| 1. |
- Adams, David, et al.
(författare)
-
Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy : 12-month results of an open-label extension study
- 2021
-
Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:1, s. 49-59
-
Tidskriftsartikel (refereegranskat)abstract
- Background Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0.3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4.0, 95 % CI -7.7 to -0.3; phase 2 OLE patisiran -4.7, -11.9 to 2.4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1.4, 95% CI -6.2 to 3.5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
|
|
| 2. |
- Benson, Merrill D., et al.
(författare)
-
Tissue biopsy for the diagnosis of amyloidosis : experience from some centres
- 2022
-
Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 29:1, s. 8-13
-
Tidskriftsartikel (refereegranskat)abstract
- A reliable diagnosis of amyloidosis is usually based on a tissue biopsy. With increasing options for specific treatments of the different amyloid diseases, an exact and valid diagnosis including determination of the biochemical fibril nature is imperative. Biopsy sites as well as amyloid typing principles vary and this paper describes methods employed at some laboratories specialised in amyloidosis in Europe, Japan and USA.
|
|
| 3. |
- Ihse, Elisabet, et al.
(författare)
-
Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis
- 2013
-
Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 20:3, s. 142-150
-
Tidskriftsartikel (refereegranskat)abstract
- The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.
|
|
| 4. |
- Obayashi, Konen, et al.
(författare)
-
Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine
- 2013
-
Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 419C, s. 127-131
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study investigated whether a relationship exists between the presence of de novo antibodies and the clinical manifestations of familial amyloidotic polyneuropathy (FAP). METHODS: Serum samples were collected from 25 Japanese and 6 Swedish FAP amyloidogenic transthyretin (ATTR) Valine30Methionine (V30M) patients, 4 asymptomatic Japanese ATTR V30M gene carriers, and 24 Japanese healthy volunteers. Study methods included enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. RESULTS: Three Japanese and 5 Swedish patients had significantly higher levels of antibodies against ATTR than did healthy volunteers and asymptomatic gene carriers (P<0.05). All 8 patients with higher antibody levels were late-onset cases. The ratio of wild-type TTR to ATTR V30M in serum from the high-antibody group was higher than that of the low-antibody group. ELISA results revealed two epitopes at positions 24-35 and 105-115 of ATTR V30M. We found a significant positive correlation between levels of the antibody at positions 24-35 and the age at FAP onset (r=0.751, P<0.05). An age-dependent increase in the occurrence of antibodies was observed in these patients with an epitope at positions 24-35. CONCLUSIONS: These findings may help explain the differences in early- and late-onset FAP and/or the progression of FAP.
|
|
| 5. |
- Obayashi, Konen, et al.
(författare)
-
Impact of serotonin transporter and catechol-O-methyl transferase genes polymorphism on gastrointestinal dysfunction in Swedish and Japanese familial amyloidotic polyneuropathy patients.
- 2008
-
Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 398:1-2, s. 10-4
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Differences in the gastrointestinal manifestations have emerged between Swedish and Japanese familial amyloidotic polyneuropathy amyloidogenic transthyretin Valine30Methionine (FAP ATTR Val30Met) patients. To elucidate the cause of the differences, we investigated the associations between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and/or catechol-O-methyl transferase (COMT) gene polymorphism and their gastrointestinal in these patients. METHODS: Twenty-six Swedish and 24 Japanese patients with gastrointestinal disturbances, in whom genetic material was available, were included in the study. The initial gastrointestinal manifestations of the disease were classified as constipation, constipation alternating with diarrhoea, continuous diarrhoea, and nausea/vomiting. 5-HTTLPR and COMT gene polymorphism were assessed by polymerase chain reaction and enzymatic digestion. RESULTS: A significantly higher LA allele frequency of 5-HTTLPR was noted in the Swedish population compared with that of the Japanese. Moreover, the LA allele frequency tended to be lower in the continuous diarrhoea group than in that of the remaining groups of both Swedish and Japanese patients. No association between COMT genotype and initial gastrointestinal symptoms was noted. CONCLUSION: A high expression of serotonin transporter induced by LA allele of 5-HTTLPR may be one of the factors implicated with the inhibition of severe diarrhoea in early stages of Swedish FAP ATTR Val30Met patients.
|
|
| 6. |
- Oshima, Toshinori, et al.
(författare)
-
Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation
- 2014
-
Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 85:7, s. 740-746
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To elucidate the long-term effects of liver transplantation (LT) on familial amyloid polyneuropathy (FAP). Methods We investigated clinicopathological and biochemical characteristics of systemic tissues in four autopsied cases of FAP patients surviving more than 10 years after LT and seven autopsied cases without LT. For analysing the truncated form of transthyretin (TTR) in amyloid, we also employed specimens from additional 18 FAP patients. Results Several tissue sites such as the heart, tongue and spinal cord had moderate-to-severe amyloid deposits but other tissues showed no or mild amyloid deposition. Those findings seemed similar to those observed in senile systemic amyloidosis (SSA), a sporadic amyloidosis caused by wild-type (WT) TTR. Also, amyloid deposits in systemic tissue sites except for the spinal cord in patients after LT derived mostly from WT TTR secreted from the normal liver grafts. In addition, in non-transplantation patients, proportions of WT TTR seemed to be relatively high in those tissue sites in which patients after LT had severe amyloid deposition, which suggests that WT TTR tends to form amyloid in those tissue sites. Finally, although the truncation of TTR in amyloid deposits did not depend on undergoing LT, we elucidated the truncation of TTR occurred predominantly in patients from non-endemic areas of Japan, where FAP amyloidogenic TTR V30M patients are late onset and low penetrance, compared with patients from an endemic area of Japan. Conclusions FAP may shift to systemic WT TTR amyloid formation after LT, which seems to be similar to the process in SSA. The truncation of TTR in amyloid deposits may depend on some genetic or environmental factors other than undergoing LT.
|
|
| 7. |
- Ueda, Mitsuharu, et al.
