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      Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

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          Most cited references 28

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          Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study.

          We designed a phase II, open-label study to evaluate the efficacy, tolerability, safety, and pharmacokinetics of orally doxycycline (100 mg BID) and tauroursodeoxycholic acid (TUDCA) (250 mg three times/day) administered continuously for 12 months. Primary endpoint is response rate defined as nonprogression of the neuropathy and of the cardiomyopathy. Since July 2010, we enrolled 20 patients. Seventeen patients have hereditary ATTR, two patients have senile systemic amyloidosis, and one is a domino recipient. Seven patients completed 12-month treatment, 10 completed 6-month treatment, two discontinued because of poor tolerability, and one is lost at follow-up. No serious adverse events were registered. No clinical progression of cardiac involvement was observed. The neuropathy (Neuropathy Impairment Score in the Lower Limbs [NIS-LL] and Kumamoto score) remained substantially stable over 1 year. These preliminary data indicate that the combination of Doxy-TUDCA stabilizes the disease for at least 1 year in the majority of patients with an acceptable toxicity profile.
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            Synergy of combined Doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models

            Familial Amyloidotic Polyneuropathy (FAP) is a disorder characterized by the extracellular deposition of fibrillar Transthyretin (TTR) amyloid, with a special involvement of the peripheral nerve. We had previously shown that doxycycline administered for 3 months at 40 mg/Kg/ml in the drinking water, was capable of removing TTR amyloid deposits present in stomachs of old TTR-V30M transgenic mice; the removal was accompanied by a decrease in extracellular matrix remodeling proteins that accompany fibrillar deposition, but not of non-fibrillar TTR deposition and/or markers associated with pre-fibrillar deposits. On the other hand, Tauroursodeoxycholic acid (TUDCA), a biliary acid, administrated to the same mouse model was shown to be effective at lowering deposited non-fibrillar TTR, as well as the levels of markers associated with pre-fibrillar TTR, but only at young ages. In the present work we evaluated different doxycycline administration schemes, including different periods of treatment, different dosages and different FAP TTR V30M animal models. Evaluation included CR staining, immunohistochemistry for TTR, metalloproteinase 9 (MMP-9) and serum amyloid P component (SAP). We determined that a minimum period of 15 days of treatment with a 8 mg/Kg/day dosage resulted in fibril removal. The possibility of intermittent treatments was also assessed and a maximum period of 15 days of suspension was determined to maintain tissues amyloid-free. Combined cycled doxycycline and TUDCA administration to mice with amyloid deposition, using two different concentrations of both drugs, was more effective than either individual doxycycline or TUDCA, in significantly lowering TTR deposition and associated tissue markers. The observed synergistic effect of doxycycline/TUDCA in the range of human tolerable quantities, in the transgenic TTR mice models prompts their application in FAP, particularly in the early stages of disease.
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              AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin.

              The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.
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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                Expert Review of Clinical Pharmacology
                Expert Review of Clinical Pharmacology
                Informa UK Limited
                1751-2433
                1751-2441
                August 03 2019
                July 03 2019
                August 03 2019
                : 12
                : 8
                : 701-711
                Affiliations
                [1 ] Department of Hematology, Transplant Center, Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, USA
                [2 ] Department of Rheumatology, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
                [3 ] Neuromuscular Diseases Unit, Federal University of Rio de Janeiro, University Hospital, Rio de Janeiro, Brazil
                [4 ] Hypertrophic Cardiomyopathy Clinic, Knight Cardiovascular Institute, Portland, OR, USA
                [5 ] Department of Neurology, ALS and Neuromuscular Center, Oregon Health and Science University, Portland, OR, USA
                [6 ] Department of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA, USA
                [7 ] Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
                [8 ] Consultant Cardiologist, University College London-National Amyloidosis Centre, London, UK
                [9 ] Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
                Article
                10.1080/17512433.2019.1635008
                © 2019

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