GENE THERAPY MILESTONES MEDWEBUS0002 History of Gene Therapy

GENE THERAPY MILESTONES MEDWEB-US-0002

History of Gene Therapy: Major Milestones 1970 1990 Gene therapy concept established 1 First clinical trial to deliver a therapeutic gene (ex vivo, retroviral vector) 5– 8 – 3 1989 2003 2017 2012 August China approved recombinant First gene therapy First CAR T-cell therapy, tisagenlecleucel¶, human p 53 adenovirus* approved in the EU, approved by the FDA for B-cell ALL that is (in vivo, adenoviral vector) alipogene tiparvovec‡, refractory or in second or later relapse for the treatment of head for the treatment of (ex vivo, lentiviral vector)28, 29 and neck squamous cell patients with familial LPLD 12– 15 18– 23 carcinoma (HNSCC) (in vivo, AAV vector) October FDA approved axicabtagene ciloleucel# (ex vivo, retroviral vector) for the treatment of relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy 30, 31 December First r. AAV product, voretigene neparvovec-rzyl**, approved in the US for the treatment of bi-allelic RPE 65 gene mutation-associated retinal dystrophy 32– 34 1999 2008 2016 2019 May 24 First gene therapy approved in the US for the treatment of SMA, onasemnogene abeparvovec-xioi (in vivo; AAV vector)42– 44 May 29 First gene therapy approved for the treatment of transfusiondependent β-thalassemia, autologous CD 34+ cells encoding βA-T 87 Q-globin gene†† 45– 47 2018 First ex vivo gene May therapy, autologous FDA approved tisagenlecleucel for DLBCL 29, 35 CD 34+ cells encoding August the human ADA c. DNA Ex vivo gene therapy products tisagenlecleucel, for the treatment sequence§, for the of B-cell ALL that is refractory, in relapse post-transplant, or in treatment of ADA-SCID, second or later relapse, and axicabtagene ciloleucel, for the was approved treatment of relapsed/refractory DLBCL and primary mediastinal 24– 27 AAV, adeno-associated virus; ADA, adenosine deaminase; ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; (retroviral vector) large B-cell lymphoma, were approved in the EU 29, 36– 38 c. DNA, complementary DNA; DLBCL, diffuse large B-cell lymphoma; FDA, U. S. Food and Drug Administration; November LPLD, lipoprotein lipase deficiency; r. AAV, recombinant adeno-associated virus; RPE 65, retinal pigment epithelium-specific 65 k. Da protein; First gene therapy targeting a genetic disease, voretigene SCID, severe combined immunodeficiency; SMA, spinal muscular atrophy. References are listed on the next slide. neparvovec-rzyl, approved in both the US and EU 39– 41 First approved clinical trial protocol to use gene transfer into humans 4 Death of a clinical trial participant due to severe immune reaction following in vivo adenoviral vector administration 9– 11 First adenovirus-based gene therapy, sitimagene ceradenovec†, intended for the treatment of malignant brain tumors, to complete a Phase 3 clinical trial 5, 16, 17 Brand names: *Gendicine®; †Cerepro®; ‡Glybera; §Strimvelis®; ¶Kymriah®; #Yescarta®; **Luxturna™; ††Zynteglo™.

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