milascevic, Darko, Tachibana, Shotaro, Ravelli, Claudia, Cardas, Ruxandra, Taytard, Jessica, Aubertin, Guillaume, Vanden Brande, Laure, Davion, Jean-Baptiste, Coopman, Stephanie, Bouacha, Ikram, Debruyne, Philippe, Defoort, Sabine, Derlyn, Gilles, Leroy, Florian, Danjoux, Loïc, Guilbaud, Julie, Desguerre, Isabelle, Barnérias, Christine, Semeraro, Michaela, Bremond-Gignac, Dominique, Bruere, Lenaic, Rateaux, Maxence, Deladrière, Élodie, Germa, Virginie, Pereon, Yann, Mercie, Sandra, Billaud, Fanny, Le Goff, Lucie, Letellier, Guy, Vuillerot, Carole, Portefaix, Aurélie, De-Montferrand, Camille, Le-Goff, Laure, Fontaine, Stephanie, Saidi, Manel, Bouzid, Nabil, Barriere, Aurélie, Tinat, Marie, Kirschner, Janbernd, Dreesbach, Michelle, Lagréze, Wolf, Michaelis, Bettina, Molnar, Fanni, Seger, Dorina, Vogt, Sibylle, Bertini, Enrico, D'Amico, Adele, Petroni, Sergio, Bonetti, Anna Maria, Carlesi, Adelina, Mizzoni, Irene, Bruno, Claudio, Priolo, Enrico, Rao, Giuseppe, Morando, Simone, Tacchetti, Paola, Zuffi, Ambra, Comi, Giacomo Pietro, Brusa, Roberta, Corti, Stefania, Daniele, Velardo, Govoni, Alessandra, Magri, Francesca, Minorini, Valeria, Osnaghi, Silvia Gabriella, Abbati, Francesca, Fassini, Federica, Foa, Michaela, Lopopolo, Amaqlia, Meneri, Megi, Zoppas, Francesca, Parente, Valeria, Baranello, Giovanni, Masson, Riccardo, Bianchi Marzoli, Stefania, Santarsiero, Diletta, Garcia Sierra, Myriam, Tremolada, Gemma, Arnoldi, Maria Teresa, Vigano, Marta, Zanin, Riccardo, Mercuri, Eugenio, Antonaci, Laura, de Sanctis, Roberto, Pane, Marika, Pera, Maria Carmela, Amorelli, Giulia Maria, Barresi, Costanza, D'Amico, Gugliemo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, Kazuhiro, Kato, Atsuko, Morishita, Yuko, Kira, Ryutaro, Akiyama, Kiyomu, Goto, Miwako, Mori, Yujiro, Okamoto, Misato, Tsutsui, Saki, Takatsuji, Yuta, Tanaka, Aya, Komaki, Hirofumi, Omori, Miina, Suzuki, Ippei, Takeuchi, Mizuki, Todoroki, Daisuke, Watanabe, Seji, Matsubayashi, Tomoko, Inakazu, Emi, Nagura, Hiroe, Suzuki, Akira, Usui, Manami, Ishikawa, Nobutsune, Harada, Yousuke, Fudeyasu, Kenishi, Hirata, Kazuhiko, Michiue, Kana, Ueda, Kazuyuki, Saito, Kayoko, Fujitani, Junko, Arakawa, Reiko, Takano, Kozue, Yashiro, Shigeko, Seki, Maiko, Sano, Nozomi, Fukuyama, Koji, Matsumoto, Yuki, Miyazaki, Hirofumi, Shibata, Minoru, Kobayashi, Kyoko, Nakamura, Yukie, Takeshima, Yasuhiro, Kuma, Moe, Kostera-Pruszczyk, Anna, Fraczek, Anna, Jedrzejowska, Maria, Lusakowska, Anna, Czeszyk-Piotrowicz, Agnieszka, Hautz, Wojciech, Rakusiewicz, Klaudia, Burlewicz, Malgorzata, Gierlak-Wojcicka, Zuzanna, Kepa, Malwina, Sikorski, Adam, Sobieraj, Marcin, Mazurkiewicz-Beldzinska, Maria, Lemska, Anna, Modrzejewska, Sandra, Koberda, Mateusz, Stodolska-Koberda, Urszula, Waskowska, Agnieszka, Kolendo, Jagoda, Sobierajska-Rek, Agnieszka, Steinborn, Barbara, Dalz, Magdalena, Grabowska, Julia, Hajduk, Wojciech, Janasiewicz-Karachitos, Justyna, Klimas, Monika, Stopa, Marcin, Gajewska, Ewa, Pusz, Beata, Vlodavets, Dmitry, Melnik, Evgenia, Leppenen, Natalya, Yupatova, Nataliya, Monakhova, Anastasya, Papina, Yulia, Shidlovsckaia, Olga, Milic Rasic, Vedrana, Brankovic, Vesna, Kosac, Ana, Djokic, Olivera, Jakšic, Vesna, Pepic, Ana, Martinovic, Jelena, Munell Casadesus, Francina, Tizzano, Eduardo, Martín Begué, Nieves, Wolley Dod, Charlotte, Subira, Olaia, Planas Pascual, Bernat, Toro Tamargo, Esther, Madruga Garrido, Marcos, Medina Romero, José David, Salinas, Marta Peña, Nascimento Osorio, Andrés, Díaz Cortés, Ana, Jiménez Gañan, Enrique, Suh, Simone Dowon, Medina Cantillo, Julita, Moya, Obdulia, Padros, Nuria, Urraca, Sandra Roca, Valdivia, Hugo Gonzalez, Pascual Pascual, Samuel, de Manuel, Sofía, Martin, Susana Noval, Burnham, Paul, Espinosa, Sandra, Moreno, Mercedes Martinez, Topaloglu, Haluk, Oncel, Ibrahim, Eroglu Ertugru, Nesibe, Konuskan, Bahadir, Eldem, Bora, Kadayifçilar, Sibel, Alemdaroglu, Ipek, Karaduman, Aynur Ayse, Yilmaz, Oznur Tunca, Bilgin, Neslihan, Sari, Seher, Chiriboga, Claudia, Lee, John J., Rome-Martin, Donnielle, Day, John W., Beres, Shannon, Duong, Tina, Gee, Richard, Dunaway Young, Sally, Fuerst-Recktenwald, Sabine, Marquet, Anne, Muelhardt, Nicoletta, Trundell, Dylan, Mazzone, Elena S, Nascimento, Andres, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Staunton, Hannah, Yeung, Wai Yin, Martin, Carmen, Fontoura, Paulo, and Day, John W

