Terapias gênicas e celulares para a doença de Huntington: revisão sistemática das evidências clínicas recentes
DOI:
https://doi.org/10.5281/zenodo.19225518Palavras-chave:
Doença de Huntington, Terapia gênica, Neuroproteção, Modulação de splicing, Oligonucleotídeos antissensoResumo
Introdução: A doença de Huntington (DH) é um transtorno neurodegenerativo genético progressivo, caracterizado por sintomas motores, cognitivos e psiquiátricos, sem tratamentos modificadores da doença aprovados. Objetivo: Avaliar as principais estratégias terapêuticas em investigação para a DH, com ênfase na terapia gênica e abordagens complementares. Metodologia: Realizamos uma revisão sistemática da literatura seguindo as diretrizes PRISMA, incluindo estudos de 2020 a 2025 em inglês e português, abrangendo pesquisas clínicas e experimentais sobre terapia gênica, terapia celular, imunoterapia e modulação farmacológica. Resultados: Moduladores de splicing orais (Branaplam, PTC518) reduziram significativamente os níveis de huntingtina mutante ou total, com boa segurança e penetração no SNC. Oligonucleotídeos antissenso (ex.: tominersen) demonstraram silenciamento gênico por administração intratecal. A imunoterapia com pepinemab mostrou potencial neuroprotetor, enquanto a terapia celular não gerou benefícios clínicos. Considerações: Essas abordagens representam avanços promissores em direção a tratamentos modificadores da doença para a DH; no entanto, estudos maiores e de longo prazo são necessários para confirmar a eficácia clínica.
Referências
BACHOUD-LÉVI, A. et al. Human fetal cell therapy in Huntington's disease: a randomized, multicenter, phase II trial. Movement Disorders, v. 35, p. 1323-35, 2020. https://doi.org/10.1002/mds.28201
BEATRIZ, M. et al. Revisiting cell and gene therapies in Huntington's disease. Journal of Neuroscience Research, v. 99, p. 1744-62, 2021. https://doi.org/10.1002/jnr.24845
FEIGIN, A. et al. Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nature Medicine, v. 28, p. 2183-93, 2022. https://doi.org/10.1038/s41591-022-01919-8
GAO, L. et al. Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: a first-in-human study. British Journal of Clinical Pharmacology, v. 90, p. 3242-51, 2024. https://doi.org/10.1111/bcp.16202
HOFFMANN-LA ROCHE. An open-label adaptive multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of RO7234292 in CSF and plasma, and safety and tolerability following intrathecal administration in patients with Huntington's disease. ClinicalTrials.gov, 2024.
HOFFMANN-LA ROCHE. An open-label extension study to evaluate the long-term safety and tolerability of intrathecally administered RO7234292 (RG6042) in patients with Huntington's disease. ClinicalTrials.gov, 2023.
HOFFMANN-LA ROCHE. An open-label extension study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7234292 (ISIS 443139) in Huntington's disease patients who participated in prior investigational studies of RO7234292 (ISIS 443139). ClinicalTrials.gov, 2022.
IONIS PHARMACEUTICALS, INC. A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of intrathecally administered ISIS 443139 in patients with early manifest Huntington's disease. ClinicalTrials.gov, 2019.
KRACH, F. et al. An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons. Nature Communications, v. 13, p. 6797, 2022. https://doi.org/10.1038/s41467-022-34419-x
McGARRY, A. et al. Suicidality risk factors across the CARE-HD, 2CARE, and CREST-E clinical trials in Huntington disease. Neurology: Clinical Practice, v. 12, p. 131-8, 2022. https://doi.org/10.1212/CPJ.0000000000001161
MULLIN, A. P. et al. Standardized data structures in rare diseases: CDISC user guides for Duchenne Muscular Dystrophy and Huntington's disease. Clinical and Translational Science, v. 14, p. 214-21, 2021. https://doi.org/10.1111/cts.12845
PFIZER. A phase 2, randomized, placebo controlled, double blind proof-of-concept study of the efficacy and safety of PF-02545920 in subjects with Huntington's disease. ClinicalTrials.gov, 2017.
RODRIGUES, F. B.; WILD, E. J. Huntington's disease clinical trials corner: April 2020. Journal of Huntington's Disease, v. 9, p. 185-97, 2020. https://doi.org/10.3233/JHD-200002
WIJEKOON, N. et al. Gene therapy for selected neuromuscular and trinucleotide repeat disorders: an insight to subsume South Asia for multicenter clinical trials. IBRO Neuroscience Reports, v. 14, p. 146-53, 2023. https://doi.org/10.1016/j.ibneur.2023.01.009