(författare)
-
SELDI-TOF mass spectrometry evaluation of variant transthyretins for diagnosis and pathogenesis of familial amyloidotic polyneuropathy.
- 2009
-
Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 55:6, s. 1223-7
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mass spectrometric analyses are valuable for detection of transthyretin (TTR) variants, which cause familial amyloidotic polyneuropathy (FAP). However, those methods require an immunoprecipitation step with an anti-TTR antibody and are not suitable for quantitative detection. We investigated the usefulness of SELDI-TOF mass spectrometry (MS) without an immunoprecipitation step. METHODS: We used ProteinChips with chromatographic capture formats to detect TTRs. We attempted to correlate the intensity of mixed samples of amyloidogenic TTR (ATTR) V30M to wild-type (WT) TTR. We analyzed the proportion of ATTR V30M in amyloid-laden cardiac tissues from FAP patients, and also evaluated samples from FAP patients with 16 other TTR mutations. RESULTS: Detection of ATTR required only 3 h of SELDI-TOF MS analysis. We determined that SELDI-TOF MS was suitable for quantitative detection of ATTR V30M and demonstrated that the proportion of ATTR V30M to WT TTR was 46.6% in amyloid-laden cardiac tissue from an FAP patient who died 10 years after liver transplantation. With this method, we identified 12 of 17 TTR variants. Small mass shifts and low concentrations of variants prevented ATTR detection. By changing the analytical conditions, we achieved detection of low concentrations of ATTR Y114C in serum. CONCLUSIONS: SELDI-TOF MS is a reliable tool for quantitative evaluation of TTR variants, in both tissue amyloid deposits and body fluids. This method is useful for the diagnosis and investigation of the pathogenesis of FAP.
|
|
| 8. |
- Yanagisawa, Akihiro, et al.
(författare)
-
Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis.
- 2015
-
Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 28:2, s. 201-207
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloidosis is a protein conformational disorder with the distinctive feature of extracellular accumulation of amyloid fibrils that come from different proteins. In the ligamentum flavum of the lumbar spine, amyloid deposits were frequently found in elderly patients with lumbar spinal canal stenosis and were at least partially formed by wild-type transthyretin. However, how amyloid deposits in the ligamentum flavum affect lumbar spinal canal stenosis has remained unclear. In this study, we analyzed clinical, pathologic, and radiologic findings of patients with lumbar spinal canal stenosis who had amyloid deposits in the ligamentum flavum. We studied 95 ligamentum flavum specimens obtained from 56 patients with lumbar spinal canal stenosis and 21 ligamentum flavum specimens obtained from 19 patients with lumbar disk herniation. We evaluated histopathologic findings and clinicoradiologic manifestations, such as thickness of the ligamentum flavum and lumbar spinal segmental instability. We found that all 95 ligamentum flavum specimens resected from patients with lumbar spinal canal stenosis had amyloid deposits, which we classified into two types, transthyretin-positive and transthyretin-negative, and that transthyretin amyloid formation in the ligamentum flavum of patients with lumbar spinal canal stenosis was an age-associated phenomenon. The amount of amyloid in the ligamentum flavum was related to clinical manifestations of lumbar spinal canal stenosis, such as thickness of the ligamentum flavum and lumbar spinal segmental instability, in the patients with lumbar spinal canal stenosis with transthyretin-positive amyloid deposits. To our knowledge, this report is the first to show clinicopathologic correlations in transthyretin amyloid deposits of the ligamentum flavum. In conclusion, transthyretin amyloid deposits in the ligamentum flavum may be related to the pathogenesis of lumbar spinal canal stenosis in elderly patients.Modern Pathology advance online publication, 5 September 2014; doi:10.1038/modpathol.2014.102.
|
|
| 9. |
- Yanagisawa, Akihiro, et al.
(författare)
-
Knee osteoarthritis associated with different kinds of amyloid deposits and the impact of aging on type of amyloid
- 2016
-
Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 23:1, s. 26-32
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloidosis is a protein conformational disorder in which amyloid fibrils accumulate in the extracellular space and induce organ dysfunction. Recently, two different amyloidogenic proteins, transthyretin (TTR) and apolipoprotein A-I (Apo A-I), were identified in amyloid deposits in knee joints in patients with knee osteoarthritis (OA). However, clinicopathological differences related to those two kinds of amyloid deposits in the knee joint remain to be clarified. Here, we investigated the clinicopathological features related to these knee amyloid deposits associated with knee OA and the biochemical characteristics of the amyloid deposits. We found that all of our patients with knee OA had amyloid deposits in the knee joints, especially in the meniscus, and those deposits were primarily derived from TTR and/or Apo A-I. Some patients with knee OA, however, had unclassified amyloid deposits. One of our interesting observations concerned the different effects of aging on each type of amyloid formed. The frequency of formation of ATTR deposits clearly increased with age, but that of AApo A-I deposits decreased. Furthermore, we found that similar to 16% of patients with knee OA developed ATTR/AApo A-I double deposits in the meniscus. Amyloid deposition may therefore be a common histopathological feature associated with knee OA. Also, aging may induce ATTR formation in the knee joint in elderly patients with knee OA, whereas AApo A-I formation may be inversely correlated with age.
|
|