Published
2022
Full Text
View/download PDF

36. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Author

Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke JFA, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, ITALSGEN Consortium, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Genomic Translation for ALS Care (GTAC) Consortium, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B, ALS Sequencing Consortium, Gitler, Aaron D, Harris, Tim, Myers, Richard M, NYGC ALS Consortium, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Answer ALS Foundation, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, SLAGEN Consortium, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, French ALS Consortium, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, and Orrell, Richard W

Subjects
ITALSGEN Consortium, Genomic Translation for ALS Care (GTAC) Consortium, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Foundation, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consortium, Humans, Amyotrophic Lateral Sclerosis, Cohort Studies, Amino Acid Sequence, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Young Adult, Loss of Function Mutation, Kinesins, ALS, GWAS, KIF5A, WES, WGS, axonal transport, cargo, Brain Disorders, Genetics, Human Genome, Rare Diseases, Neurosciences, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

37. Early spinal muscular atrophy treatment following newborn screening: A 20‐month review of the first Italian regional experience

Author

Gagliardi, Delia, primary, Canzio, Eleonora, additional, Orsini, Paola, additional, Conti, Pasquale, additional, Sinisi, Vita, additional, Maggiore, Cosimo, additional, Santarsia, Maria Carla, additional, Lagioia, Giuseppina, additional, Lupis, Giovanna, additional, Roppa, Isabella, additional, Scianatico, Gaetano, additional, Mancini, Daniela, additional, Corti, Stefania, additional, Comi, Giacomo Pietro, additional, Gentile, Mattia, additional, and Gagliardi, Delio, additional

Published
2024
Full Text
View/download PDF

38. Three-Dimensional Stem Cell-derived Spinal Cord Model for Investigating Therapeutic Mechanisms of Risdiplam-like Compounds in Spinal Muscular Atrophy (P2-11.001)

Author

D'Angelo, Andrea, primary, Beatrice, Francesca, additional, Ongaro, Jessica, additional, Rinchetti, Paola, additional, Faravelli, Irene, additional, Miotto, Matteo, additional, Lodato, Simona, additional, Nizzardo, Monica, additional, Comi, Giacomo, additional, Ottoboni, Linda, additional, and Corti, Stefania, additional

