Treatment of Genetic Diseases: Current Trends in the Development of Biomedical Cell Products

Genetic diseases are often progressive in nature, and without proper treatment may result in disability or death. Difficulties with diagnosis of genetic diseases and lack of effective treatment are global public health challenges. Medical care for patients with genetic diseases is often confined to symptomatic and palliative care. Starting from the 2000s, great hopes have been placed on cell-based medicinal products (which are referred to as biomedical cell products in the Russian legislation) and gene therapy products. The aim of the study was to review current trends in the development of biomedical cell products for the treatment of genetic diseases. The paper focuses on cell-based products for the treatment of monogenic genetic diseases, such as severe combined immunodeficiency (SCID), recessive dystrophic epidermolysis bullosa (RDEB), beta-haemoglobinopathies, alpha-1-antitrypsin deficiency, haemophilia A, and Duchenne muscular dystrophy. Such drugs are being developed in many countries and are now entering preclinical and different stages of clinical trials. Products based on various types of viable cells, including differentiated cells, stem cells, induced pluripotent cells, as well as cells genetically modified ex vivo, may be developed for the treatment of one and the same disease. The main priority is the creation of such products that will obviate the need for replacement therapy or palliative care, and that will significantly increase life expectancy and quality of life.

biomedical cell products, genetic diseases, orphan diseases, gene therapy products, stem cells, induced pluripotent cells

1. Guttmacher AE, Collins FS. Genomic medicine – a primer. N Engl J Med. 2002;347(19):1512–20. https://doi.org/10.1056/NEJMra012240

2. Fischer A, Cavazzana-Calvo M. Gene therapy of inherited diseases. Lancet. 2008;371(9629):2044–7. https://doi.org/10.1016/S0140-6736(08)60874-0

3. Melnikova EV, Merkulova OV, Rachinskaya OA, Chaplenko AA, Merkulov VA, Olefir YuV, et al. Modern approaches to the assessment of the quality control of cell-therapy products. Biofarmatsevticheskiy zhurnal = Russian Journal of Biopharmaceuticals. 2016;8(4):35–46

4. Abbott A. Italians first to use stem cells. Nature. 1992;356(6369):465. https://doi.org/10.1038/356465a0

5. Bordignon C, Notarangelo LD, Nobili N, Ferrari G, Casorati G, Panina P, et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science. 1995;270(5235):470–5. https://doi.org/10.1126/science.270.5235.470

6. Chan B, Wara D, Bastian J, Hershfield MS, Bohnsack J, Azen CG, et al. Long-term efficacy of enzyme replacement therapy for Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (SCID). Clin Immunol. 2005;117(2):133–43. https://doi.org/10.1016/j.clim.2005.07.006

7. Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. 1995;270(5235):475–80. https://doi.org/10.1126/science.270.5235.475

8. Aiuti A, Vai S, Mortellaro A, Casorati G, Ficara F, Andolfi G, et al. Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med. 2002;8(5):423–5. https://doi.org/10.1038/nm0502-423

9. Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002;296(5577):2410–3. https://doi.org/10.1126/science.1070104

10. Rashidghamat E, McGrath JA. Novel and emerging therapies in the treatment of recessive dystrophic epidermolysis bullosa. Intractable Rare Dis Res. 2017;6(1):6–20. https://doi.org/10.5582/irdr.2017.01005

11. Wong T, Gammon L, Liu L, Mellerio JE, Dopping-Hepenstal PJ, Pacy J, et al. Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2008;128(9):2179–89. https://doi.org/10.1038/jid.2008.78

12. Nagy N, Almaani N, Tanaka A, Lai-Cheong JE, Techanukul T, Mellerio JE, McGrath JA. HB-EGF induces COL7A1 expression in keratinocytes and fibroblasts: possible mechanism underlying allogeneic fibroblast therapy in recessive dystrophic epidermolysis Bullosa. J Invest Dermatol. 2011;131(8):1771–4. https://doi.org/10.1038/jid.2011.85

13. Natsuga K, Sawamura D, Goto M, Homma E, Goto-Ohguchi Y, Aoyagi S, et al. Response of intractable skin ulcers in recessive dystrophic epidermolysis bullosa patients to an allogeneic cultured dermal substitute. Acta Derm Venereol. 2010;90(2):165–9. https://doi.org/10.2340/00015555-0776

14. Falabella AF, Schachner LA, Valencia IC, Eeaglstein WH. The use of tissue-engineered skin (Apligraf) to treat a newborn with epidermosis bullosa. Arch Dermatol. 1999;135(10):1219–22. https://doi.org/10.1001/archderm.135.10.1219

15. Prockop DJ. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol Ther. 2009;17(6):939–46. https://doi.org/10.1038/mt.2009.62

16. Conget P, Rodriguez F, Kramer S, Allers C, Simon V, Palisson F, et al. Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa. Cytotherapy. 2010;12(3):429–31. https://doi.org/10.3109/14653241003587637

17. Jonkman MF, Scheffer H, Stulp R, Pas HH, Nijenhuis M, Heeres K, et al. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell. 1997;88(4):543–51. https://doi.org/10.1016/s0092-8674(00)81894-2

18. Gostynski A, Deviaene FC, Pasmooij AM, Pas HH, Jonkman MF. Adhesive stripping to remove epidermis in junctional epidermolysis bullosa for revertant cell therapy. Br J Dermatol. 2009;161(2):444–7. https://doi.org/10.1111/j.1365-2133.2009.09118.x

19. Tolar J, McGrath JA, Xia L, Riddle MJ, Lees CJ, Eide C, et al. Patient-specific naturally gene-reverted induced pluripotent stem cells in recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2014;134(5):1246–54. https://doi.org/10.1038/jid.2013.523

