Pierre Lozeron

Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis

BACKGROUND Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).

Long-term Course of Demyelinating Neuropathies Occurring During Tumor Necrosis Factor-α–Blocker Therapy

OBJECTIVE To report the long-term follow-up (mean, 41 months; range, 25-55 months) of patients with demyelinating neuropathy occurring after tumor necrosis factor-alpha (TNF-alpha) blocker treatment (infliximab [Remicade], etanercept [Enbrel], and adalimumab [Humira]). BACKGROUND Demyelinating neuropathy is a rare adverse event of anti-TNF-alpha therapy. Improvement usually occurs after drug interruption and/or in association with usual treatments for demyelinating neuropathies. DESIGN Case report with review of the previously published cases. SETTING University hospital in Le Kremlin-Bicêtre, France: tertiary reference center for peripheral neuropathies and national reference center for rare peripheral neuropathies (www.nnerf.fr). PATIENTS Five patients (4 men, mean age, 47 years) who developed a demyelinating neuropathy during anti-TNF-alpha therapy. MAIN OUTCOME MEASURE Development of neuropathy. RESULTS Neuropathy developed early (8 months) after treatment introduction. Various clinical patterns were encountered, including pure sensory neuropathy. Immunomodulating treatments were always required for neuropathy control. Chronic demyelinating neuropathy developed either after change of anti-TNF-alpha drug or spontaneously after treatment discontinuation without any drug reintroduction. CONCLUSION Influence of anti-TNF-alpha treatment continuation on the long-term course of neuropathy is variable, suggesting that anti-TNF-alpha treatment withdrawal is not always necessary for neuropathy control.

Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin.

We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating β(2)-microglobulin values. The Asp76Asn β(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β(2)-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.

Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients

We have reviewed the clinical and pathological data of a series of 100 consecutive diabetic patients with symptomatic neuropathy in order to learn more about the causes of neuropathy in this population and on the signs and symptoms that could suggest another cause than diabetes in this setting. After diagnostic procedures, patients were assigned one (at most two) of a final total of 18 different causes of neuropathy. Diabetes accounted for 74 % of the neuropathies in the whole group of patients and for 79 % of those with a fiber length dependent pattern of neuropathy. One third of patients had a neuropathy unrelated to diabetes. As a group, 71 % of the patients presented either a length dependent diabetic polyneuropathy (LDDP) or a proximal diabetic neuropathy (PDN). The LDDP group was biased towards more severely affected patients owing to our specialization. Conversely, most patients with proximal diabetic neuropathy had usual features. Chronic inflammatory demyelinating neuropathy that was diagnosed in 9 % of the patients was the most common non-diabetic cause of neuropathy in this population. We conclude that a short interval between diagnosis of diabetes and the onset of the neuropathy, early motor deficit, markedly asymmetrical deficit and generalized areflexia, which are all uncommon in the LDDP, argue in favor of a non diabetic origin of the neuropathy and should lead to further investigation.

Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy

The aim of this study was to assess the effect of Tafamidis, which slows the progression of early stages of Met30 transthyretin (TTR) familial amyloidosis polyneuropathy (FAP) in more advanced cases.

Regional difference and similarity of familial amyloidosis with polyneuropathy in France.

Familial amyloidosis with polyneuropathy (FAP) in France have a large genetic heterogeneity with 29 transthyretin (TTR) gene mutations; Met30-TTR is the most frequent one (62%); followed by Tyr77-TTR (11.8%) and Phe77-TTR (6.2%). Analysis of 60 FAP patients diagnosed during the period 2008–2010 showed amyloid polyneuropathy was initially suspected in only 38% patients. TTR Met30 of Portuguese ancestry is different from TTR Met30 of non Portuguese ancestry and other non Met30 variants in geographical distribution and clinical presentation. There are three additional phenotypes of the neuropathy including multifocal upper limbs neuropathy, ataxic polyneuropathy and motor neuropathy. Patients with Tyr77-TTR are characterized by a late onset (>50 years), frequent ataxic phenotype; they are localized mainly in north of France. The more frequent use of the TTR genetic tests and the French network for FAP will help in the future to improve diagnosis and care.

Symptomatic and proven de novo amyloid polyneuropathy in familial amyloid polyneuropathy domino liver recipients.

