Towards targets and treatments in transthyretin amyloidosis

ABSTRACT

Introduction: Hereditary amyloidogenic transthyretin (ATTR) amyloidosis, an autosomal dominant hereditary systemic amyloidosis, occurs because of mutation of transthyretin (TTR). Although liver transplantation has become a well-established therapy, this therapy has given rise to several problems. During the past decade, several different therapeutic approaches have been proposed and evaluated as an essential therapy for ATTR amyloidosis.

Areas covered: By focusing on drug discovery research for ATTR amyloidosis treatment, we review clinical presentation, pathogenesis, and recent advances in the treatment of ATTR amyloidosis, and discuss several ongoing therapeutic trials, such as, stabilizer of tetrameric structure of TTR (tafamidis and diflunisal), suppressors of amyloidogenic TTR expression (small interfering RNAs, antisense oligonucleotides), and suppressor of amyloid formation and deposits (doxycycline/TUDCA, immunotherapies).

Expert opinion: As of this moment, in addition to the conventional liver transplantation therapy, therapies stabilizing tetrameric structure of TTR are currently available for patients with ATTR amyloidosis. Based on the series of evidence obtained from clinical trials, TTR stabilizers (tafamidis and diflunisal), are generally well tolerated and delay neurological impairment in ATTR amyloidosis patients with early symptomatic polyneuropathy. Several treatment approaches, such as, gene silencing therapy (small interfering RNAs, antisense oligonucleotides), and suppressor of amyloid formation and deposits (Doxycycline/TUDCA, immunotherapies) are in the process of drug development and are expected to be approved in the near future.

KEYWORDS:

• ATTR amyloidosis
• transthyretin
• tafamidis
• diflunisal
• small interfering RNAs
• antisense oligonucleotides
• doxycycline
• tauroursodeoxycholic acid
• immunotherapy

Article highlights

• ATTR amyloidosis, an autosomal dominant hereditary systemic amyloidosis, occurs as a result of mutation of transthyretin.

• Although liver transplantation has become a well-established therapy for halting the progression of ATTR amyloidosis, this therapy has given rise to several problems.

• TTR stabilizers (tafamidis and diflunisal) are currently available therapy for the patients with ATTR amyloidosis.

• Clinical trials of gene silencing therapy (siRNA, ASO) are currently ongoing.

• Suppressor of amyloid formation and deposits (Doxycycline/TUDCA, immunotherapies) are in the process of drug development.

• Novel therapeutic approaches target the late stage of ATTR amyloidosis are urgently needed.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded