Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis

ABSTRACT

Introduction: Systemic amyloidosis occurs when one of a growing list of circulating proteins acquires an abnormal fold, aggregates and gives rise to extracellular amyloid deposits in different body sites, leading to organ dysfunction and eventually death. Current approaches are mainly aimed at lowering the supply of the amyloidogenic precursor or at stabilizing it in a non-amyloidogenic state, thus interfering with the initial phases of amyloid formation and toxicity.

Areas covered: Improved understanding of the pathophysiology is indicating novel steps and molecules that could be therapeutically targeted. Here, we will review emerging molecular targets and therapeutic approaches against the main forms of systemic amyloidosis at the early preclinical level.

Expert opinion: Conspicuous efforts in drug design and drug discovery have provided an unprecedented list of potential new drugs or therapeutic strategies, from gene-based therapies to small molecules and peptides, from novel monoclonal antibodies to engineered cell-based therapies. The challenge will now be to validate and optimize the most promising candidates, cross the bridge from the preclinical phase to the clinics and identify, through innovative trials design, the safest and most effective combination therapies, striving for a better care, possibly a definitive cure for these diseases.

KEYWORDS:

• Amyloidosis
• AL amyloidosis
• ATTR amyloidosis
• emerging therapies
• molecular targets
• systemic amyloidosis
• amyloid
• structure-based drug design
• drug repurposing
• high throughput screening

Article highlights

• Systemic amyloidoses are complex, multi-organ, multifaceted diseases and they are often fatal if untreated or not responding to therapy

• Abolishing, reducing or stabilizing the amyloidogenic precursor can prevent amyloid formation and toxicity and is – and should continue to be – the mainstay of anti-amyloid therapy

• Interfering with the mechanisms of cytotoxicity, tissue damage and organ dysfunction is highly desirable but requires a deeper understanding of molecular mechanisms of these diseases

• Targeting conformational epitopes shared by different types of amyloid deposits or common amyloid constituents (e.g. SAP) to induce amyloid clearance may be valuable at promoting recovery of affected organs and has the potential to profoundly impact on the management of rarer forms of amyloidosis which still lack etiological therapies

• Therapeutic management of systemic amyloidosis will most likely benefit from the concerted use of different agents, likely targeting different steps of the disease process

• Transition from preclinical studies to novel treatments in the clinics will require conspicuous efforts to validate and optimize the best candidates and identify the safest and most effective combination therapies

This box summarizes key points contained in the article.

Declaration of Interest

M. Nuvolone has received consultancy fees from AC Immune and Genentech. G. Merlini serves in advisory boards of GSK, Janssen, Millennium-Takeda, Prothena and Coelum. The authors have no other 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 apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This study was supported by grants from ‘Associazione Italiana per la Ricerca sul Cancro - Special Program Molecular Clinical Oncology 5 per mille n. 9965’, from Fondazione Cariplo ‘Structure-function relation of amyloid: understanding the molecular bases of protein misfolding diseases to design new treatments n. 2013-0964’, and from Fondazione Cariplo ‘Molecular mechanisms of Ig toxicity in age-related plasma cell dyscrasias n. 2015-0591’ (to G. Merlini) and from the Stiftung Synapsis - Alzheimer Forschung Schweiz AFS Synapsis foundation (to M. Nuvolone).