hATTR Amyloidosis Treatment Overview

Therapeutic targets in TTR amyloidosis pathogenesis1,2

Liver

Liver

TTR Tetramer

TTR Tetramer

TTR Monomer

TTR Monomer

TTR Misfolding

TTR Misfolding

TTR Amyloid Fibrils

TTR Amyloid Fibrils
Production, secretion
Dissociation
Misfolding
Polymerization

Suppression of the production of amyloidogenic TTR

EMERGING THERAPIES

  • Antisense oligonucleotide therapeutics
  • RNA interference therapeutics

CURRENT TREATMENT

  • Orthotopic liver transplant (OLT)

Stabilization
of TTR tetramers

EMERGING THERAPIES

  • Stabilizers of TTR tetramers

Inhibition
of amyloid deposits

EMERGING THERAPIES

  • Immunotherapy
Adapted with permission from Ueda M, Ando Y. Recent advances in transthyretin amyloidosis therapy. Transl Neurodegener. 2014;3:19. doi:10.1186/2047-9158-3-19. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).1
Liver

Liver

Production, secretion

Suppression of the production of amyloidogenic TTR

EMERGING THERAPIES

  • Antisense oligonucleotide therapeutics
  • RNA interference therapeutics

CURRENT TREATMENT

  • Orthotopic liver transplant (OLT)
TTR Tetramer

TTR Tetramer

Dissociation

Stabilization of TTR tetramers

EMERGING THERAPIES

  • Stabilizers of TTR tetramers
TTR Monomer

TTR Monomer

Misfolding

Inhibition of amyloid deposits

EMERGING THERAPIES

  • Immunotherapy
Adapted with permission from Ueda M, Ando Y. Recent advances in transthyretin amyloidosis therapy. Transl Neurodegener. 2014;3:19. doi:10.1186/2047-9158-3-19. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0).1

Current hATTR amyloidosis treatment options

Current hereditary transthyretin amyloidosis (hATTR) treatment options are limited, but multiple potential therapies are emerging to help mitigate the underlying genetic mutation in patients with hATTR amyloidosis.2

Orthotopic liver transplant (OLT)2:

Because most transthyretin (TTR) protein is produced in the liver, replacing the major source of the amyloidogenic TTR protein with a transplanted liver can slow or halt the progression of the disease. Although OLT is an established option for patients with early-stage disease, several limitations exist to using this approach for hATTR amyloidosis treatment; in addition, OLT might not eliminate progression of disease, because TTR produced by the transplanted liver can accumulate on the preexisting deposits. Other limitations include limited organ availability, surgical morbidity and mortality, need for lifelong immunosuppression, and the high cost of liver transplantation.

Emerging therapies for the treatment of hATTR amyloidosis1

Suppression of the production of amyloidogenic TTR2,3:

Currently, 2 distinct RNA-based therapies for hATTR amyloidosis are being evaluated in phase 3 clinical trials. Both agents bind to target TTR mRNA through base pairing, leading to its degradation and resulting in the production of less TTR protein, both mutant and wild type.

  • The antisense oligonucleotides (ASO) approach utilizes single-strand oligonucleotides designed to be exactly complementary to the mRNA to cause enzymatic degradation of the target mRNA
  • The RNA interference (RNAi) approach utilizes double-stranded small interfering RNAs (siRNA) encapsulated in lipid nanoparticles to target mRNA

Stabilizers of TTR tetramers2:

The TTR stabilizers slow the progression of TTR amyloidogenesis by preventing the dissociation, misfolding, and misassembly of the mutated TTR tetramer. Currently, there are no TTR stabilizers approved for the treatment of hATTR amyloidosis in the United States

Inhibition of amyloid deposits4:

Immunotherapy produces a regulated immune response against the specific amyloid protein by enhancing the clearance of these deposits with monoclonal antibodies. Currently, a number of antibodies are undergoing testing in patients with various forms of amyloidosis

In Life-Threatening hATTR Amyloidosis, Hope Starts With Diagnosis.5

Current clinical trials investigating hATTR amyloidosis treatment.

Learn More
References: 1. Ueda M, Ando Y. Recent advances in transthyretin amyloidosis therapy. Transl Neurodegener. 2014;3:19. doi:10.1186/2047-9158-3-19. 2. Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(suppl 7):S107-S112. 3. Donnelly JP, Hanna M. Cardiac amyloidosis: an update on diagnosis and treatment. Cleve Clin J Med. 2017;84(12 suppl 3):12-26. 4. Adams D, Suhr OB, Hund E, et al; European Network for TTR-FAP (ATTReuNET). First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016;29(suppl 1):S14-S26. 5. Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.