RESEARCH
`
`REVIEW SUMMARY ◥
`
`MEDICINE
`
`Gene therapy comes of age
`
`Cynthia E. Dunbar,* Katherine A. High, J. Keith Joung, Donald B. Kohn,
`Keiya Ozawa, Michel Sadelain*
`
`BACKGROUND: Nearly five decades ago, vi-
`sionary scientists hypothesized that genetic
`modification by exogenous DNA might be an
`effective treatment for inherited human dis-
`eases. This “gene therapy” strategy offered the
`theoretical advantage that a durable and pos-
`sibly curative clinical benefit would be achieved
`by a single treatment. Although the journey
`from concept to clinical application has been
`long and tortuous, gene therapy is now bring-
`ing new treatment options to multiple fields of
`medicine. We review critical discoveries lead-
`ing to the development of successful gene ther-
`apies, focusing on direct in vivo administration
`of viral vectors, adoptive transfer of genetically
`engineered T cells or hematopoietic stem cells,
`and emerging genome editing technologies.
`
`ADVANCES: The development of gene deliv-
`ery vectors such as replication-defective retro
`viruses and adeno-associated virus (AAV), cou-
`pled with encouraging results in preclinical dis-
`ease models, led to the initiation of clinical trials
`in the early 1990s. Unfortunately, these early
`trials exposed serious therapy-related toxic-
`ities, including inflammatory responses to the
`
`vectors and malignancies caused by vector-
`mediated insertional activation of proto-
`oncogenes. These setbacks fueled more basic
`research in virology, immunology, cell biology,
`model development, and target disease, which
`ultimately led to successful clinical translation
`of gene therapies in the 2000s. Lentiviral vec-
`tors improved efficiency of gene transfer to
`nondividing cells. In early-phase clinical trials,
`these safer and more efficient vectors were
`used for transduction of autologous hemato-
`poietic stem cells, leading to clinical benefit in
`patients with immunodeficiencies, hemoglobi-
`nopathies, and metabolic and storage disorders.
`T cells engineered to express CD19-specific chi-
`meric antigen receptors were shown to have
`potent antitumor activity in patients with
`lymphoid malignancies. In vivo delivery of
`therapeutic AAV vectors to the retina, liver,
`and nervous system resulted in clinical improve-
`ment in patients with congenital blindness,
`hemophilia B, and spinal muscular atrophy,
`respectively. In the United States, Food and
`Drug Administration (FDA) approvals of the
`first gene therapy products occurred in 2017,
`including chimeric antigen receptor (CAR)–
`
`Three essential tools for human gene therapy. AAV and lentiviral vectors are the basis of
`several recently approved gene therapies. Gene editing technologies are in their translational
`and clinical infancy but are expected to play an increasing role in the field.
`
`T cells to treat B cell malignancies and AAV
`vectors for in vivo treatment of congenital
`blindness. Promising clinical trial results in
`neuromuscular diseases and hemophilia will
`likely result in additional approvals in the near
`future.
`In recent years, genome editing technolo-
`gies have been developed that are based on
`engineered or bacterial nucleases. In contrast
`to viral vectors, which can mediate only gene
`addition, genome editing approaches offer
`a precise scalpel for gene
`addition, gene ablation,
`and gene “correction.” Ge-
`nome editing can be per-
`formed on cells ex vivo or
`the editing machinery can
`be delivered in vivo to ef-
`fect in situ genome editing. Translation of
`these technologies to patient care is in its in-
`fancy in comparison to viral gene addition
`therapies, but multiple clinical genome edit-
`ing trials are expected to open over the next
`decade.
`
`ON OUR WEBSITE
`
`◥
`
`Read the full article
`at http://dx.doi.
`org/10.1126/
`science.aan4672
`..................................................
`
`OUTLOOK: Building on decades of scientific,
`clinical, and manufacturing advances, gene ther-
`apies have begun to improve the lives of patients
`with cancer and a variety of inherited genetic
`diseases. Partnerships with biotechnology and
`pharmaceutical companies with expertise in
`manufacturing and scale-up will be required
`for these therapies to have a broad impact on
`human disease. Many challenges remain, includ-
`ing understanding and preventing genotoxicity
`from integrating vectors or off-target genome
`editing, improving gene transfer or editing effi-
`ciency to levels necessary for treatment of many
`target diseases, preventing immune responses
`that limit in vivo administration of vectors or
`genome editing complexes, and overcoming
`manufacturing and regulatory hurdles. Impor-
`tantly, a societal consensus must be reached on
`the ethics of germline genome editing in light
`of rapid scientific advances that have made this
`a real, rather than hypothetical, issue. Finally,
`payers and gene therapy clinicians and com-
`panies will need to work together to design and
`test new payment models to facilitate delivery
`of expensive but potentially curative therapies
`to patients in need. The ability of gene therapies
`to provide durable benefits to human health,
`exemplified by the scientific advances and clin-
`ical successes over the past several years, just-
`ifies continued optimism and increasing efforts
`toward making these therapies part of our stan-
`dard treatment armamentarium for human
`
`disease.▪
`
`The list of author affiliations is available in the full article online.
`*Corresponding author. Email: dunbarc@nhlbi.nih.gov (C.E.D);
`m-sadelain@ski.mskcc.org (M.S.)
`Cite this article as C. E. Dunbar et al., Science 359, eaan4672
`(2018). DOI: 10.1126/science.aan4672
`
`Dunbar et al., Science 359, 175 (2018)
`
`12 January 2018
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`KELONIA EXHIBIT 1008
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`

`

`RESEARCH
`
`REVIEW ◥
`
`MEDICINE
`
`Gene therapy comes of age
`
`Cynthia E. Dunbar,1* Katherine A. High,2 J. Keith Joung,3 Donald B. Kohn,4
`Keiya Ozawa,5 Michel Sadelain6*
`
`After almost 30 years of promise tempered by setbacks, gene therapies are rapidly
`becoming a critical component of the therapeutic armamentarium for a variety of inherited
`and acquired human diseases. Gene therapies for inherited immune disorders, hemophilia,
`eye and neurodegenerative disorders, and lymphoid cancers recently progressed to
`approved drug status in the United States and Europe, or are anticipated to receive
`approval in the near future. In this Review, we discuss milestones in the development of
`gene therapies, focusing on direct in vivo administration of viral vectors and adoptive
`transfer of genetically engineered T cells or hematopoietic stem cells. We also discuss
`emerging genome editing technologies that should further advance the scope and efficacy
`of gene therapy approaches.
`
`G ene therapies are bringing new treatment
`
`options to multiple fields of medicine.
`Forty-five years ago, Theodore Friedmann
`provided a prophetic account of the poten-
`tial and challenges of using gene therapy
`to treat inherited monogenic disorders (1). Grow-
`ing interest in gene therapy was inspired by the
`recognition that—at least in principle—a single
`treatment might achieve durable, potentially cu-
`rative clinical benefit. Investigators hypothesized
`that in contrast to protein-based drugs that may
`require repeated infusion, gene-based therapies
`delivered to long-lived cells might afford sus-
`tained production of endogenous proteins, such
`as clotting factors in hemophilia (2). Long-term
`cell replacement afforded by genetically engi-
`neered hematopoietic stem cells (HSCs) may dura-
`bly alleviate a range of conditions, obviating, for
`example, the need for lifelong enzyme adminis-
`tration or transfusion therapy (3, 4). Originally
`envisioned as a treatment solely for inherited dis-
`orders, gene therapy is now being applied to
`acquired conditions, a concept best illustrated by
`genetic engineering of T cells for cancer immu-
`notherapy. Recent clinical studies have found
`that single infusions of T cells engineered with
`synthetic genes encoding a chimeric antigen re-
`ceptor can produce durable responses in a subset
`of patients (5).
`Translation of gene therapy concepts to pa-
`tient care began in the early 1990s but was plagued
`by repeated cycles of optimism followed by dis-
`appointing clinical trial results. A number of these
`early experimental therapies were found to provide
`
`1Hematology Branch, National Heart, Lung and Blood Institute,
`Bethesda, MD USA. 2Spark Therapeutics, Philadelphia, PA, USA.
`3Massachussetts General Hospital and Harvard Medical School,
`Boston, MA, USA. 4David Geffen School of Medicine, University
`of California, Los Angeles, CA, USA. 5The Institute of Medical
`Science, The University of Tokyo, Tokyo, Japan. 6Memorial
`Sloan Kettering Cancer Center, New York, NY, USA.
`*Corresponding author. Email: dunbarc@nhlbi.nih.gov (C.E.D);
`m-sadelain@ski.mskcc.org (M.S.)
