Are we creating a new phenotype? Physiological barriers and ethical considerations in the treatment of hereditary transthyretin-amyloidosis

Abstract

Hereditary transthyretin (TTR) amyloidosis (ATTRv) is an autosomal dominant, systemic disease transmitted by amyloidogenic mutations in the TTR gene. To prevent the otherwise fatal disease course, TTR stabilizers and mRNA silencing antisense drugs are currently approved treatment options. With 90% of the amyloidogenic protein produced by the liver, disease progression including polyneuropathy and cardiomyopathy, the two most prominent manifestations, can successfully be halted by hepatic drug targeting or—formerly—liver transplantation. Certain TTR variants, however, favor disease manifestations in the central nervous system (CNS) or eyes, which is mostly associated with TTR production in the choroid plexus and retina. These compartments cannot be sufficiently reached by any of the approved medications. From liver-transplanted patients, we have learned that with longer lifespans, such CNS manifestations become more relevant over time, even if the underlying TTR mutation is not primarily associated with such. Are we therefore creating a new phenotype? Prolonging life will most likely lead to a shift in the phenotypic spectrum, enabling manifestations like blindness, dementia, and cerebral hemorrhage to come out of the disease background. To overcome the first therapeutic limitation, the blood–brain barrier, we might be able to learn from other antisense drugs currently being used in research or even being approved for primary neurodegenerative CNS diseases like spinal muscular atrophy or Alzheimer’s disease. But what effects will unselective CNS TTR knock-down have considering its role in neuroprotection? A potential approach to overcome this second limitiation might be allele-specific targeting, which is, however, still far from clinical trials. Ethical standpoints underline the need for seamless data collection to enable more evidence-based decisions and for thoughtful consenting in research and clinical practice. We conclude that the current advances in treating ATTRv amyloidosis have become a meaningful example for mechanism-based treatment. With its great success in improving patient life spans, we will still have to face new challenges including shifts in the phenotype spectrum and the ongoing need for improved treatment precision. Further investigation is needed to address these closed barriers and open questions.

Ophthalmological involvement in wild‐type transthyretin amyloidosis: A multimodal imaging study

“…Therefore, the clinical manifestations involving the central nervous system and eye might become the most prevalent in the near future. 9,40,41 Moreover, the eye examination, eventually also using aqueous humor samples, might provide possible markers of response to treatments. 42 Since no plasma or urinary biomarkers are available for the diagnosis of ATTR, recently, the development of specific screening programs for the early identification of ATTR, particularly ATTRwt, has been proposed.…”

“…5,8 The advancement in the diagnostic techniques and therapies and the greater awareness for the clinical characteristics of ATTR, particularly for ATTRwt, have led to a wider disease clinical spectrum and an increased rate of new diagnoses. 2,9 The aim of the present study was to analyze the ocular involvement in ATTRwt and to compare the findings with those detected in ATTRv and AL. Moreover, we used new noninvasive imaging techniques to identify signs of damage at the level of corneal nerve fibers and the retinal vascularization, which are more difficult to disclose at a systemic level.…”

Liver‐directed drugs for transthyretin‐mediated amyloidosis

“…Additionally, long‐term risk of ocular manifestations has been noted after liver transplantation and ATTR stabilization, due to intraocular production and deposition of mutant TTR in patients with prolonged survival 76,79 . These tissue compartments, however, are protected by the blood‐brain barrier and inaccessible to current RNA silencers and gene editors administered by parenteral routes of delivery 80 . Access to these regions could potentially be addressed by intrathecal and/or intravitreal injection 81,82 or advancements in delivery across the blood‐brain barrier 83‐85 …”

“…76,79 These tissue compartments, however, are protected by the bloodbrain barrier and inaccessible to current RNA silencers and gene editors administered by parenteral routes of delivery. 80 Access to these regions could potentially be addressed by intrathecal and/or intravitreal injection 81,82 or advancements in delivery across the blood-brain barrier. 83…”

Amyloidogenicity assessment of transthyretin gene variants

“…Despite being an autosomal dominantly inherited disorder, penetrance can be low, depending on the variant 6 . Additionally, despite being a systemic amyloid disease, 7 it can be difficult to detect amyloid fibrils in tissue samples, e.g. after nerve biopsy.…”