Advertisement

Molecular Diagnosis & Therapy

, Volume 23, Issue 2, pp 153–154 | Cite as

Theranostics of Genetic Diseases

  • Roberto GambariEmail author
  • Marina Kleanthous
Editorial
  • 122 Downloads

This thematic issue of Molecular Diagnosis and Therapy focuses on novel therapeutic approaches and diagnostic strategies for the management of genetic diseases, including rare genetic diseases. These two issues are strictly associated when patient stratification and personalized therapy in precision medicine are to be applied. For this reason, the term ‘theranostics’ has been proposed—combining ‘therapeutic strategies’ and ‘diagnostics’ within the same term. Four articles in this issue review therapeutic approaches, discussing the issue of gene therapy [1], gene editing [2, 3], and microRNA (miRNA) therapeutics [4]. Ghiaccio et al. [1] review gene therapy for β-thalassemia with respect to the milestones reached, novel developments, and present (and future) challenges. This is a very important issue, as gene therapy for β-thalassemia is currently undergoing validation in several clinical trials [5, 6, 7, 8]. Encouraging results have recently been presented on transfusion-dependent β-thalassemia patients in trials based on different therapeutic vectors carrying a therapeutic β-globin gene. The phase III clinical trials underway at present are expected to help determine benefit/risk/cost ratios to move gene therapy toward clinical practice [5].

The relatively new approach based on gene editing is the object of two review articles by Lederer and Kleanthous [2, 3]. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-based tools and therapy development for rare genetic diseases is indeed a fascinating possibility for site-specific correction of the genetic mutations causing hereditary pathologies, as also summarized in other review articles available in the recent literature [9, 10, 11, 12, 13]. Growing interest appears to be associated with novel markers and molecular targets, which might lead to implementation of the therapeutic protocols in pre-clinical studies. In this respect, the network constituted by transcription factors and non-coding RNAs (ncRNAs; including miRNAs) might be of great interest in the regulation of gene expression in genetic diseases, as described by Finotti et al. [4]. In fact, since their discovery and classification, the roles of ncRNAs have gained great attention in genetic diseases, and both miRNAs and long ncRNAs (lncRNAs) can be considered excellent markers for advanced diagnostic protocols and suitable targets for therapeutic interventions [14, 15, 16, 17]. The obvious conclusion of these review articles is that they indicate miRNA-targeting transcription factors as novel targets (miRNA therapeutics). In this respect, both anti-miRNA molecules or miRNA mimicking strategies might be of interest [14]. The review by Finotti et al. [4] points to the regulation of the γ-globin transcriptional repressor as a possible key element to be modified to obtain clinically relevant outcomes in β-thalassemia and other hemoglobinopathies. This article should be considered together with the papers by Katsantoni [18] (Omics as a tool for identification of novel biomarkers associated to β-thalassemia) and Menzel and Thein [19] (describing gene modifiers in sickle-cell disease). The Omics approach requires in-depth analyses, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics. The review by Katsantoni [18] discusses how novel gene variants/sequences, transcripts, ncRNAs, proteins, and metabolites involved in the pathogenesis of β-thalassemia are expected to be identified in the near future through Omics methodologies. One selected example is that reported by Menzel and Thein [19], in which several polymorphisms involve miRNA-regulated transcription factors (such as MYB and BCL11A) [20, 21]. An example of the importance of targeting other pathophysiological features (in addition to those related to the primary genetic mutation) is presented by Fibach and Dana [22], who describe the consequences of oxidative stress in β-thalassemia [22]. Finally, further examples supporting studies aimed at patient stratification and personalized therapy in precision medicine are discussed in the case of cystic fibrosis [23] and Shwachman-Diamond syndrome [24]. As already mentioned, the identification of the molecular mechanisms underlying the genetic diseases of interest might allow the definition of the parameters to be investigated in diagnostics, including the very important issue of non-invasive prenatal diagnosis, as presented by Breveglieri et al. [25].

Notes

Acknowledgements

Several studies presented in this thematic issue of Molecular Diagnosis and Therapy [1, 2, 3, 18, 19, 22, 23, 24, 25] were partially supported by the EU FP6 ITHANET Project (eInfrastructure for THAlassaemia research NETwork) [26] and by the EU FP7 THALAMOSS Project (THALAssaemia MOdular Stratification System for personalized therapy of beta-thalassemia).

Compliance with Ethical Standards

Conflict of interest

Roberto Gambari and Marina Kleanthous have no conflicts of interest to report.

Funding

Roberto Gambari and Marina Kleanthous report no funding relating to this editorial.