`
`no clinical benefit or produce unexpected toxicities
`that in some cases led to widely publicized patient
`deaths (6). In 1996, a National Institutes of Health
`(NIH) advisory panel concluded that these dis-
`appointing clinical results were due to insuffi-
`cient knowledge of the biology of the viral vectors,
`the target cells and tissues, and the diseases. The
`panel recommended that investigators return to
`the laboratory and focus on the basic science un-
`derlying gene therapy approaches (7). Develop-
`ment of new vectors and a better understanding
`of target cells sparked a second generation of
`clinical trials in the late 1990s and early 2000s.
`These trials produced evidence of sustained ge-
`netic modification of target tissues and, in some
`instances, evidence for clinical benefit. However,
`progress was slowed by the emergence of serious
`toxicities related to high gene transfer efficiency;
`for instance: insertional genotoxicity, immune de-
`struction of genetically modified cells, and im-
`mune reactions related to administration of certain
`vectors (6, 8, 9).
`Over the past 10 years, further maturation of
`the “science” of gene therapy, safety modifications,
`and improvements in gene transfer efficiency and
`delivery have finally resulted in substantial clinical
`progress. Several gene and gene-modified cell-
`based therapies are already approved drugs, and
`over a dozen others have earned “breakthrough
`therapy” designation by regulators in the United
`States and around the world. In this Review, we
`highlight key developments in the gene therapy
`field that form the foundation for these recent
`successes and examine recent advances in targeted
`genome editing likely to transform gene therapies
`in the future.
`
`Genetic engineering from viral vectors
`to genome editing
`Recombinant, replication-defective viral vectors
`were the first molecular tool enabling efficient,
`nontoxic gene transfer into human somatic cells
`(10). Retroviruses and adeno-associated virus (AAV)
`
`have shown the most clinical promise, and we will
`limit our discussions to these vectors.
`
`Retroviral vectors
`The identification of a genome packaging signal
`(11) and the creation of a producer cell line (12)
`paved the way for design and facile production of
`vectors capable of undergoing reverse transcrip-
`tion and DNA integration but lacking replication
`potential (13, 14). The g-retroviral vectors devel-
`oped in the 1980s and early 1990s were the first
`to be shown to deliver genes into repopulat-
`ing HSCs (15–17). C-type retroviruses were also
`adapted for efficient gene transfer into primary T
`lymphocytes (18–21). These vectors were used in
`first-generation clinical trials designed to deliver
`a normal copy of a specific defective gene into
`the genome of T cells or HSCs from patients with
`immunodeficiencies or cancer [reviewed in (22)]
`(Fig. 1).
`Two other genera of the retroviruses were
`subsequently added to this armamentarium: the
`lentiviruses (23) and spumaviruses (24). In con-
`trast to g-retroviral vectors, lentiviral vectors
`enabled gene transfer into nondividing cells but
`still left quiescent G0 cells out of reach (25).
`Lentiviral vectors can carry larger and more com-
`plex gene cassettes than g-retroviral vectors and
`thus their development provided a critical ad-
`vance for hemoglobinopathies (26). Lentiviral and
`spumavirus vectors have another advantage over
`g-retroviral vectors in that they preferentially
`integrate into the coding regions of genes. The
`g-retroviral vectors, by contrast, can integrate
`into the 5′-untranslated region of genes (27), a
`feature that increases the risk of potentially on-
`cogenic insertional mutagenesis in hematopoietic
`cells (28). Lentiviral vectors are currently the
`tools of choice for most HSC applications, but
`g-retroviral vectors are still used for certain ap-
`plications in T cell engineering and HSC gene
`therapy (Table 1). Removal of endogenous strong
`enhancer elements from lentiviral and g-retroviral
`vectors using a “self-inactivating” SIN design (29)
`is another approach that decreases the risk of
`genotoxicity (30); this design is used in most cur-
`rent clinical trials (Table 1). Integrating retroviral
`vectors are reviewed in more detail in (31, 32).
`
`Adeno-associated viral (AAV) vectors
`AAV vectors are engineered from a nonpatho-
`genic, nonenveloped parvovirus that is naturally
`replication-defective. Wild-type AAV requires an-
`other virus such as an adenovirus or a herpesvirus
`to replicate (33, 34). All viral coding sequences in
`AAVs are replaced with a gene expression cassette
`of interest. One limitation of AAV vectors is that
`they cannot package more than ~5.0 kb of DNA
`(in contrast to g-retroviral or lentiviral vectors, which
`can accommodate up to 8 kb). AAV vectors are
`predominantly nonintegrating; the transferred
`DNA is stabilized as an episome. This feature less-
`ens risks related to integration but also limits
`long-term expression from AAV vectors to long-
`lived postmitotic cells.
