Céline Labeyrie

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies

ABSTRACT Introduction: Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU. Areas covered: We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov. Expert opinion: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.

Assessing mNIS+7Ionis and International Neurologists' Proficiency in an FAP Trial.

Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial

Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.

Transcriptome Analysis of Peripheral Blood in Chronic Inflammatory Demyelinating Polyradiculoneuropathy Patients Identifies TNFR1 and TLR Pathways in the IVIg Response

AbstractWe have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83–6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC] > 1.2, P < 0.001, false discovery rate [FDR] <0.05). Among these 52 genes, 7 were related to immunity, 3 were related to the tumor necrosis factor (TNF)-&agr; receptor 1 (TNFR1) pathway (inhibitor of caspase-activated DNase (ICAD): FC = 1.8, P = 1.7E-7, FDR = 0.004; p21 protein-activated kinase 2 [PAK2]: FC = 1.66, P = 2.6E-5, FDR = 0.03; TNF-&agr;-induced protein 8-like protein 1 [TNFAIP8L1]: P = 1.00E-05, FDR = 0.026), and 2 were related to Toll-like receptors (TLRs), especially TLRs 7 and 9, and were implicated in autoimmunity. These genes were UNC93B1 (FC = 1.6, P = 2E-5, FDR = 0.03), which transports TLRs 7 and 9 to the endolysosomes, and RNF216 (FC = 1.5, P = 1E-05, FDR = 0.03), which promotes TLR 9 degradation. Pathway analysis showed that the TNFR1 pathway was significantly lessened by IVIg (enrichment score = 24, Fischer exact test = 0.003). TNF-&agr; gene expression was higher in responder patients than in nonresponders; however, it decreased after IVIg in responders (P = 0.04), but remained stable in nonresponders. Our data suggest the actions of IVIg on the TNFR1 pathway and an original mechanism involving innate immunity through TLRs in CIDP pathophysiology and the response to IVIg. We conclude that responder patients have stronger inflammatory activity that is lessened by IVIg.

Familial amyloid polyneuropathy: elaboration of a therapeutic patient education programme, “EdAmyl”

Abstract Background: Transthyretin-related amyloidosis (ATTR) is an autosomal dominant disease affecting the peripheral and autonomic nervous system, heart, eyes and kidneys. It is the most disabling hereditary polyneuropathy in adults. The French National Reference centre for this disease was accredited in 2005 with 10 lines of action. One of them is to inform and educate patients about their disease to improve their care and reduce morbidities. We thus decided to elaborate a therapeutic patient education (TPE) programme, starting with patients’ needs assessment. Methods: A qualitative research study was conducted with one-to-one semi-structured interviews of selected individuals. Recorded interviews were analysed to identify the skills that patients need to acquire. A TPE programme was elaborated on the basis of these findings. Results: Seven patients, one asymptomatic carrier and two healthy spouses were interviewed. Analysis of the interviews showed that interviewees had a good knowledge of the disease and its symptoms but they had difficulties explaining the disease mechanism and did not have an adequate knowledge of the available treatment options, although they knew that liver transplant might halt progression of the disease. ATTR amyloidosis appeared to have a major negative impact on the patient’s physical and mental well-being. Patients feared loss of autonomy and having to require assistance from their relatives and spouses. All interviewees were keen to participate in a TPE programme. Based on this needs assessment, we identified seven skills that patients need to acquire and several pedagogical goals to be achieved during the education programme. An interdisciplinary team then elaborated a complete TPE programme. Conclusion: Elaboration of a TPE programme for ATTR amyloidosis required to obtain useful information from the patients themselves, and their relatives, concerning their perception of their disease. This needs’ assessment constituted the basis for designing the first TPE programme, to our knowledge, for ATTR amyloidosis. After translation, this programme could be applied in other EU countries and worldwide for this rare disease.

Refractory T-Cell Anergy and Rapidly Fatal Progressive Multifocal Leukoencephalopathy After Prolonged CTLA4 Therapy

Abstract Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches. Progressive multifocal leukoencephalopathy secondary to biotherapy-induced T-cell anergy may thus represent a subset of PML with major resistance to anti-JCV immune recovery.

Management of stage 1 TTR FAP: French experience

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a worldwide autosomal dominant disease due to point mutation of TTR gene. The main endemic area is Portugal, associated with V30M variant and an early onset (EO) (mean age 30 yo). Phenotype is a progressive length dependent small fiber polyneuropathy with autonomic dysfunction and cardiac conduction disorders; the median survival is 12 years. France is a prototypic non endemic country, characterized by sporadic cases in 50%, a late onset (LO>50 yo) in 75%, a genetic heterogeneity (41 variants ; V30M in 55%). Liver transplantation (LT) is the gold standard treatment allows to stop progression of the neuropathy in EO V30M patients and to prolonge significantly the survival. Tafamidis, a TTR kinetic stabilizer, received marketing authorization in Europe for stage 1 FAP (walking unaided) allowing to slow progression of the neuropathy. Aims of the study was to assess the place of tafamidis in the management of TTR-FAP.

Somatostatin analogues for refractory diarrhoea in familial amyloid polyneuropathy

Introduction Familial amyloid polyneuropathy (FAP) is a genetic disease leading to the production of a variant transthyretin (TTR) or a beta variant β2-microglobulin. FAP may be associated with refractory diarrhoea. In this study, we assessed the efficacy and tolerance of somatostatin analogues in refractory diarrhoea associated with FAP. Methods FAP patients from the French national referral center who received somatostatin analogues for a refractory diarrhoea were retrospectively studied. We assessed remission of diarrhoea, as defined by a stool consistence of five or less on the Bristol stool scale, assessed after three to six months of follow-up. Stool frequency and continence before and after three to six months of treatment were also compared by the means of Wilcoxon and McNemars exact tests, respectively. Results Fourteen patients treated with somatostatin analogues were evaluable. After three to six months of follow-up, 9/14 patients (64% 95%CI = [35%; 87%]) had remission of diarrhoea. This was significantly higher than a theoretical remission rate of 20% (p = 0.0004). There was a significant decrease of daily bowel movement from 6 to 2.5 per day (p = 0.002). Twelve/14 (85%) patients had incontinence at baseline vs 8/14 (57%) after three to six months of follow-up (p = 0.134). Three out of 14 patients (21%) had a severe adverse event; two patients had hypoglycaemia, and one had endocarditis due to an injection-site bacterial infection. Conclusion This study suggests that somatostatin analogues may benefit to patients with FAP and refractory diarrhoea. Approximately 20% of patients had severe adverse events, including hypoglycaemia.

Upper Limb Onset of Hereditary Transthyretin Amyloidosis is common in Non-Endemic Areas

The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset.

Cerebral infarction following subcutaneous immunoglobulin therapy for chronic inflammatory demyelinating polyradiculoneuropathy.

Steve Vucic, FRACP, PhD Karl Ng, FRACP, PhD Department of Neurology and Neurophysiology, Royal North Shore Hospital, St Leonards, New South Wales, Australia Brisbane Waters Private Hospital, Woy Woy, New South Wales, Australia Neurogenetics Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, QE II Medical Centre, Nedlands, Western Australia, Australia Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia Department of Neurophysiology, Westmead Hospital, Westmead, New South Wales, Australia