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Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid plexus and retinal pigment epithelium. Detailed clinical characterisation, identification of clinical red flags for misdiagnosis, and use of biomarkers enable early diagnosis and treatment. In addition to liver transplantation and TTR stabilisers, three other disease-modifying therapies have regulatory approval: one antisense oligonucleotide (inotersen) and two small interfering RNAs (siRNAs; patisiran and vutrisiran). The siRNAs have been shown to stop progression of neuropathy and improve patients’ quality of life. As none of the disease-modifying therapies can cross the blood–brain barrier, TTR deposition in the CNS, which can cause stroke and cognitive impairment, remains an important unaddressed issue. CRISPR-Cas9-based one-time TTR editing therapy is being investigated in a phase 1 clinical study. Identification of the earliest stages of pathogenesis in TTR variant carriers is a major challenge that needs addressing for optimal management.

Background Hereditary transthyretin-mediated amyloidosis, also known as ATTRv amyloidosis (v for variant), is a rare, autosomal dominant, fatal disease, in which systemic amyloid progressively impairs multiple organs, leading to disability and death. The recent approval of disease-modifying therapies offers the hope of stabilization or eventual reversal of disease progression, and yet highlights a lack of disease-management guidance. A multidisciplinary panel of expert clinicians from France and the US came to consensus on monitoring the disease and identifying progression through a clinical opinion questionnaire, a roundtable meeting, and multiple rounds of feedback. Monitoring disease and progression A multidisciplinary team should monitor ATTRv amyloidosis disease course by assessing potential target organs at baseline and during follow-up for signs and symptoms of somatic and autonomic neuropathy, cardiac dysfunction and restrictive cardiomyopathy, and other manifestations. Variability in penetrance, symptoms, and course of ATTRv amyloidosis requires that all patients, regardless of variant status, undergo regular and standardized assessment in all these categories. Progression in ATTRv amyloidosis may be indicated by: worsening of several existing quantifiable symptoms or signs; the appearance of a new symptom; or the worsening of a single symptom that results in a meaningful functional impairment. Conclusions We suggest that a multisystem approach to monitoring the signs and symptoms of ATTRv amyloidosis best captures the course of the disease. We hope this work will help form the basis of further, consensus-based guidance for the treatment of ATTRv amyloidosis.

BackgroundHereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years.MethodsPatients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004.ResultsIn the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen–inotersen) and 39 switched from placebo to inotersen (placebo–inotersen). The placebo–inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen–inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo–inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study.ConclusionInotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Background Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis . In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup. Results Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran’s impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months. Conclusions Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis. Trial registration The study was registered at ClinicalTrials.gov (identifier: NCT01961921 ) on October 14, 2013.

Ethoxyquin (EQ), a quinolone-based antioxidant, has demonstrated neuroprotective properties against several neurotoxic drugs in a phenotypic screening and is shown to protect axons in animal models of chemotherapy-induced peripheral neuropathy. We assessed the effects of EQ on peripheral nerve function in the db/db mouse model of type II diabetes. After a 7 week treatment period, 12-week-old db/db-vehicle, db/+ -vehicle and db/db-EQ treated animals were evaluated by nerve conduction, paw withdrawal against a hotplate, and fiber density in hindlimb footpads. We found that the EQ group had shorter paw withdrawal latency compared to vehicle db/db group. The EQ group scored higher in nerve conduction studies, compared to vehicle-treated db/db group. Morphology studies yielded similar results. To investigate the potential role of mitochondrial DNA (mtDNA) deletions in the observed effects of EQ, we measured total mtDNA deletion burden in the distal sciatic nerve. We observed an increase in total mtDNA deletion burden in vehicle-treated db/db mice compared to db/+ mice that was partially prevented in db/db-EQ treated animals. These results suggest that EQ treatment may exert a neuroprotective effect in diabetic neuropathy. The prevention of diabetes-induced mtDNA deletions may be a potential mechanism of the neuroprotective effects of EQ in diabetic neuropathy.