`In the mid-1990s, two groups demonstrated
`long-term expression of a transgene following
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`in vivo muscle administration of AAV vectors to
`mice (35, 36). This seminal work led to the dem-
`onstration that AAV vectors could also efficiently
`transduce a variety of target tissues in animal
`models, including liver, retina, cardiac muscle,
`and central nervous system, with specific tissue
`tropisms discovered for several naturally occurring
`AAV serotypes and AAV engineered with opti-
`mized capsids (37). Improved manufacturing tech-
`niques [reviewed in (38)] increased both yield and
`purity of AAV vector product, allowing proof-of-
`concept studies in large-animal models of disease
`(Fig. 2). Pioneering AAV gene therapy clinical
`trials for hemophilia B were initiated in the late
`1990s, first testing delivery of AAV vectors to
`muscle via injection (39) and then moving to in-
`travenous administration, taking advantage of
`AAV2 liver tropism (40). These early trials estab-
`lished safety but were limited by insufficient
`dosing, and anti-AAV immune responses, most
`likely because many people carry neutralizing anti-
`bodies and memory T cells directed against the
`AAV capsid. The full exploitation of the therapeutic
`potential of AAV vectors, as described below, re-
`quired rigorous analysis of anti-AAV immune re-
`sponses (41), including both cellular and humoral
`responses to a range of serotypes (42).
`
`Genome editing
`In contrast to viral vectors, which can mediate
`only one type of gene modification (“gene ad-
`dition”), new genome editing technologies can
`mediate gene addition, gene ablation, “gene
`correction,” and other highly targeted genome
`modifications in cells. Genome editing can be
`performed on cells ex vivo or the editing ma-
`chinery can be delivered in vivo to effect in situ
`genome editing. A targeted DNA alteration is
`initiated by creation of a nuclease-induced double-
`stranded break (DSB), which stimulates highly
`efficient recombination in mammalian cells (43).
`
`Nonhomologous end-joining (NHEJ)–mediated
`repair results in the efficient creation of variable-
`length insertion or deletion mutations (indels) at
`the site of the DSB, which generally inactivates
`gene function. Homology-directed repair (HDR)
`can be used to create specific sequence alter-
`ations in the presence of a homologous donor
`DNA template, which following recombination
`results in correction of a mutation or insertion
`of new sequences in a site-specific manner (44).
`Early genome editing studies relied on engi-
`neering of specific zinc finger nucleases (ZFNs)
`(45) or meganucleases (46) for each individual
`DNA target site to induce the required DSBs.
`These nuclease platforms required specialized
`expertise to customize the DNA binding nucle-
`ase effector proteins for each cleavage target,
`which limited their broader use and application.
`The demonstration in 2009 that the DNA binding
`domain of bacterial proteins called transcription
`activator–like effectors (TALEs) can be readily
`altered (47, 48) opened the door to the creation
`of TALE nucleases (TALENs) (49, 50). These en-
`zymes can efficiently cleave essentially any DNA
`sequence of interest (51). However, TALEN ap-
`proaches still require design of a specific pair of
`nucleases for each new DNA target.
`The genome editing landscape changed in 2012
`with a seminal discovery by Doudna and Char-
`pentier, who showed that a bacterial defense sys-
`tem composed of clustered regularly interspaced
`short palindromic repeat (CRISPR)–CRISPR-
`associated 9 (Cas9) nucleases can be efficiently
`programmed to cleave DNA at sites of interest,
`simply by designing a specific short guide RNA
`(gRNA) complementary to the target site of in-
`terest (52). The CRISPR-Cas9 nuclease technol-
`ogy was rapidly extended to mammalian cells
`(53, 54), thereby simplifying the process of ge-
`nome editing (55). TALENs and CRISPR-Cas9
`nucleases, which can be easily reprogrammed
`
`to cleave specific target DNA sequences, are
`now widely used for a myriad of applications in
`basic research (56–58). A number of clever strat-
`egies that could eventually be applied clinically
`involve the use of RNA-guided catalytically in-
`active Cas9 (“dead Cas9” or dCas9) to turn genes
`on and off by blocking transcriptional machinery
`or recruiting epigenetic regulators (59, 60). Cor-
`rection of mutations at a single-base level via Cas9-
`based targeting of “base editors” has recently been
`reported (61, 62).
