Branaplam como um Promissor Modulador de Splicing: Da Atrofia Muscular Espinhal à Doença de Huntington
DOI:
https://doi.org/10.46531/sinapse/AR/230005/2023Palavras-chave:
Atrofia Muscular Espinhal/ tratamento, Doença de Huntington/ tratamento, Éxons/genética, Splicing RNA/efeitos dos fármacos, Splicing AlternativoResumo
Os moduladores de splicing, que têm como alvo o RNA, revolucionaram a medicina moderna ao permitirem a regulação de expressão genética de forma reversível. A primeira molécula encontrada com a capacidade de alterar um processo de splicing particular num local específico foi o branaplam. Inicialmente, o branaplam foi desenvolvido como um modulador de splicing para a atrofia muscular espinhal (AME), a segunda doença autossómica recessiva mais comum e a principal causa de mortalidade infantil genética. Mais recentemente, foi investigada a sua utilização na doença de Huntington (DH), uma doença neurodegenerativa autossómica dominante fatal, com controlo sintomático limitado. Nesta revisão analisa-se, de forma abrangente, o programa de desenvolvimento do branaplam em ambas as situações clínicas mencionadas, projetando-se alguns dos aspetos que podem carecer de investigação futura, quando se consideram os moduladores de splicing, como classe terapêutica, nestas doenças.Downloads
Referências
Costales MG, Childs-Disney JL, Haniff HS, Disney MD. How we think about targeting RNA with small molecules. J Med Chem. 2020;63:8880-8900. doi: 10.1021/acs. jmedchem.9b01927.
Arechavala-Gomeza V, Khoo B, Aartsma-Rus A. Splicing modulation therapy in the treatment of genetic diseases. Appl Clin Genet. 2014;7:245-52. doi:10.2147/TACG.S71506.
Tang Z, Zhao J, Pearson ZJ, Boskovic ZV, Wang J. RNA targeting splicing modifiers: drug development and screening assays. Molecules. 2021;26:2263. doi:10.3390/molecules26082263.
Crooke ST, Baker BF, Crooke RM, Liang XH. Antisense technology: an overview and prospectus. Nat Rev Drug Discov. 2021;20:427-53. doi:10.1038/s41573-021-00162-z.
Yu AM, Choi YH, Tu MJ. RNA drugs and RNA targets for small molecules: principles, progress, and challenges. Pharmacol Rev. 2020;72:862-98. doi:10.1124/pr.120.019554.
Schneider-Poetsch T, Chhipi-Shrestha JK, Yoshida M. Splicing modulators: on the way from nature to clinic. J Antibiot. 2021;74:603-16. doi:10.1038/s41429-021-00450-1.
Nicolau S, Waldrop MA, Connolly AM, Mendell JR. Spinal muscular atrophy. Semin Pediatr Neurol. 2021;37:100878. doi:10.1016/j.spen.2021.100878.
Ferguson MW, Kennedy CJ, Palpagama TH, Waldvogel HJ, Faull RLM, Kwakowsky A. Current and possible future therapeutic options for Huntington’s disease. J Cent Nerv Syst Dis. 2022;14:11795735221092517. doi:10.1177/11795735221092517.
Keinath MC, Prior DE, Prior TW. Spinal muscular atrophy: mutations, testing, and clinical relevance. Appl Clin Genet. 2021;14:11-25. doi:10.2147/TACG.S239603.
Chaytow H, Huang YT, Gillingwater TH, Faller KM. The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci. 2018;75:3877-94. doi:10.1007/ s00018-018-2849-1.
Butchbach ME. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7. doi:10.3389/fmolb.2016.00007.
Singh NN, O’Leary CA, Eich T, Moss WN, Singh RN. structural context of a critical exon of spinal muscular atrophy gene. Front Mol Biosci. 2022;9:928581. doi:10.3389/ fmolb.2022.928581.
Yeo CJJ, Darras BT. Overturning the paradigm of spinal muscular atrophy as just a motor neuron disease. Pediatr Neurol. 2020;109:12-9. doi:10.1016/j.pediatrneurol.2020.01.003.
Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, et al. Corrigendum: SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol. 2015;11:741. doi:10.1038/nchembio0915-741a.
Novartis Pharmaceuticals. An Open Label Study of LMI070 (Branaplam) in Type 1 Spinal Muscular Atrophy (SMA) [Internet]. 2014 [updated 2022 May 17, cited 2022 Dec 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT02268552
SMA SMA News Today. After 2-Year Hiatus, Novartis Resumes Branaplam Clinical Trial in SMA Type 1 Infants [Internet]. 2017 [cited 2022 Dec 18]. Available from: https:// smanewstoday.com/news/sma-type-1-clinical-trial-of-bran-aplam-resumes-after-2-year-hiatus-says-novartis/
Charnas L, Voltz E, Pfister C, Peters T, Hartmann A, Berghs Clairmont C, et al. Safety and efficacy findings in the first-in-human trial (FIH) of the oral splice modulator branaplam in type 1 spinal muscular atrophy (SMA): interim results. Neuromuscular Disorders. 2017;27:S207-S208. doi: 10.1016/j. nmd.2017.06.411.
