Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis

Benson, Merrill D.; Waddington-Cruz, Márcia; Berk, John L.; Polydefkis, Michael; Dyck, Peter James; Wang, Annabel K.; Planté‐Bordeneuve, Violaine; Barroso, Fabio; Merlini, Giampaolo; Obici, Laura; Scheinberg, Morton; Brannagan, Thomas H.; Litchy, William J.; Whelan, Carol; Drachman, Brian; Adams, David; Heitner, Stephen B.; Conceição, Isabel; Schmidt, Hartmut; Vita, Giuseppe; Campistol, Josep M.; Gamez, Josep; Gorevic, Peter D.; Gane, Edward; Shah, Amil M.; Solomon, Scott D.; Monia, Brett P.; Hughes, Steven G.; Kwoh, T. Jesse; McEvoy, Bradley W.; Jung, Shiangtung W.; Baker, Brenda F.; Ackermann, Elizabeth J.; Gertz, Morie A.; Coelho, Teresa

doi:10.1056/nejmoa1716793

Cited by 1,028 publications

(996 citation statements)

References 26 publications

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“…Patients receiving patisiran had a significant improvement in the Modified Neuropathy Impairment Score +7 (mNIS+7) (P<0.001), on the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (P<0.001), and gait speed (P<0.001). In addition, a large phase III randomized double blind placebo controlled trial of inotersen, an antisense oligonucleotide that inhibits the hepatic production of transthyretin, has recently been published 215. One hundred and seventy two patients(112 in the inotersen group and 60 in the placebo group) were given weekly subcutaneous injections for 66 weeks.…”

Section: Current Disease Specific Treatmentsmentioning

confidence: 99%

Diagnosis and management of sensory polyneuropathy

Gwathmey

Pearson

2019

BMJ

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Sensory polyneuropathies, which are caused by dysfunction of peripheral sensory nerve fibers, are a heterogeneous group of disorders that range from the common diabetic neuropathy to the rare sensory neuronopathies. The presenting symptoms, acuity, time course, severity, and subsequent morbidity vary and depend on the type of fiber that is affected and the underlying cause. Damage to small thinly myelinated and unmyelinated nerve fibers results in neuropathic pain, whereas damage to large myelinated sensory afferents results in proprioceptive deficits and ataxia. The causes of these disorders are diverse and include metabolic, toxic, infectious, inflammatory, autoimmune, and genetic conditions. Idiopathic sensory polyneuropathies are common although they should be considered a diagnosis of exclusion. The diagnostic evaluation involves electrophysiologic testing including nerve conduction studies, histopathologic analysis of nerve tissue, serum studies, and sometimes autonomic testing and cerebrospinal fluid analysis. The treatment of these diseases depends on the underlying cause and may include immunotherapy, mitigation of risk factors, symptomatic treatment, and gene therapy, such as the recently developed RNA interference and antisense oligonucleotide therapies for transthyretin familial amyloid polyneuropathy. Many of these disorders have no directed treatment, in which case management remains symptomatic and supportive. More research is needed into the underlying pathophysiology of nerve damage in these polyneuropathies to guide advances in treatment.

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Section: Current Disease Specific Treatmentsmentioning

confidence: 99%

Diagnosis and management of sensory polyneuropathy

Gwathmey

Pearson

2019

BMJ

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“…As TTR is a relatively redundant protein, therapeutic strategies have focused on supressing total TTR production from the liver in an effort to reduce the rate of amyloid deposition and disease progression. In 2018, two genetic therapies (an antisense oligonucleotide and a RNAi) both achieved their primary outcome measures in a trial of ATTRm peripheral neuropathy and have been approved by the FDA and EMA . As ATTRm has a wide range of age of onset with some mutations not being fully penetrant, one of the most pressing issues in the current management of ATTRm is both to diagnose ATTRm as early as possible and to define the optimum time to start gene silencing therapy.…”

Section: Introductionmentioning

confidence: 99%

Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Kapoor

Foiani

Heslegrave

et al. 2019

J Peripheral Nervous Sys

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Hereditary transthyretin amyloidosis (ATTRm) causes a disabling peripheral neuropathy as part of a multisystem disorder. The recent development of highly effective gene silencing therapies has highlighted the need for effective biomarkers of disease activity to guide the decision of when to start and stop treatment. In this study, we measured plasma neurofilament light chain (pNfL) concentration in 73 patients with ATTR and found that pNfL was significantly raised in ATTRm patients with peripheral neuropathy compared to healthy controls. Furthermore, pNFL correlated with disease severity as defined by established clinical outcome measures in patients for whom this information was available. These findings suggest a potential role of pNfL in monitoring disease activity and progression in ATTRm patients.

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“…Our results could also open the door to new clinical opportunities for the diagnosis of some disorders. For example, QST with the MLe is used as a primary endpoint in the assessment of sensory loss in familial amyloid polyneuropathy . Although the temperature ramps used to apply the MLe are currently relatively slow (about 4°C/s), use of a very fast cooling technique could significantly improve clinical diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Effects of thermosensory aging well demonstrated by cold stimulations with high temporal resolution

Després¹,

Lithfous²,

Pébayle

et al. 2019

Muscle and Nerve

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Introduction: The method of limits (MLi) is the most commonly used paradigm to measure the threshold of thermal stimuli. However, the threshold measured by MLi is dependent on reaction time (RT). Because RT in adults increases with age, the inclusion of RT in the MLi paradigm may result in an overestimation of thermal threshold in the older individuals. Methods: A device with a very rapid cooling rate (300°C/s) was employed to measure cool thresholds by using the method of levels (MLe), a method independent of RT, in 11 older patients and 14 younger adults. Results: Compared with the MLi, the MLe resulted in a greater than 2°C gain in threshold measurement accuracy in older patients. Discussion: The MLe confirmed that cool perception threshold is dependent on age. The use of MLe provides new opportunities for the study of mechanisms underlying age‐associated alterations in thermal perception. Muscle Nerve 60: 141–146, 2019

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Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis

Cited by 1,028 publications

References 26 publications

Diagnosis and management of sensory polyneuropathy

Diagnosis and management of sensory polyneuropathy

Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Effects of thermosensory aging well demonstrated by cold stimulations with high temporal resolution

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