`Genome editing approaches offer a precise
`scalpel for correcting or altering the genome
`and can overcome many of the drawbacks of
`strategies that rely on viral vector–mediated
`semi-random genomic insertion. For instance,
`genotoxicity due to ectopic activation of nearby
`proto-oncogenes, knockout of tumor suppressor
`genes, or perturbation of normal splicing should
`not occur with on-target editing. In addition, the
`regulation of an introduced or corrected gene
`will be controlled by the endogenous promoter,
`resulting in more physiologic and appropriately
`regulated gene expression (63). Targeted intro-
`duction of clotting factor genes downstream of
`the highly active albumin promoter in hepato-
`cytes has shown promise in animal models (64).
`The potential of genome editing strategies to
`bypass pathology in muscular dystrophy by al-
`tering splicing of the mutated dystrophin gene
`or by directly correcting the dystrophin muta-
`tion has been demonstrated in preclinical models
`(65–67). Finally, disease due to dominant negative
`mutations, which cannot be treated by gene ad-
`dition therapy, should be amenable to gene cor-
`rection strategies.
`There are challenges in delivering all the com-
`ponents required for editing into target cells. Ge-
`nome mutation by NHEJ is simplest, requiring
`just targeted nucleases for meganuclease, ZFN,
`or TALEN techniques, or a nuclease plus gRNA
`
`Fig. 1. Historical overview of HSC gene therapy. HSCT: hematopoietic
`stem cell transplantation; HSC: Hematopoietic stem cell; SCID: severe
`combined immunodeficiency; NHP: nonhuman primate; ZFN: zinc finger
`
`nuclease; TALEN: transcription activator–like effector nuclease; CRISPR/
`Cas9: clustered regularly interspaced short palindromic repeat (CRISPR)–
`CRISPR-associated 9 (Cas9) nucleases.
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`Table 1. Clinical and product development landmarks for ex vivo gene therapies.
`
`Cell type
`
`Disease
`
`Vector/transgene
`
`Key publication(s) or
`clinicaltrials.gov no.
`
`Primary institution and/or
`company
`
`Breakthrough designation
`or product approval
`
`T cells
`
`(134, 143, 144)
`Memorial Sloan Kettering Cancer Center FDA 2014
`gRV CD19 (CD28) CAR-T
`Adult ALL*
`....................................................................................................................................................................................................................................................................................................................
`(145)
`Pediatric ALL
`LV CD19 (4-1BB) CAR-T
`University of Pennsylvania/Novartis
`FDA Oncology Advisory
`Committee recommended
`approval 2017; EMA 2016
`.............................................................................................................................................................................................................................................................
`(146)
`National Cancer Institute/Kite
`gRV CD19 (CD28) CAR-T
`.............................................................................................................................................................................................................................................................
`(74)
`Cellectis/Servier/Pfizer
`LV CD19 CAR-T, TALEN
`NCT02808442
`knockout of TCR
`and CD52
`....................................................................................................................................................................................................................................................................................................................
`(147)
`gRV CD19 (CD28) CAR-T
`Diffuse large B cell
`National Cancer Institute/Kite
`FDA 2014
`lymphoma
`NCT00924326
`.............................................................................................................................................................................................................................................................
`NCT02348216
`Multiple academic sites/Kite
`FDA 2015; EMA 2016
`gRV CD19 (CD28) CAR
`.............................................................................................................................................................................................................................................................
`(148)
`LV CD19 (4-1BB) CAR-T
`Multiple academic sites/Juno
`FDA 2016; EMA 2016
`NCT02631044
`.............................................................................................................................................................................................................................................................
`NCT02445248
`LV CD19 (4-1BB) CAR-T
`Multiple academic sites/Novartis
`FDA 2017
`....................................................................................................................................................................................................................................................................................................................
`(149)
`CLL/indolent lymphoma LV CD19 (4-1BB) CAR-T
`University of Pennsylvania/Novartis
`.............................................................................................................................................................................................................................................................
`(150)
`gRV CD19 (CD28) CAR-T
`National Cancer Institute
`....................................................................................................................................................................................................................................................................................................................
`(136)
`gRV BCMA (CD28) CAR-T
`National Cancer Institute/Kite
`Multiple myeloma
`NCT02215967
`.............................................................................................................................................................................................................................................................
`NCT03070327
`Memorial Sloan Kettering Cancer
`gRV BCMA (4-1BB) CAR T
`Center/Juno
`.............................................................................................................................................................................................................................................................
