Leveraging proteomics in orphan disease research: pitfalls and potential

ABSTRACT

Introduction: The term ‘orphan diseases’ includes conditions meeting prevalence-based or commercial viability criteria: they affect a small number of individuals and are considered an unviable market for drug development. Proteomics is an important technology to study them, providing information on mechanisms and evolution, biomarkers, and effects of therapeutic interventions.

Areas covered: Herein, we review how proteomics and bioinformatic tools could be applied to the study of rare diseases and discuss pitfalls and potential.

Expert opinion: Research in the field of rare diseases has to face many challenges, and implementation plans should foresee highly specialized collaborative consortia to create multidisciplinary frameworks for data sharing, advancing research, supporting clinical studies, and accelerating drug development. The integration of different technologies will allow better knowledge of disease pathophysiology, and the inclusion of proteomics and other omics technologies in this context will be pivotal to this aim.

Several aspects of rare diseases, often perceived as limiting factors, might actually be advantages for a precision medicine approach: the limited number of patients, the collaboration with patient societies, and the availability of curated clinical registries could allow the development of homogeneous clinical databases and ultimately a better control over the data to be analyzed.

KEYWORDS:

• Bioinformatics
• rare diseases
• biomarkers
• proteogenomics
• congenital proteomics
• precision medicine

Article highlights

• The definition ‘orphan diseases’ includes conditions meeting prevalence-based or commercial viability criteria: rare diseases affecting a small number of individuals and diseases that are considered an unviable market for the development of therapeutics.

• Research on rare genetic diseases can provide a useful way to study the function of the most evolutionarily conserved genes and cellular mechanisms and be paradigmatic for the development of precision medicine approaches.

• Compared to genomics, transcriptomics, and metabolomics, often used successfully for diagnostic and characterization purposes, proteomics seems to lag behind in this field. Nevertheless, knowledge of the proteome could provide vital information on altered cellular pathways, timely information on disease evolution, effects of therapeutic interventions, and identify candidate biomarkers.

• Several technological and methodological innovations improved the analytical performance of proteomics, opening novel opportunities for the quali-quantitative analysis of proteins involved in human diseases and enabling previously impossible applications. A large variety of bioinformatics tools have been established to aid in assay development, process data, and link them with clinical phenotypes.

• There is the need to combine multiple targeted and untargeted proteomic approaches, also including the analysis of protein post-translational modifications, and to integrate such information with other omics repertoires (e.g. genomics, metabolomics, and epigenomics) in a systems biology perspective to get a more complete picture of disease pathophysiology.

• Future efforts should be focused to create multidisciplinary networks for collaboration and data sharing, advancing research, supporting clinical studies, and accelerating the uptake of therapeutics. In parallel, curated sample biobanks and disease registries must be implemented as well.

Acknowledgments

The authors thank aimAKU, Associazione Italiana Malati di Alcaptonuria (ORPHA263402).

This work is in memory of Dr. Duccio Calamandrei, a man of science and a friend.

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.

Author contribution

All authors have substantially contributed to the conception and design of the review article and interpreting the relevant literature, have been involved in writing the review article and have revised it for intellectual content.

Additional information

Funding

This manuscript was funded in part by Regione Toscana [PIF2017, project USALI to AS and Bando Ricerca Salute 2018, project MAGIC to AS] and Ministero dell’Ambiente e della Tutela del Territorio e del Mare [project OmniAlgae to AS].