Published
2024
Full Text
View/download PDF

39. Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease

Author

Donkervoort, Sandra, primary, van de Locht, Martijn, additional, Ronchi, Dario, additional, Reunert, Janine, additional, McLean, Catriona A., additional, Zaki, Maha, additional, Orbach, Rotem, additional, de Winter, Josine M., additional, Conijn, Stefan, additional, Hoomoedt, Daan, additional, Neto, Osorio Lopes Abath, additional, Magri, Francesca, additional, Viaene, Angela N., additional, Foley, A. Reghan, additional, Gorokhova, Svetlana, additional, Bolduc, Véronique, additional, Hu, Ying, additional, Acquaye, Nicole, additional, Napoli, Laura, additional, Park, Julien H., additional, Immadisetty, Kalyan, additional, Miles, Lee B., additional, Essawi, Mona, additional, McModie, Salar, additional, Ferreira, Leonardo F., additional, Zanotti, Simona, additional, Neuhaus, Sarah B., additional, Medne, Livija, additional, ElBagoury, Nagham, additional, Johnson, Kory R., additional, Zhang, Yong, additional, Laing, Nigel G., additional, Davis, Mark R., additional, Bryson-Richardson, Robert J., additional, Hwee, Darren T., additional, Hartman, James J., additional, Malik, Fady I., additional, Kekenes-Huskey, Peter M., additional, Comi, Giacomo Pietro, additional, Sharaf-Eldin, Wessam, additional, Marquardt, Thorsten, additional, Ravenscroft, Gianina, additional, Bönnemann, Carsten G., additional, and Ottenheijm, Coen A. C., additional

Published
2024
Full Text
View/download PDF

40. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

Mercuri, Eugenio, primary, Vilchez, Juan J, additional, Boespflug-Tanguy, Odile, additional, Zaidman, Craig M, additional, Mah, Jean K, additional, Goemans, Nathalie, additional, Müller-Felber, Wolfgang, additional, Niks, Erik H, additional, Schara-Schmidt, Ulrike, additional, Bertini, Enrico, additional, Comi, Giacomo P, additional, Mathews, Katherine D, additional, Servais, Laurent, additional, Vandenborne, Krista, additional, Johannsen, Jessika, additional, Messina, Sonia, additional, Spinty, Stefan, additional, McAdam, Laura, additional, Selby, Kathryn, additional, Byrne, Barry, additional, Laverty, Chamindra G, additional, Carroll, Kevin, additional, Zardi, Giulia, additional, Cazzaniga, Sara, additional, Coceani, Nicoletta, additional, Bettica, Paolo, additional, and McDonald, Craig M, additional

Published
2024
Full Text
View/download PDF

41. The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy

Author

Foley, A. Reghan, primary, Bolduc, Veronique, additional, Guirguis, Fady, additional, Donkervoort, Sandra, additional, Hu, Ying, additional, Orbach, Rotem, additional, McCarty, Riley M., additional, Sarathy, Apurva, additional, Norato, Gina, additional, Cummings, Beryl B., additional, Lek, Monkol, additional, Sarkozy, Anna, additional, Butterfield, Russell J., additional, Kirschner, Janbernd, additional, Nascimento, Andres, additional, Natera-de Benito, Daniel, additional, Quijano-Roy, Susana, additional, Stojkovic, Tanya, additional, Merlini, Luciano, additional, Comi, Giacomo, additional, Ryan, Monique, additional, McDonald, Denise, additional, Munot, Pinki, additional, Yoon, Grace, additional, Leung, Edward, additional, Finanger, Erika, additional, Leach, Meganne E., additional, Collins, James, additional, Tian, Cuixia, additional, Mohassel, Payam, additional, Neuhaus, Sarah B., additional, Saade, Dimah, additional, Cocanougher, Benjamin, additional, Chu, Mary-Lynn, additional, Scavina, Mena, additional, Grosmann, Carla, additional, Randal, Richardson, additional, Kossak, Brian D., additional, Gospe, Sidney M., additional, Bhise, Vikram, additional, Taurina, Gita, additional, Lace, Baiba, additional, Troncoso, Monica, additional, Shohat, Mordechai, additional, Shalata, Adel, additional, Chan, Sophelia H.S., additional, Jokela, Manu, additional, Palmio, Johanna, additional, Haliloglu, Goknur, additional, Jou, Cristina, additional, Gartioux, Corine, additional, Solomon-Degefa, Herimela, additional, Freiburg, Carolin D., additional, Schiavinato, Alvise, additional, Zhou, Haiyan, additional, Aguti, Sara, additional, Nevo, Yoram, additional, Nishino, Ichizo, additional, Jimenez-Mallebrera, Cecilia, additional, Lamande, Shireen R., additional, Allamand, Valerie, additional, Gualandi, Francesca, additional, Ferlini, Alessandra, additional, MacArthur, Daniel, additional, Wilton, Steve D., additional, Wagener, Raimund, additional, Bertini, Enrico, additional, Muntoni, Francesco, additional, and Bonnemann, Carsten G., additional

Published
2024
Full Text
View/download PDF

42. Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition

Author

Piga, Daniela, primary, Rimoldi, Martina, additional, Magri, Francesca, additional, Zanotti, Simona, additional, Napoli, Laura, additional, Ripolone, Michela, additional, Pagliarani, Serena, additional, Ciscato, Patrizia, additional, Velardo, Daniele, additional, D’Amico, Adele, additional, Bertini, Enrico, additional, Comi, Giacomo Pietro, additional, Ronchi, Dario, additional, and Corti, Stefania, additional

