Small Transthyretin (TTR) Ligands as Possible Therapeutic Agents in TTR Amyloidoses

Almeida, M. R.; Gales, L.; Damas, A. M.; Cardoso, I.; Saraiva, M. J.
October 2005
Current Drug Targets - CNS & Neurological Disorders;Oct2005, Vol. 4 Issue 5, p587
Academic Journal
In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or amyloid deposition in the eye. More than eighty TTR variants are known, most of them being pathogenic. The mechanism of TTR fibril formation is still not completely elucidated. However it is widely accepted that the amino acid substitutions in the TTR variants contribute to a destabilizing effect on the TTR tetramer molecule, which in particular conditions dissociate into non native monomeric intermediates that aggregate and polymerize in amyloid fibrils that further elongate. Since this is a multi-step process there is the possibility to impair TTR amyloid fibril formation at different stages of the process namely by tetramer stabilization, inhibition of fibril formation or fibril disruption. Till now the only efficient therapy available is liver transplant when performed in an early phase of the onset of the disease symptoms. Since this is a very invasive therapy alternatives are desirable. In that sense, several compounds have been proposed to impair amyloid formation or disruption. Based on the proposed mechanism for TTR amyloid fibril formation we discuss the action of some of the proposed TTR stabilizers such as derivatives of some NSAIDs (diflunisal, diclofenac, flufenamic acid, and derivatives) and the action of amyloid disrupters such as 4'-iodo-4'-deoxydoxorubicin (I-DOX) and tetracyclines. Among all these compounds, TTR stabilizers seem to be the most interesting since they would impair very early the process of amyloid formation and could also have a prophylactic effect.


Related Articles

  • Skin Involvement in Generalized Amyloidosis. Rubinow, Alan; Cohen, Alan S. // Annals of Internal Medicine;Jun78, Vol. 88 Issue 6, p781 

    Provides information on a study which examined clinically involved and uninvolved skin in 50 patients with primary and secondary amyloidosis. Description of primary and multiple myeloma-associated amyloidosis; Extent of amyloid involvement in skin biopsies in primary and multiple...

  • Imaging cardiac amyloidosis: a pilot study using F-florbetapir positron emission tomography. Dorbala, Sharmila; Vangala, Divya; Semer, James; Strader, Christopher; Bruyere, John; Carli, Marcelo; Moore, Stephen; Falk, Rodney // European Journal of Nuclear Medicine & Molecular Imaging;Sep2014, Vol. 41 Issue 9, p1652 

    Purpose: Cardiac amyloidosis, a restrictive heart disease with high mortality and morbidity, is underdiagnosed due to limited targeted diagnostic imaging. The primary aim of this study was to evaluate the utility of F-florbetapir for imaging cardiac amyloidosis. Methods: We performed a pilot...

  • Typing of Amyloidosis in Renal Biopsies: Diagnostic Pitfalls. Satoskar, Anjali A.; Burdge, Kelly; Cowden, Daniel J.; Nadasdy, Gyongyi M.; Hebert, Lee A.; Nadasdy, Tibor // Archives of Pathology & Laboratory Medicine;Jun2007, Vol. 131 Issue 6, p917 

    Context.—Amyloidosis represents a group of diseases with extracellular deposition of congophilic fibrils of similar morphology but differing chemical composition. The types commonly involving the kidney are AL (light chain amyloid) and AA (serum amyloid A). Familial amyloidosis can also...

  • Pilot Study of the Reducing Effect on Amyloidosis In Vivo by Three FDA Pre-Approved Drugs Via the Alzheimer's APP 5'Untranslated Region. Tucker, Stephanie; Ahl, Michelle; Bush, Ashley; Westaway, David; Xudong Huang; Rogers, Jack T. // Current Alzheimer Research;Apr2005, Vol. 2 Issue 2, p249 

    A pilot study was conducted employing a well known mouse model for Alzheimer's disease to evaluate the anti-amyloid efficacy of three FDA pre-approved drugs. Paroxetine (SSRI and APP 5'UTR directed lead compound), Nacetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic) were...

  • 'Hypersynchronisation' by tissue velocity imaging in patients with cardiac amyloidosis. D Bellavia // Heart;Feb2009, Vol. 95 Issue 3, p234 

    OBJECTIVE: It is unknown if some patients with cardiac amyloidosis (CA) have mechanical dyssynchrony, as has been demonstrated in patients with ischaemic and dilated cardiomyopathies. The aim of this study was to assess mechanical dyssynchrony in patients with CA using tissue velocity imaging...

  • SPONTANEOUS RUPTURE OF THE LIVER IN AMYLOIDOSIS. Bujanda, Luis; Beguiristain, Adolfo; Alberdi, Fermín; Cosme, Angel; De la Hermosa, Jose Ruiz; Gutiérrez-Stampa, María A.; Arenas, Juan Ignacio // American Journal of Gastroenterology;Aug1997, Vol. 92 Issue 8, p1385 

    Hepatic rupture is an unusual complication of hepatic amyloidosis. We report the case of a 59-yr-old man with a subcapsular hematoma of the liver with hepatic rupture secondary to amyloidosis. The patient died during the surgery. The etiology, pathology, diagnosis, and treatment of this...

  • Amyloid Mimics Chronic Inflammatory Demyelinating Polyneuropathy. Rubin, Michael // Neurology Alert;Oct2011, Vol. 30 Issue 2, p10 

    Amyloidosis may present with the clinical and electrophysiologic features of chronic inflammatory demyelinating polyneuropathy. Nerve biopsy may be necessary to make an accurate diagnosis.

  • Primary nasal amyloidosis. Prasad, Devi; Somayaji, Gangadhara K. S.; Aroor, Rajeshwari; Abdulla, Mohammad N. // Internet Journal of Otorhinolaryngology;2009, Vol. 9 Issue 2, p11 

    Introduction: Amyloidosis in the head and neck is a rare but benign disease. Primary amyloidosis localized to the sinonasal tract is extremely rare. This is a report of one such case with a brief review of the literature. Case report: A 42 year old lady who presented with epistaxis and left...

  • Amyloidosis Complicating Rhinophyma Amyloidosis Complicating Rhinophyma. Nanda, V.; Garg, B.K.; Chittoria, R.; Biswas, G.; Sharma, R.K. // Aesthetic Plastic Surgery;Mar/Apr2004, Vol. 28 Issue 2, p98 

    Rhinophyma is the advanced stage of acne rosacea and a source of embarrassment for the patient. Secondary localized cutaneous amyloidosis complicating rhinophyma is not reported in the literature. A patient with rhinophyma was treated by excision and primary closure. The histologic examination...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics