Terapia génica como potencial tratamiento para la osteopetrosis maligna

Autores

Andrey Montero Bonilla

RESUMEN

La osteopetrosis maligna es una enfermedad rara, y Costa Rica se sitúa con la incidencia más alta del mundo con 3,4 casos por cada 100 000 nacimientos comparada con 1 caso por cada 250 000 nacimientos a nivel mundial. Por lo tanto, es de vital importancia conocer los avances en el diagnóstico y nuevas terapias que puedan surgir. Al tratarse de una enfermedad rara, los avances han sido escasos en los últimos años, y el tratamiento se limita actualmente al trasplante de células madre hematopoyéticas. Sin embargo, en algunos casos esta terapia no se puede aplicar por falta de donantes HLA idénticos, y presenta complicaciones asociadas como la enfermedad de injerto versus hospedero y el rechazo agudo. Recientemente, se han presentado nuevas aplicaciones de la terapia génica como una potencial herramienta curativa para estos pacientes. Con el uso de vectores lentivirales y mediante métodos ex vivo, se desarrolla un ensayo clínico en fase I; de esta manera se está a la expectativa de posibles resultados favorables para su aplicación futura en fases clínicas avanzadas. En esta revisión, se abordan aspectos generales de esta patología, así como las estrategias terapéuticas convencionales, culminando con el diseño de modelos animales y experimentales en fase clínica de prueba para vectores virales que acarrean los genes que corrigen los defectos genéticos implicados.

Palabras clave

Osteopetrosis, terapia génica.

ABSTRACT

Malignant osteopetrosis is a rare disease, and Costa Rica has the highest incidence with a rate of approximately 3.4 out of every 100,000 births compared with 1 out of every 250,000 births around the world. Updates and advances in diagnosis and new therapies in the future is crucial. Since it has been classified as a rare disease, in recent years progress has been limited.  Hematopoietic Stem Cell Transplantation is the first line treatment. However, in some cases this therapy cannot be useful due to the lack of HLA-identical donors and associated complications such as graft versus host disease and acute rejection. New applications of gene therapy have recently been arising as a potential curative treatment for these patients. With lentiviral vectors and ex vivo methods, with a phase I clinical trial in progress, favorable results are expected for its future application in advanced clinical phases. In this review, we describe general aspects of this disease, and the conventional therapeutic strategies. We will analyze the design of animal and experimental models in the clinical trial phase I for viral vectors that carry the genes that correct the genetic defects involved.

Keywords

Osteopetrosis, gene therapy
1. Al-Rasheed SA. Osteopetrosis. In: Elzouki A.Y., Harfi H.A., Nazer H.M., Stapleton F.B., Oh W., Whitley R.J. (eds) Textbook of Clinical Pediatrics. Springer, Berlin: Heidelberg; 2012. Recuperado de: https://doi.org/10.1007/978-3-642-02202-9_40 2. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009; 4 (5). Recuperado de: https://doi.org/10.1186/1750-1172-4-5 3. Mortier GR, Cohn DH, CormierDaire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet Part A. 2019;179A: 2393–2419. Recuperado de: https://doi.org/10.1002/ajmg.a.61366 4. Bollerslev J, Henriksen K, Nielsen MF, Brixen K, Van Hul W. Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol. 2013; 169: R39–57. 5. Johnston CC Jr, Lavy N, Lord T, Vellios F, Merritt AD, Deiss WP Jr. Osteopetrosis. A clinical, genetic, metabolic, and morphologic study of the dominantly inherited, benign form. Medicine (Baltimore). 1968; 47(2): 149–67. 6. Balemans W, Van Wesenbeeck L, Van Hul W. A clinical and molecular overview of the human osteopetroses. Calcif Tissue Int. 2005; 77 (5): 263–74. 7. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009; 4(5). 8. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013; 9(9): 522–36. 9. Manolagas S. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000, 21: 115-137. 10. Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ: Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. 2001, 104: 205-215. Recuper1ado de: doi:10.1016/S0092-8674(01)00206-9. 11. Penna S, Capo V, Palagano E, Sobacchi C, Villa A. One Disease, Many Genes: Implications for the Treatment of Osteopetroses. Front Endocrinol (Lausanne). 2019;10:85. Recuperado de: doi: 10.3389/fendo.2019.00085. PMID: 30837952; PMCID: PMC6389615. 12. Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet. 2000; 25(3): 343–6. 13. Vaananen HK, Zhao H, Mulari M, Halleen JM. The cell biology of osteoclast function. J Cell Sci. 2000; 113(3): 377–81. 14. Huybrechts Y, Van Hul W. Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking. Bone. 2022;164:116520. Recuperado de: doi: 10.1016/j.bone.2022.116520. Epub ahead of print. PMID: 35981699. 15. Palagano, E, Menale, C, Sobacchi, C. et al. Genetics of Osteopetrosis. Curr Osteoporos Rep. 2018; 16, 13–25. Recuperado de: https://doi.org/10.1007/s11914-018-0415-2 16. Wu C, Econs MJ, DiMeglio LA, Insogna KL, Michael A Levine, Orchard PJ, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group, The Journal of Clinical Endocrinology & Metabolism; 102(9): 3111–3123. Recupera1do de: https://doi.org/10.1210/jc.2017-01127 17. Norwood I, Szondi D, Ciocca,M, Coudert A, Cohen-Solal M, Rucci N, e al. Transcriptomic and bioinformatic analysis of Clcn7-dependent Autosomal Dominant Osteopetrosis type 2. Preclinical and clinical implications. Bone . 2021; 144(115828) Recuperado de: doi:10.1016/j.bone.2020.115828. 18. Ogbureke KU, Zhao Q, Li YP. Human osteopetroses and the osteoclast V-H+-ATPase enzyme system. Front Biosci. 2005;10: 2940-54. Recuperado de: doi: 10.2741/1750. PMID: 15970548. 19. Demir K, Nalbantoğlu Ö, Karaer K, Korkmaz HA, Yıldız M, Tunç S, et al. Genetic Diagnosis Using Whole Exome Analysis in Two Cases with Malignant Osteopetrosis of Infancy. J Clin Res Pediatr Endocrinol. 2015;7(4): 356-7. Recuperado de: doi: 10.4274/jcrpe.2597. PMID: 26777052; PMCID: PMC4805220. 20. Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N: Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007; 39: 960-962. Recuperado de: doi:10.1038/ng2076. 21. Vacher J. OSTM1 pleiotropic roles from osteopetrosis to neurodegeneration. Bone. 2022;163(1165059). Recuperado de: doi: 10.1016/j.bone.2022.116505. PMID: 35902071 22. Askmyr, MK, Fasth A, Richter J. Towards a better understanding and new therapeutics of osteopetrosis. British Journal of Haematology. 2008; 140(6), 597–609. Recuperado de: doi:10.1111/j.1365-2141.2008.06983.x 23. Teti A, Econs MJ. Osteopetroses, emphasizing potential approaches to treatment. Bone. 2017; 102:50-59. Recuperado de: doi: 10.1016/j.bone.2017.02.002. Epub 2017 Feb 4. PMID: 28167345. 24. Askmyr M, Flores C, Fasth A, Richter J. Prospects for gene therapy of osteopetrosis. Curr Gene Ther. 2009; 9(3):150-9. Recuperado de: doi: 10.2174/156652309788488613. PMID: 19519360. 25. Lofvall H, Rothe M, Schambach A, Henriksen K, Richter J, Moscatelli I. Hematopoietic stem cell-targeted neonatal gene therapy with a clinically applicable lentiviral vector corrects osteopetrosis in oc/oc mice. Hum Gene Ther. 2019;30(11): 1395–404. 26. Johansson MK, de Vries TJ, Schoenmaker T, et al. Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice. Blood. 2007;109(12): 5178–5185 27. Demeulemeester J, et al. The BET family of proteins targets moloney murine leukemia virus integration near transcription start sites. Cell Rep. 2013;5(4): 886–894. 28. Carbonaro DA, Zhang L, Jin X, et al. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014;22(3): 607–622. 29. De Ravin SS, Wu X, Moir S, et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016;8(335). 30. Zhou S, Mody D, DeRavin SS, et al. A selfinactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. Blood. 2010;116(6): 900–908. 31. Moscatelli I, Lofvall H, Schneider Thudium C, et al. Targeting NSG mice engrafting cells with a clinically applicable lentiviral vector corrects osteoclasts in infantile malignant osteopetrosis. Hum Gene Ther. 2018;29(8): 938–949. 32. Xian, X, Moraghebi, R, Löfvall, H et al. Generation of gene-corrected functional osteoclasts from osteopetrotic induced pluripotent stem cells. Stem Cell Res Ther. 2020. 11 (1). 33. Moscatelli I, Thudium CS, Flores C, Schulz A, Askmyr M, Gudmann NS, et al. Lentiviral gene transfer of TCIRG1 into peripheral blood CD34(+) cells restores osteoclast function in infantile malignant osteopetrosis. Bone. 2013;57(1):1-9. Recuperado de: doi: 10.1016/j.bone.2013.07.026. Epub 2013 Jul 29. PMID: 23907031. 34. Moscatelli I, Almarza E, Schambach A, Ricks D, Schulz A, Herzog CD, et al. Gene Therapy for Infantile Malignant Osteopetrosis: Review of Pre-Clinical Research and Proof-of-Concept for Phenotypic Reversal, Mol Ther Methods Clin Dev. 2021; 20: 389-397. Recuperado de: doi: https://doi.org/10.1016/j.omtm.2020.12.009.