D. Adams, C. Lacroix, T. Antonini, P. Lozeron, C. Denier, A. M. Kreib, S. Epelbaum, F. Blandin, V. Karam, D. Azoulay, R. Adam, D. Castaing, & D. Samuel 1,3,5,6,7 French Reference Center for FAP, Université Paris Sud, Paris, France, Department of Neurology, CHU Bicetre, Paris, France, Univ Paris Sud 11, Paris, France, INSERM U788, Universite Paris Sud, Paris, France, APHP, Hôpitaux de Paris, Paris, France, CHU Paul Brousse, Centre HepatoBiliaire, Villejuif, France, and INSERM U785 Villejuif, Paris

A brief compound test for assessment of autonomic and sensory-motor dysfunction in familial amyloid polyneuropathy

BackgroundFamilial amyloid polyneuropathies (FAP) patients manifest progressive sensory-motor length dependent polyneuropathy and severe autonomic dysfunction. In this setting the autonomic manifestations include mainly postural hypotension, nausea and vomiting, diarrhea and constipation, sphincter distur- bances and erectile dysfunction. Reproducible quantitative evaluation of signs and symptoms are necessary for the assessment of treatment efficacy.ObjectiveTo determine the reliability of a new compound test cumulating evaluation of autonomic and sensorymotor dysfunction in FAP.MethodsCompound Autonomic Dysfunction Test (CADT) is a new questionnaire to evaluate the main symptoms of autonomic dysfunction observed in FAP. A separate functional questionnaire assesses the disability due to the sensorymotor deficit (Modified Norris Test; MNT). The compound test takes approximately 10 minutes to perform. In this prospective study, we enrolled consecutively 60 FAP patients to test interexaminer reliability, i.e., both questionnaires rated independently by 2 examiners. We also evaluate the reliability of testing patients face to face and by phone call, by the same examiner.ResultsInterexaminer reliabilities tested were high (ICC=0.92 for the CADT, p < 0.001; and ICC = 0.99 for the MNT, p < 0.001). In addition, testing by phone as compared to testing during the initial medical visit by the same investigator gave similar results (ICC = 0.91 for the CADT, p < 0.001; and ICC = 0.98 for the MNT, p < 0.001).ConclusionIn FAP, the CADT and the MNT have good reliability inter-investigators as well as between face to face and by phone call, by the same examiner. This newly designed compound test is a simple and reproducible scale which is adapted to evaluate the main neuropathic manifestations and will be useful for assessment of future treatments in this condition.

Monoclonal gammopathy and neuropathy.

Purpose of reviewTo provide clinically useful guidelines in the management of neuropathy associated with monoclonal gammopathy from a review of the most recent literature and our own experience. Recent findingsRecent data on neuropathy associated with monoclonal gammopathy come from better descriptions of subgroups, and from new treatment compounds that have shown encouraging results in different entities. SummaryNeuropathies associated with monoclonal gammopathy are relatively rare and most often the neuropathy reveals the monoclonal gammopathy. These conditions require combined neurological and haematological assessments. Their clinical presentations are highly heterogeneous but most have an electrophysiological demyelinating pattern. The main described subgroup is IgM anti-(myelin-associated glycoprotein) neuropathy, which presents as a relatively benign, slowly progressive sensory neuropathy. Nerve biopsy should be considered in patients with progressive and disabling axonal neuropathy. Neuropathies associated with monoclonal gammopathy have various neurological and general outcomes, including life-threatening entities such as light-chain amyloid neuropathy and POEMS syndrome. Treatment choice is wide and depends both on the underlying haematological disorder and severity of the neuropathy. Intravenous immunoglobulin should be assessed in demyelinating monoclonal gammopathy of undetermined significance neuropathy. Malignant haematological disorders should be treated per se. The possibility of a malignant evolution of monoclonal gammopathy of undetermined significance warrants regular haematological monitoring.

An amyotrophic lateral sclerosis-like syndrome revealing an amyloid polyneuropathy associated with a novel transthyretin mutation

Abstract Objective: Familial amyloid polyneuropathy (FAP) is typically a predominantly sensory and autonomic neuropathy with progressive and late motor involvement leading to death within 10 years. Recently, prognosis was transformed with liver transplantation. Methods: We report an atypical sporadic pure motor and bulbar neuropathy initially mistaken for amyotrophic lateral sclerosis (ALS) in a 50-year-old Malian man. Results: The diagnostic procedure of this clinical purely motor and bulbar neuropathy disclosed amyloid deposits on nerve biopsy which led to the identification of a new Val93Met mutation of transthyretin. This case was also remarkable by its slow progression. Conclusions: This report confirms the motor phenotype of TTR-FAP. That should be considered in the differential diagnosis of motor neuron diseases in order to start accurate therapy.