20. Umegaki-Arao N, Pasmooij AM, Itoh M, Cerise JE, Guo Z, Levy B, et al. Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa. Sci Transl Med. 2014;6(264):264ra164. https://doi.org/10.1126/scitranslmed.3009342

21. De Rosa L, Carulli S, Cocchiarella F, Quaglino D, Enzo E, Franchini E, et al. Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa. Stem Cell Reports. 2013;2(1):1–8. https://doi.org/10.1016/j.stemcr.2013.11.001

22. Siprashvili Z, Nguyen NT, Gorell ES, Loutit K, Khuu P, Furukawa LK, et al. Safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with recessive dystrophic epidermolysis bullosa. JAMA. 2016;316(17):1808–17. https://doi.org/10.1001/jama.2016.15588

23. Titeux M, Pendaries V, Zanta-Boussif MA, Décha A, Pironon N, Tonasso L, et al. SIN retroviral vectors expressing COL7A1 under human promoters for ex vivo gene therapy of recessive dystrophic epidermolysis bullosa. Mol Ther. 2010;18(8):1509–18. https://doi.org/10.1038/mt.2010.91

24. Ortiz-Urda S, Lin Q, Green CL, Keene DR, Marinkovich MP, Khavari PA. Injection of genetically engineered fibroblasts corrects regenerated human epidermolysis bullosa skin tissue. J Clin Invest. 2003;111(2):251–5. https://doi.org/10.1172/JCI17193

25. Piel FB. The present and future global burden of the inherited disorders of hemoglobin. Hematol Oncol Clin North Am. 2016;30(2):327–41. https://doi.org/10.1016/j.hoc.2015.11.004

26. Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010;12(2):61–76. https://doi.org/10.1097/GIM.0b013e3181cd68ed

27. Lucarelli G, Isgrò A, Sodani P, Gaziev J. Hematopoietic stem cell transplantation in thalassemia and sickle cell anemia. Cold Spring Harb Perspect Med. 2012;2(5):a011825. https://doi.org/10.1101/cshperspect.a011825

28. Takekoshi KJ, Oh YH, Westerman KW, London IM, Leboulch P. Retroviral transfer of a human beta-globin/delta-globin hybrid gene linked to beta locus control region hypersensitive site 2 aimed at the gene therapy of sickle cell disease. Proc Natl Acad Sci USA. 1995;92(7):3014–8. https://doi.org/10.1073/pnas.92.7.3014

29. Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018;378(16):1479–93. https://doi.org/10.1056/NEJMoa1705342

30. Ingram VM. A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature. 1956;178(4537):792–4. https://doi.org/10.1038/178792a0

31. Strouse JJ, Lanzkron S, Beach MC, Haywood C, Park H, Witkop C, et al. Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children. Pediatrics. 2008;122(6):1332–42. https://doi.org/10.1542/peds.2008-0441

32. Krishnamurti L, Abel S, Maiers M, Flesch S. Availability of unrelated donors for hematopoietic stem cell transplantation for hemoglobinopathies. Bone Marrow Transplant. 2003;31(7):547–50. https://doi.org/10.1038/sj.bmt.1703887

33. Badat M, Davies J. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376(21):2093–4. https://doi.org/10.1056/NEJMc1704009

34. Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol. 2008;103(8):2136–41.

35. Gooptu B, Lomas DA. Conformational pathology of the serpins: themes, variations, and therapeutic strategies. Annu Rev Biochem. 2009;78:147–76. https://doi.org/10.1146/annurev.biochem.78.082107.133320

36. Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, et al. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature. 2011;478(7369):391–6. https://doi.org/10.1038/nature10424

37. Wang W, Lin C, Lu D, Ning Z, Cox T, Melvin D, et al. Chromosomal transposition of PiggyBac in mouse embryonic stem cells. Proc Natl Acad Sci USA. 2008;105(27):9290–5. https://doi.org/10.1073/pnas.0801017105

38. Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet. 2005;6(6):488–501. https://doi.org/10.1038/nrg1617

39. Park CY, Kim DH, Son JS, Sung JJ, Lee J, Bae S, et al. Functional correction of large factor VIII gene chromosomal inversions in hemophilia A patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell. 2015;17(2):213–20. https://doi.org/10.1016/j.stem.2015.07.001

40. Béroud C, Tuffery-Giraud S, Matsuo M, Hamroun D, Humbertclaude V, Monnier N, et al. Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Hum Mutat. 2007;28(2):196–202. https://doi.org/10.1002/humu.20428

41. Wilton SD, Lloyd F, Carville K, Fletcher S, Honeyman K, Agrawal S, Kole R. Specific removal of the nonsense mutation from the mdx dystrophin mRNA using antisense oligonucleotides. Neuromuscul Disord. 1999;9(5):330–8. https://doi.org/10.1016/s0960-8966(99)00010-3

42. Young CS, Hicks MR, Ermolova NV, Nakano H, Jan M, Younesi S, et al. A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell. 2016;18(4):533–40. https://doi.org/10.1016/j.stem.2016.01.021

43. Law PK, Goodwin TG, Fang Q, Duggirala V, Larkin C, Florendo JA, et al. Feasibility, safety, and efficacy of myoblast transfer therapy on Duchenne muscular dystrophy boys. Cell Transplant. 1992;1(2-3):235–44. https://doi.org/10.1177/0963689792001002-305

44. Skuk D, Goulet M, Roy B, Chapdelaine P, Bouchard JP, Roy R, et al. Dystrophin expression in muscles of Duchenne muscular dystrophy patients after high-density injections of normal myogenic cells. J Neuropathol Exp Neurol. 2006;65(4):371–86. https://doi.org/10.1097/01.jnen.0000218443.45782.81