Published
2024
Full Text
View/download PDF

45. Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Author

Johari, Mridul, Sarparanta, Jaakko, Vihola, Anna, Jonson, Per Harald, Savarese, Marco, Jokela, Manu, Torella, Annalaura, Piluso, Giulio, Said, Edith, Vella, Norbert, Cauchi, Marija, Magot, Armelle, Magri, Francesca, Mauri, Eleonora, Kornblum, Cornelia, Reimann, Jens, Stojkovic, Tanya, Romero, Norma B., Luque, Helena, Huovinen, Sanna, Lahermo, Päivi, Donner, Kati, Comi, Giacomo Pietro, Nigro, Vincenzo, Hackman, Peter, and Udd, Bjarne

Published
2021
Full Text
View/download PDF

46. The nonsense mutation stop+4 model correlates with motor changes in Duchenne muscular dystrophy

Author

Brogna, Claudia, Coratti, Giorgia, Rossi, Rachele, Neri, Marcella, Messina, Sonia, Amico, Adele D’, Bruno, Claudio, Lucibello, Simona, Vita, Gianluca, Berardinelli, Angela, Magri, Francesca, Ricci, Federica, Pedemonte, Marina, Mongini, Tiziana, Battini, Roberta, Bello, Luca, Pegoraro, Elena, Baranello, Giovanni, Politano, Luisa, Comi, Giacomo P., Sansone, Valeria A, Albamonte, Emilio, Donati, Alice, Bertini, Enrico, Goemans, Nathalie, Previtali, Stefano, Bovis, Francesca, Pane, Marika, Ferlini, Alessandra, and Mercuri, Eugenio

Published
2021
Full Text
View/download PDF

49. A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy

Author

Victor, Ronald G, Sweeney, H Lee, Finkel, Richard, McDonald, Craig M, Byrne, Barry, Eagle, Michelle, Goemans, Nathalie, Vandenborne, Krista, Dubrovsky, Alberto L, Topaloglu, Haluk, Miceli, M Carrie, Furlong, Pat, Landry, John, Elashoff, Robert, Cox, David, Abdel-Hamid, Hoda, Apkon, Susan, Barohn, Richard, Belousova, Elena, Bertini, Enrico, Brandsema, John, Bruno, Claudio, Burnette, William, Butterfield, Russell, Campbell, Craig, Carlo, Jose, Chae, Jong-Hee, Chandratre, Saleel, Comi, Giacomo, Connolly, Anne, De Groot, Imelda, Deconinck, Nicolas, Dooley, Joseph, Dubrovsky, Alberto, Durigneux, Julien, Finanger, Erika, Frank, L Matthew, Harper, Amy, Hattori, Ayako, Herguner, Ozlem, Iannaccone, Susan, Janas, Joanne, Jong, Yuh-Jyh, Kirschner, JanBerd, Komaki, Hirofumi, Kuntz, Nancy, Lee, Wang-Tso, Leung, Edward, Mah, Jean, Mathews, Katherine, McDonald, Craig, Mercuri, Eugenio, McMillan, Hugh, Mueller-Felber, Wolfgang, de Munain, Adolfo Lopez, Nakamura, Akinori, Niks, Erik, Ogata, Katsuhisa, Pascual, Samuel, Pegoraro, Elena, Pereon, Yann, Renfroe, Ben, Sanka, Ratna Bhavaraju, Schallner, Jens, Schara, Ulrike, Selby, Kathryn, Sendra, Isabel Illa, Servais, Laurent, Smith, Edward, Sparks, Susan, Victor, Ron, Vilchez, Juan Jose, Wicklund, Matthew, Wilichoswki, Ekkehard, and Wong, Brenda

Subjects
Pediatric, Clinical Research, Duchenne/ Becker Muscular Dystrophy, Clinical Trials and Supportive Activities, Muscular Dystrophy, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Rare Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Musculoskeletal, Adolescent, Area Under Curve, Child, Dose-Response Relationship, Drug, Double-Blind Method, Follow-Up Studies, Glucocorticoids, Heart Rate, Humans, International Cooperation, Male, Muscular Dystrophy, Duchenne, Quality of Life, Respiratory Function Tests, Tadalafil, Treatment Outcome, Vasodilator Agents, Ventricular Function, Left, Walking, Tadalafil DMD Study Group, Clinical Sciences, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD).MethodsThree hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg-1·d-1, tadalafil 0.6 mg·kg-1·d-1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome.ResultsTadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state.ConclusionsTadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age.Clinicaltrialsgov identifierNCT01865084.Classification of evidenceThis study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.

Published
2017

Catalog

Books, media, physical & digital resources
See catalog results