Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin (hATTR) amyloidosis is a progressive disease characterized by impairment of the peripheral nervous system.^1,2 Mutations of the transthyretin (TTR) gene result in the formation of abnormal transthyretin protein and the consequent deposition of amyloid fibrils in several organs, predominantly the peripheral nerves (leading to polyneuropathy) and heart (leading to cardiomyopathy).^1,2 Other organs and tissues can be also affected, including the eyes and kidneys.^1,2

TTR protein is a transporter for thyroxine (T4) and retinol-binding protein. It is synthesized mainly in the liver, and in smaller amounts in the choroid plexus and the retinal and ciliary pigment epithelia.² Mutations of the TTR gene result in the formation of TTR protein with reduced stability; the protein then misfolds, aggregates, and is deposited in tissues and organs as fibrils.² hATTR amyloidosis is a life-threatening disease, and individuals with a cardiac phenotype have a shortened life expectancy, dying within 2 to 5 years after the onset of symptoms.²

Given that hATTR amyloidosis is a systemic disease, management requires a multidisciplinary approach focusing on reducing the deposition of TTR.^1,3 Three main therapeutic approaches are currently being explored to treat hATTR amyloidosis: inhibition of transthyretin synthesis (by liver transplant and gene-silencing therapies), stabilization of the TTR native structure, and removal of misfolded TTR.¹ Other therapies are available for managing the symptoms of hATTR amyloidosis.⁴ Supportive therapies are also available for patients with hATTR amyloidosis, including physical and occupational therapy.

Liver Transplant

Because TTR protein is formed mainly in the liver, the synthesis of abnormal TTR can be suppressed with a liver transplant, a procedure first introduced in 1990 for the treatment of amyloidosis.^2,4 The 20-year survival rate after transplant has been reported to be 55.3%; cardiovascular complications are the most frequent cause of death.⁴ A patient’s outcome following a liver transplant depends not only on the type of TTR mutation but also on the patient’s individual characteristics and the severity of disease before surgery.² 

Gene-Silencing Therapies

Disease may progress in various organs and tissues, such as the eyes, heart, and nerves, following surgery; for this reason, drugs that can block the production of TTR in the liver have been developed.^1,4 Patisiran and inotersen are gene-silencing drugs that decrease the hepatic production of abnormal TTR in patients with either wild-type or mutant TTR.² Both drugs have been approved for the treatment of stage 1 or 2 polyneuropathy associated with hATTR amyloidosis.² 

The small interfering RNA (siRNA) therapeutic patisiran can control genetic expression in hepatocytes by targeting and cleaving the mRNA of amyloid TTR.^1-3 siRNA drugs are delivered by means of lipid nanoparticles and administered intravenously.^1,2 

Antisense oligonucleotide (ASO) technologies use short nucleotide oligomers that target and bind mRNA to destroy it.¹ Inotersen is a short ASO that selectively targets and degrades TTR mRNA, preventing translation and TTR production.^2,3

Other gene therapies currently under development use clustered, regularly interspaced short palindromic repeats with Cas9 endonuclease (CRISPR-Cas9) systems for gene editing, such as NTLA-2001, to reduce TTR protein levels. However, further clinical studies are required to determine the efficacy and safety of these systems.³ 

TTR Stabilizers

TTR stabilizers are molecules that can bind to T4-binding sites in circulating TTR. Binding stabilizes the native TTR structure, preventing dissociation, misfolding, and aggregation.^2,4 Tafamidis is an oral kinetic TTR tetramer protein stabilizer that binds to T4-binding sites. Diflunisal, a nonsteroidal anti-inflammatory drug, also binds to T4-binding sites of the TTR protein.^2,3

TTR Fibril Removal

The use of monoclonal antibodies to disrupt and remove amyloid deposits is being explored.¹ Monoclonal antibodies such as dezamizumab may help to deplete serum amyloid P component (SAP), a non-fibrillar plasma protein that can be found in the amyloid deposits; TTR89-97 and TTR115-124 have been designed to target 2 epitopes comprising regions of the protein that are exposed in the monomer form.^1,3,4,5 The administration of doxycycline and tauroursodeoxycholic acid (TUDCA), either individually or in combination, has shown results during investigations.⁵ Drugs to remove TTR fibrils, however, have not been approved for the treatment of hATTR amyloidosis, and further studies are ongoing.⁵

Physical, Occupational, and Supportive Therapy

Patients who have peripheral neuropathy can undergo physical therapy to decrease neuropathic pain and maintain strength, mobility, and function. Occupational therapy can benefit patients by helping them cope with the day-to-day changes caused by their disease. Therapists can teach patients how to perform self-care activities and to be aware of safety issues while they move.⁶ 

Therapies for managing the symptoms of hATTR amyloidosis include pregabalin, gabapentin, and amitriptyline for neuropathic pain and surgical procedures to address issues such as carpal tunnel syndrome.⁷

References

1. Ando Y, Adams D, Benson MD, et al. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022:1-13. doi:10.1080/13506129.2022.2052838

2. Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979

3. Carroll A, Dyck PJ, de Carvalho M, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678. doi:10.1136/jnnp-2021-327909

4. Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387-404. doi:10.1038/s41582-019-0210-4

5. Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci. 2020. Epub ahead of print. doi:10.1007/s10072-020-04889-2.

6. Exercise + physical therapy for neuropathy. The Foundation for Peripheral Neuropathy. Accessed July 8, 2022.

7. Treatment overview: hereditary transthyretin amyloidosis. Amyloidosis Research Consortium. Accessed July 8, 2022.

Reviewed by Harshi Dhingra, MD, on 7/15/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.