References

  1. 1.
    Ghiaccio V, Chappell M, Rivella S, Breda L. Gene therapy for beta-hemoglobinopathies: milestones, new therapies and challenges. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-019-00383-4 (Epub 2019 Jan 30).Google Scholar
  2. 2.
    Lederer CW, Kleanthous M. Rare opportunities: CRISPR/Cas-based therapy development for rare genetic diseases. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-019-00392-3 (Epub 2019).Google Scholar
  3. 3.
    Lederer CW, Kleanthous M. Disruptive technology: CRISPR/Cas-based tools and approaches. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-019-00391-4 (Epub 2019).Google Scholar
  4. 4.
    Finotti A, Fabbri E, Lampronti L, Gasparello J, Borgatti M, Gambari R. MicroRNAs and long non-coding RNAs in genetic diseases. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-018-0380-6 (Epub 2019 Jan 4).Google Scholar
  5. 5.
    Sii-Felice K, Giorgi M, Leboulch P, Payen E. Hemoglobin disorders: lentiviral gene therapy in the starting blocks to enter clinical practice. Exp Hematol. 2018;64:12–32.CrossRefGoogle Scholar
  6. 6.
    Biffi A. Gene therapy as a curative option for β-thalassemia. N Engl J Med. 2018;378:1551–2.CrossRefGoogle Scholar
  7. 7.
    Boulad F, Mansilla-Soto J, Cabriolu A, Rivière I, Sadelain M. Gene therapy and genome editing. Hematol Oncol Clin N Am. 2018;32:329–42.CrossRefGoogle Scholar
  8. 8.
    Lidonnici MR, Ferrari G. Gene therapy and gene editing strategies for hemoglobinopathies. Blood Cells Mol Dis. 2018;70:87–101.CrossRefGoogle Scholar
  9. 9.
    Ewart DT, Peterson EJ, Steer CJ. Gene editing for inflammatory disorders. Ann Rheum Dis. 2019;78:6–15.  https://doi.org/10.1136/annrheumdis-2018-213454.CrossRefGoogle Scholar
  10. 10.
    Marangi M, Pistritto G. Innovative therapeutic strategies for cystic fibrosis: moving forward to CRISPR technique. Front Pharmacol. 2018;9:396.CrossRefGoogle Scholar
  11. 11.
    Lyu C, Shen J, Wang R, Gu H, Zhang J, Xue F, et al. Targeted genome engineering in human induced pluripotent stem cells from patients with hemophilia B using the CRISPR-Cas9 system. Stem Cell Res Ther. 2018;9:92.CrossRefGoogle Scholar
  12. 12.
    Uppada V, Gokara M, Rasineni GK. Diagnosis and therapy with CRISPR advanced CRISPR based tools for point of care diagnostics and early therapies. Gene. 2018;656:22–9.CrossRefGoogle Scholar
  13. 13.
    Long C, Li H, Tiburcy M, Rodriguez-Caycedo C, Kyrychenko V, Zhou H, et al. Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing. Sci Adv. 2018;4(1):eaap9004.CrossRefGoogle Scholar
  14. 14.
    Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22.CrossRefGoogle Scholar
  15. 15.
    Gambari R, Fabbri E, Borgatti M, Lampronti I, Finotti A, Brognara E, et al. Targeting microRNAs involved in human diseases: a novel approach for modification of gene expression and drug development. Biochem Pharmacol. 2011;82:1416–29.CrossRefGoogle Scholar
  16. 16.
    Finotti A, Gambari R. Recent trends for novel options in experimental biological therapy of β-thalassemia. Expert Opin Biol Ther. 2014;14:1443–54.CrossRefGoogle Scholar
  17. 17.
    Chakraborty C, Sharma AR, Sharma G, Doss GP, Lee S-S. Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine. Mol Ther Nucleic Acids. 2017;8:132–43.CrossRefGoogle Scholar
  18. 18.
    Katsantoni E. Omics studies in β-thalassemia. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-019-00386-1 (Epub 2019 Feb 2).Google Scholar
  19. 19.
    Menzel S, Thein S-L. Genetic modifiers of fetal hemoglobin in sickle cell disease. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-018-0370-8 (Epub 2019).Google Scholar
  20. 20.
    Sankaran VG, Menne TF, Šćepanović D, Vergilio JA, Ji P, Kim J, et al. MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13. Proc Natl Acad Sci USA. 2011;108:1519–24.CrossRefGoogle Scholar
  21. 21.
    Lulli V, Romania P, Morsilli O, Cianciulli P, Gabbianelli M, Testa U, et al. MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A. PLoS One. 2013;8(4):e60436.CrossRefGoogle Scholar
  22. 22.
    Fibach E, Dana M. Oxidative stress in β-thalassemia. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-018-0373-5 (Epub 2019).Google Scholar
  23. 23.
    Cabrini G. Innovative therapies for cystic fibrosis: the road from treatment to cure. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-018-0372-6 (Epub 2018 Nov 26).Google Scholar
  24. 24.
    Bezzerri V, Cipolli M. The Shwachman-Diamond syndrome: molecular mechanisms and current perspectives. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-018-0368-2 (Epub 2018 Nov 9).Google Scholar
  25. 25.
    Breveglieri G, D’Aversa E, Finotti A, Borgatti M. Non-invasive prenatal testing using fetal DNA. Mol Diagn Ther. 2019.  https://doi.org/10.1007/s40291-019-00385-2 (Epub 2019 Feb 2).Google Scholar
  26. 26.
    Lederer CW, Basak AN, Aydinok Y, Christou S, El-Beshlawy A, Eleftheriou A, et al. An electronic infrastructure for research and treatment of the thalassemias and other hemoglobinopathies: the Euro-Mediterranean ITHANET project. Hemoglobin. 2009;33(3):163–76.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular BiologyUniversity of FerraraFerraraItaly
  2. 2.Molecular Genetics Thalassaemia DepartmentThe Cyprus Institute of Neurology and GeneticsNicosiaCyprus

Personalised recommendations