Update on Clinical Ex Vivo Hematopoietic Stem Cell Gene Therapy for Inherited Monogenic Diseases

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2020 Nov 22

PMID 33221437

Citations 39

Authors

Francesca Tucci

Samantha Scaramuzza

Alessandro Aiuti

Alessandra Mortellaro

Affiliations

Soon will be listed here.

Abstract

Gene transfer into autologous hematopoietic stem progenitor cells (HSPCs) has the potential to cure monogenic inherited disorders caused by an altered development and/or function of the blood system, such as immune deficiencies and red blood cell and platelet disorders. Gene-corrected HSPCs and their progeny can also be exploited as cell vehicles to deliver molecules into the circulation and tissues, including the central nervous system. In this review, we focus on the progress of clinical development of medicinal products based on HSPCs engineered and modified by integrating viral vectors for the treatment of monogenic blood disorders and metabolic diseases. Two products have reached the stage of market approval in the EU, and more are foreseen to be approved in the near future. Despite these achievements, several challenges remain for HSPC gene therapy (HSPC-GT) precluding a wider application of this type of gene therapy to a wider set of diseases while gene-editing approaches are entering the clinical arena.

Citing Articles

Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial.

Khan A, Barber D, McKillop W, Rupar C, Auray-Blais C, Fraser G Clin Transl Med. 2025; 15(1):e70073.

PMID: 39794302 PMC: 11726700. DOI: 10.1002/ctm2.70073.

Efficient and correction of hemoglobin Constant Spring mutation by prime editing in human hematopoietic cells.

Shao C, Liu Q, Xu J, Zhang J, Zhang C, Xin Y Mol Ther Nucleic Acids. 2024; 35(4):102371.

PMID: 39640014 PMC: 11617223. DOI: 10.1016/j.omtn.2024.102371.

Progress toward the challenging goal of HDR-based gene editing for hyper-IgM syndrome.

Catto L, Dunbar C Mol Ther Methods Clin Dev. 2024; 32(4):101359.

PMID: 39582718 PMC: 11585743. DOI: 10.1016/j.omtm.2024.101359.

Gene therapy for polygenic or complex diseases.

Wu T, Hu Y, Tang L Biomark Res. 2024; 12(1):99.

PMID: 39232780 PMC: 11375922. DOI: 10.1186/s40364-024-00618-5.

[Advances in gene therapy for inborn errors of immunity].

Li T, Song H Zhongguo Dang Dai Er Ke Za Zhi. 2024; 26(8):865-870.

PMID: 39148393 PMC: 11334546. DOI: 10.7499/j.issn.1008-8830.2404027.

References

Malech H, Maples P, Whiting-Theobald N, Linton G, Sekhsaria S, Vowells S . Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc Natl Acad Sci U S A. 1997; 94(22):12133-8. PMC: 23727. DOI: 10.1073/pnas.94.22.12133. View

de Ravin S, Wu X, Moir S, Anaya-OBrien S, Kwatemaa N, Littel P . Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016; 8(335):335ra57. PMC: 5557273. DOI: 10.1126/scitranslmed.aad8856. View

Steinberg M, Chui D, Dover G, Sebastiani P, Alsultan A . Fetal hemoglobin in sickle cell anemia: a glass half full?. Blood. 2013; 123(4):481-5. DOI: 10.1182/blood-2013-09-528067. View

Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L . Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009; 360(5):447-58. DOI: 10.1056/NEJMoa0805817. View

Mallhi K, Smith A, DeFor T, Lund T, Orchard P, Miller W . Allele-Level HLA Matching Impacts Key Outcomes Following Umbilical Cord Blood Transplantation for Inherited Metabolic Disorders. Biol Blood Marrow Transplant. 2016; 23(1):119-125. DOI: 10.1016/j.bbmt.2016.10.019. View

Chabannon C, Kuball J, Bondanza A, Dazzi F, Pedrazzoli P, Toubert A . Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies. Sci Transl Med. 2018; 10(436). DOI: 10.1126/scitranslmed.aap9630. View

Hacein-Bey Abina S, Gaspar H, Blondeau J, Caccavelli L, Charrier S, Buckland K . Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015; 313(15):1550-63. PMC: 4942841. DOI: 10.1001/jama.2015.3253. View

Holley R, Ellison S, Fil D, OLeary C, McDermott J, Senthivel N . Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy. Brain. 2017; 141(1):99-116. DOI: 10.1093/brain/awx311. View

Ott M, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U . Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006; 12(4):401-9. DOI: 10.1038/nm1393. View

10.

Kang E, Choi U, Theobald N, Linton G, Long Priel D, Kuhns D . Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood. 2009; 115(4):783-91. PMC: 2815517. DOI: 10.1182/blood-2009-05-222760. View

11.

Park S, Matte A, Jung Y, Ryu J, Anand W, Han E . Pathologic angiogenesis in the bone marrow of humanized sickle cell mice is reversed by blood transfusion. Blood. 2020; 135(23):2071-2084. PMC: 7273832. DOI: 10.1182/blood.2019002227. View

12.

Biffi A, Capotondo A, Fasano S, Del Carro U, Marchesini S, Azuma H . Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J Clin Invest. 2006; 116(11):3070-82. PMC: 1626132. DOI: 10.1172/JCI28873. View

13.

Farinelli G, Hernandez R, Rossi A, Ranucci S, Sanvito F, Migliavacca M . Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response. Mol Ther. 2016; 24(10):1873-1880. PMC: 5112042. DOI: 10.1038/mt.2016.150. View

14.

Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, de Villartay J . Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002; 346(16):1185-93. DOI: 10.1056/NEJMoa012616. View

15.

Levasseur D, Ryan T, Pawlik K, Townes T . Correction of a mouse model of sickle cell disease: lentiviral/antisickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood. 2003; 102(13):4312-9. DOI: 10.1182/blood-2003-04-1251. View

16.

Kay M, Glorioso J, Naldini L . Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med. 2001; 7(1):33-40. DOI: 10.1038/83324. View

17.

Hershfield M . PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol. 1995; 76(3 Pt 2):S228-32. DOI: 10.1016/s0090-1229(95)90306-2. View

18.

Candotti F . Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome. J Clin Immunol. 2017; 38(1):13-27. DOI: 10.1007/s10875-017-0453-z. View

19.

Siler U, Paruzynski A, Holtgreve-Grez H, Kuzmenko E, Koehl U, Renner E . Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing. Curr Gene Ther. 2015; 15(4):416-27. DOI: 10.2174/1566523215666150515145255. View

20.

Whitmore K, Gaspar H . Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency. Front Immunol. 2016; 7:314. PMC: 4985714. DOI: 10.3389/fimmu.2016.00314. View