Efficiency of siRNA for removal of transthyretin V30M in a TTR leptomeningeal animal model

Gonçalves, Paula; Martins, Sofia; Costelha, Susete; Saraiva, Maria João

doi:10.1080/13506129.2016.1272452

Cited by 1 publication

(1 citation statement)

References 2 publications

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“…The formulation of patisiran in LNPs distributes it predominantly to the liver. LNPs have been shown to be minimally distributed to other organs that have a fenestrated endothelium (e.g., the spleen) [98][99][100] although there is no evidence for penetration of the central nervous system or eye following systemic administration of such formulations [100].…”

Section: Patisiran: Pharmacologymentioning

confidence: 99%

Patisiran, an RNAi Therapeutic for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis

Kristen

Ajroud‐Driss

Conceição

et al. 2018

Neurodegener. Dis. Manag.

201

154

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Mechanism of action• Patisiran is a double-stranded small interfering RNA that targets a sequence within the transthyretin (TTR) messenger RNA that is conserved across wild-type and all TTR variants to decrease hepatic production of mutant and wild-type TTR. Pharmacology • Patisiran has been consistently shown to achieve rapid onset (peak effect within ∼2 weeks), robust (∼80-90%) and sustained (>36 months) reduction of serum TTR when dosed at 0.3 mg/kg body weight every 3 weeks. • Prior treatment with TTR stabilizers did not interfere with the pharmacological activity of patisiran. Clinical efficacy • In the Phase III APOLLO study, patisiran treatment led to statistically significant improvements in polyneuropathy (modified Neuropathy Impairment Score +7) and Norfolk Quality of Life-Diabetic Neuropathy questionnaire measures compared with placebo in patients with hereditary TTR-mediated amyloidosis. • The beneficial effects of patisiran treatment on polyneuropathy and quality of life were consistent across all major subgroups (age, gender, race, region, genotype, neuropathy impairment score at the start of treatment, familial amyloid polyneuropathy stage, previous TTR stabilizer use and cardiac involvement) in the APOLLO study. • Patisiran improved multiple clinical end points compared with placebo in the APOLLO study, including motor strength, disability, gait speed, nutritional status and autonomic symptoms. • Patisiran treatment was associated with improvement in cardiac structure and function in a predefined cardiac subpopulation in the APOLLO study, with significant reductions in left ventricular wall thickness, left ventricular longitudinal strain and N-terminal prohormone of brain-type natriuretic peptide levels at 18 months. Safety • Patisiran was generally well tolerated and showed a consistent safety profile in patients with hereditary TTR-mediated amyloidosis across all phases of clinical development, in which 218 patients were exposed for periods of up to 4 years.Hereditary transthyretin-mediated amyloidosis is a rapidly progressive, heterogeneous disease caused by the accumulation of misfolded transthyretin protein as amyloid fibrils at multiple sites, and is characterized by peripheral sensorimotor neuropathy, autonomic neuropathy and/or cardiomyopathy. Current treatment options have limited efficacy and often do not prevent disease progression. Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein. In Phase II, III and long-term extension studies in patients with hereditary transthyretin-mediated amyloidosis, patisiran has consistently slowed or improved progression of neuropathy. In addition, the Phase III trial demonstrated significant improvements in quality of life measures and indicators of cardiomyopathy. Here, we highlight efficacy and safety data from the patisiran clinical trial programme.

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Section: Patisiran: Pharmacologymentioning

confidence: 99%