U.S. Food and Drug Administration. Search Orphan Drug Designations and Approvals [Internet]. 2018 [cited 2022 Dec 18]. Available from: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex. cfm?cfgridkey=620117
Jean-Pierre Malkowski. LMI070 (branaplam) in Spinal Muscular Atrophy (SMA) [Internet]. 2017 Sep [cited 2022 Dec 18]. Available from: https://www.fsma.pl/wp-content/uploads/2017/09/SMA-branaplam-update-Sept-17-v-1.pdf
Novartis Pharmaceuticals. External message to SMA patient community: SMA EUROPE [Internet]. 2019 May [cited 2022 Dec 18]. Available from: https://smauk.org.uk/files/ files/Novartis%20Update%20to%20SMA%20Europe%20 on%20Branaplam%20trials.pdf
Novartis Pharmaceuticals. Community update: Status of ongoing study of branaplam/LMI070 in SMA [Internet]. 2019 Dec [cited 2022 Dec 18]. Available from: https://smauk.org. uk/files/files/Research/Branaplam%20community%20update.pdf
Novartis Pharmaceuticals. Community update: Status of study of branaplam/LMI070 in SMA [Internet]. 2021 [cited 2022 Dec 18]. Available from: https://smauk.org.uk/files/ files/Research/Branaplam%20in%20SMA%20Community%20Update%20July%202021.pdf
Fonda Liu. HDYO’s International Young Adults Virtual Congress: Novartis Update [Internet]. 2022 [cited 2022 Dec 18]. Available from: https://www.youtube.com/ watch?v=l4aK8tltB1s&list=PLfha5f75-ixJxkfwkQ784YKRrXP8M6LP9
Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington’s disease: mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harb Perspect Med. 2017;7:a024240. doi:10.1101/cshperspect.a024240.
Khristich AN, Mirkin SM. On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability. J Biol Chem. 2020;295:4134-70. doi:10.1074/jbc. REV119.007678.
Roos RA. Huntington’s disease: a clinical review. Orphanet J Rare Dis. 2010;5:40. doi:10.1186/1750-1172-5-40.
Tabrizi SJ, Flower MD, Ross CA, Wild EJ. Huntington disease: new insights into molecular pathogenesis and thera-peutic opportunities. Nat Rev Neurol. 2020;16:529-46. doi:10.1038/s41582-020-0389-4.
Keller CG, Shin Y, Monteys AM, Renaud N, Beibel M, Teider N, et al. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion. Nat Commun. 2022;13:1150. doi:10.1038/s41467022-28653-6.
Dhir A, Buratti E. Alternative splicing: role of pseudoexons in human disease and potential therapeutic strategies. FEBS J. 2010;277:841-55. doi:10.1111/j.1742-4658.2009.07520.x.
Novartis Pharmaceuticals. Novartis receives US Food and Drug Administration (FDA) Orphan Drug Designation for branaplam (LMI070) in Huntington’s disease (HD) [Internet]. 2020 Oct [cited 2022 Dec 18]. Available from: https://www. novartis.com/news/media-releases/novartis-receives-us-food-and-drug-administration-fda-orphan-drug-designation-branaplam-lmi070-huntingtons-disease-hd
Novartis Pharmaceuticals. A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington’s Disease (VIBRANT-HD) [Internet]. 2021 [updated 2022 Sept 6, cited 2022 Dec 18]. Available from: https://clinicaltrials.gov/ct2/ show/NCT05111249
Novartis Pharmaceuticals. Novartis receives FDA Fast Track designation for branaplam (LMI070) for the treatment of Huntington’s Disease [Internet]. 2021 Dec [cited 2022 Dec 18]. Available from: https://www.novartis.com/news/ novartis-receives-fda-fast-track-designation-branaplamlmi070-treatment-huntingtons-disease
Novartis Pharmaceuticals. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s Disease [Internet]. 2022 Dec [cited 2022 Dec 18]. Available from: https://hdsa.org/wp-content/uploads/2022/12/ Novartis-VIBRANT-HD-Community-Letter-FINAL-PDF.pdf
Krach F, Stemick J, Boerstler T, Weiss A, Lingos I, Reischl S, et al. An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons. Nat Commun. 2022;13:6797. doi: 10.1038/s41467-022-34419-x.
Ottesen EW, Singh NN, Luo D, Kaas B, Gillette BJ, Seo J, et al. Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy. Nucleic Acids Res. 2023;gkad259. doi: 10.1093/nar/gkad259