Objective To assess the effect of diabetes type on the long‐term rate and extent of epidermal nerve regeneration. Methods Subjects with well controlled type 1 diabetes mellitus (n = 11) or type 2 diabetes mellitus (n = 36), with normal nerve conduction studies and baseline intraepidermal nerve fiber density (IENFD), and healthy controls (n = 10) underwent chemical axotomy of the intraepidermal nerves at the thigh using topical capsaicin. Skin biopsies were performed at 30, 90, 150, and 180 days post‐axotomy. Results After 180 days, IENFD in diabetic subjects remained significantly below baseline levels, while healthy controls returned to normal. At each time point, regeneration rates were significantly slower among diabetic subjects, although type 1 subjects regenerated significantly faster and achieved higher percentages of baseline IENFD compared with type 2. Interpretation Among diabetic patients, nerve injury recovery is likely to take significantly longer than in healthy individuals, and remains incomplete, particularly among type 2 patients. This may partially explain the progression of neuropathy among diabetic patients: damage accumulates because nerve recovery is slowed and incomplete. Furthermore, these findings support caution when recommending certain procedures, such as carpal tunnel repair, to patients with progressed diabetic disease.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9‐month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50‐mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double‐blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4‐week loading dose of 200 mg QD or placebo for 9 months (placebo‐controlled phase); they then entered the active‐therapy extension and received ritlecitinib 50 mg QD (with a 4‐week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I–V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans. Results of this placebo‐controlled study, which assessed the neurological and neuroaudiological effects of ritlecitinib in adults with alopecia areata, provide evidence that the brainstem auditory evoked potential (BAEP) changes and axonal swelling finding in standard chronic toxicology studies in dogs are not clinically relevant in humans.

Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.

Background Peripheral neuropathy (PN) continues to be a major complication of human immunodeficiency virus (HIV) infection despite successful anti-retroviral therapy. Human HIV-PN can be recapitulated in a CD8-depleted, simian immunodeficiency virus (SIV)-infected rhesus macaque animal model, characterized by a loss of intraepidermal nerve fiber density (IENFD) and damage to the dorsal root ganglia (DRG). Increased monocyte traffic to the DRG has previously been associated with severe DRG pathology, as well as a loss in IENFD. Here, we sought to characterize the molecular signals associated with monocyte activation and trafficking to the DRGs. Methods Eleven SIV-infected CD8-depleted rhesus macaques were compared to four uninfected control animals. sCD14, sCD163, sCD137, regulated on activation normal T cell expressed and secreted (RANTES), and monocyte chemoattractant protein 1 (MCP-1) were measured in plasma and the latter three proteins were also quantified in DRG tissue lysates. All SIV-infected animals received serial skin biopsies to measure IENFD loss as well as BrdU inoculations to measure monocyte turnover during the course of infection. The number of BrdU+ and CD14+ CD16+ peripheral blood monocytes was determined by flow cytometry. The number of MAC387+, CCR2+, CCR5+, and CD137+ cells in DRG tissue was quantified by immunohistochemistry. Results sCD14, sCD163, MCP-1, and sCD137 increased significantly in plasma from pre-infection to necropsy. Plasma sCD163 and RANTES inversely correlated with IENFD. Additionally, sCD137 in DRG tissue lysate was elevated with severe DRG pathology and associated with the recruitment of MAC387+ cells to DRG. Elevated numbers of CCR5+ and CCR2+ satellite cells in the DRG were found, suggesting a chemotactic role of their ligands, RANTES, and MCP-1 in recruiting monocytes to the tissue. Conclusions We characterized the role of systemic (plasma) and tissue-specific (DRG) monocyte activation and associated cytokines in the pathogenesis of SIV-PN. We identified sCD163 and RANTES as potential biomarkers for HIV-PN, as these were associated with a loss of IENFD. Additionally, we identified CD137 signaling to play a role in MAC387+ cell traffic to DRG and possibly contribute to severe pathology. These studies highlight the role of monocyte activation and traffic in the pathogenesis of SIV-PN, while identifying specific signaling proteins for future pharmacological blockade.

This phase 3 trial tested inotersen, a modified oligonucleotide that targets TTR messenger RNA, in the treatment of hereditary transthyretin amyloidosis, a disease in which misfolded transthyretin proteins are deposited in peripheral nerves and other tissues.