`Nanjing Legend
`LV-BCMA CAR-T
`NCT03090659
`Biotech
`....................................................................................................................................................................................................................................................................................................................
`(151)
`National Cancer Institute
`Synovial sarcoma
`gRV -NY-ESO-TCR
`.............................................................................................................................................................................................................................................................
`LV-NY-ESO-TCR
`NCT03090659
`Multiple academic sites/Adaptimmune
`FDA 2016; EMA 2016
`....................................................................................................................................................................................................................................................................................................................
`(73)
`ZFN CCR5
`University of Pennsylvania/Sangamo
`Human
`electroporation
`immunodeficiency
`virus
`............................................................................................................................................................................................................................................................................................................................................
`(120)
`HSPCs
`Hopitaux de Paris/academic centers
`FDA 2015; EMA 2016
`b-Thalassemia
`LV anti-sickling
`worldwide/Bluebird Bio
`b-hemoglobin
`NCT01745120
`NCT02151526
`NCT03207009
`.............................................................................................................................................................................................................................................................
`NCT02453477
`San Raffaele Telethon Institute of
`LV b-hemoglobin
`Gene Therapy/GlaxoSmithKline
`.............................................................................................................................................................................................................................................................
`Memorial Sloan Kettering Cancer Center
`NCT01639690
`LV b-hemoglobin
`....................................................................................................................................................................................................................................................................................................................
`(121)
`Hopitaux de Paris/US academic sites/
`LV anti-sickling
`Sickle cell anemia
`Bluebird Bio
`b-hemoglobin
`NCT02151526,
`NCT02140554
`.............................................................................................................................................................................................................................................................
`NCT02247843
`LV anti-sickling
`UCLA/California Institute of
`b-hemoglobin
`Regenerative Medicine
`....................................................................................................................................................................................................................................................................................................................
`(114)
`LV WAS
`San Raffaele Telethon Institute of
`Wiskott-Aldrich
`syndrome
`Gene Therapy/GlaxoSmithKline
`.............................................................................................................................................................................................................................................................
`(152)
`Hopital Necker-Enfants/
`LV WAS
`University College/Genethon
`....................................................................................................................................................................................................................................................................................................................
`(116)
`San Raffaele Telethon Institute of
`Adenosine deaminase
`EMA 2016 approved
`gRV ADA
`“Strimvelis”
`deficiency
`Gene Therapy/GlaxoSmithKline
`.............................................................................................................................................................................................................................................................
`University College/UCLA/
`FDA 2015
`LV ADA
`NCT02999984
`Orchard Therapeutics
`....................................................................................................................................................................................................................................................................................................................
`(115)
`Hopital Necker-Enfants/Great
`IL2Rg-deficient
`gRV SIN IL2Rg
`X-SCID
`Ormond Street
`.............................................................................................................................................................................................................................................................
`(153)
`National Institute of Allergy and
`LV IL2Rg
`Infectious Diseases
`....................................................................................................................................................................................................................................................................................................................
`(118)
`St. Vincent de Paul, Paris
`Adrenoleukodystrophy
`LV ABCD1
`.............................................................................................................................................................................................................................................................
`(119)
`LV ABCD1
`Multiple academic sites/Bluebird Bio
`....................................................................................................................................................................................................................................................................................................................
`(117, 154)
`Metachromatic
`LV ARSA
`San Raffaele Telethon Institute of
`EU Orphan Drug 2007
`leukodystrophy
`Gene Therapy/GlaxoSmithKline
`....................................................................................................................................................................................................................................................................................................................
`ZFN CCR5
`City of Hope/Sangamo
`NCT02500849
`Human
`electroporation
`Immunodeficiency
`virus
`....................................................................................................................................................................................................................................................................................................................
`
`*Abbreviations: FDA, U.S. Food and Drug Administration; EMA, European Medicines Agency; gRV, murine g-retrovirus; LV, lentivirus; ALL, acute lymphoblastic leukemia;
`CLL, chronic lymphocytic leukemia; HSPC, hematopoietic stem and progenitor cells; X-SCID, X-linked severe combined immunodeficiency; ZFN, zinc finger nuclease;
`BCMA, B cell maturation antigen; ARSA, arylsulfatase A; ABCD1, transporter gene mutated in adrenoleukodystrophy.
`
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`for CRISPR-based approaches; these components
`can be delivered by nonintegrating vi