Match!

Gene therapy comes of age

Published on Jan 12, 2018in Science41.037
· DOI :10.1126/science.aan4672
Cynthia E. Dunbar64
Estimated H-index: 64
,
A HighKatherine73
Estimated H-index: 73
+ 3 AuthorsMichel Sadelain76
Estimated H-index: 76
(MSK: Memorial Sloan Kettering Cancer Center)
Sources
Abstract
BACKGROUND Nearly five decades ago, visionary scientists hypothesized that genetic modification by exogenous DNA might be an effective treatment for inherited human diseases. This “gene therapy” strategy offered the theoretical advantage that a durable and possibly 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 bringing new treatment options to multiple fields of medicine. We review critical discoveries leading to the development of successful gene therapies, 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 delivery vectors such as replication-defective retro viruses and adeno-associated virus (AAV), coupled with encouraging results in preclinical disease models, led to the initiation of clinical trials in the early 1990s. Unfortunately, these early trials exposed serious therapy-related toxicities, 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 vectors 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 hematopoietic stem cells, leading to clinical benefit in patients with immunodeficiencies, hemoglobinopathies, and metabolic and storage disorders. T cells engineered to express CD19-specific chimeric 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 improvement 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)–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 technologies 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.” Genome editing can be performed on cells ex vivo or the editing machinery can be delivered in vivo to effect in situ genome editing. Translation of these technologies to patient care is in its infancy in comparison to viral gene addition therapies, but multiple clinical genome editing trials are expected to open over the next decade. OUTLOOK Building on decades of scientific, clinical, and manufacturing advances, gene therapies 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, including understanding and preventing genotoxicity from integrating vectors or off-target genome editing, improving gene transfer or editing efficiency 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. Importantly, 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 companies 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 clinical successes over the past several years, justifies continued optimism and increasing efforts toward making these therapies part of our standard treatment armamentarium for human disease.
Figures & Tables
  • References (150)
  • Citations (159)
📖 Papers frequently viewed together
201341.04Science
40 Authors (Alessandro Aiuti, ..., Luigi Naldini)
612 Citations
201341.04Science
37 Authors (Alessandra Biffi, ..., Luigi Naldini)
657 Citations
170 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References150
Newest
#1Savita RangarajanH-Index: 20
#2L WalshH-Index: 1
Last. K. J. PasiH-Index: 11
view all 11 authors...
BackgroundPatients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. MethodsWe infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain–deleted huma...
125 CitationsSource
#1Lindsey A. George (UPenn: University of Pennsylvania)H-Index: 8
#2Spencer K. SullivanH-Index: 12
Last. A HighKatherineH-Index: 73
view all 28 authors...
BackgroundThe prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. MethodsWe infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men...
129 CitationsSource
BackgroundSpinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. MethodsFifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA enc...
293 CitationsSource
#1Florian Eichler (Harvard University)H-Index: 27
#2Christine Duncan (Harvard University)H-Index: 18
Last. David A. Williams (Harvard University)H-Index: 96
view all 25 authors...
BackgroundIn X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. MethodsWe enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2–3 safety and efficacy study. Patients were required to h...
96 CitationsSource
#1Nicole M. GaudelliH-Index: 6
#2Alexis C. KomorH-Index: 13
Last. David R. LiuH-Index: 73
view all 7 authors...
A new DNA ‘base editor’ can change targeted A•T base pairs to G•C, allowing disease-associated mutations to be corrected and disease-suppressing mutations to be introduced into cells.
457 CitationsSource
#1Janice S. ChenH-Index: 8
#2Yavuz S. DagdasH-Index: 6
Last. Jennifer A. DoudnaH-Index: 98
view all 10 authors...
A new engineered version of SpCas9, called HypaCas9, displays enhanced accuracy of editing without significant loss of efficiency at the desired target.
229 CitationsSource
#1Stephen R. Russell (UI: University of Iowa)H-Index: 35
#2Jean Bennett (UPenn: University of Pennsylvania)H-Index: 61
Last. Albert M. Maguire (UPenn: University of Pennsylvania)H-Index: 53
view all 36 authors...
Summary Background Phase 1 studies have shown potential benefit of gene replacement in RPE65 -mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. Methods In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or wors...
211 CitationsSource
#1Kevin Talbot (John Radcliffe Hospital)H-Index: 57
#2E F TizzanoH-Index: 1
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expres...
34 CitationsSource
#1Michel SadelainH-Index: 76
#2Isabelle RiviereH-Index: 19
Last. Stanley R. RiddellH-Index: 85
view all 3 authors...
The use of genetically engineered T cells in the treatment of cancer is reviewed, with particular focus on anti-CD19 chimaeric antigen receptor therapy, providing a summary of past progress and current status, and potential future directions.
165 CitationsSource
#1Isabelle Riviere (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 28
#2Michel Sadelain (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 76
Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T lymphocytes to target chosen antigens. The targeting of CD19, a cell surface molecule expressed in the vast majority of leukemias and lymphomas, has been successfully translated in the clinic, earning CAR therapy a special distinction in the selection of "cancer immunotherapy" by Science as the breakthrough of the year in 2013. CD19 CAR therapy is predicated on advances in genetic engineering, T cell biology, tumor immuno...
32 CitationsSource
Cited By159
Newest
Last. Robert A. HoltH-Index: 78
view all 5 authors...
Anti-CD19 CAR-T therapy for B cell malignancies has shown clinical success, but a major limitation is the logistical complexity and high cost of manufacturing autologous cell products. Direct infusion of viral gene transfer vectors to initiate in vivo CAR-T transduction, expansion and anti-tumor activity could provide an alternative, universal approach for CAR-T and related immune effector cell therapies that circumvents ex vivo cell manufacturing. To explore the potential of this approach we fi...
Source
Abstract The industrial revolution that began in the late 1800’s has resulted in dramatic changes in the environment, human lifestyle, dietary habits, social structure, and so on. Almost certainly because this rapid evolution has outpaced the ability of the body to adapt to a number of environmental and behavioral changes, there has been a parallel emergence of several chronic inflammatory diseases, among which are inflammatory bowel diseases (IBD), primarily ulcerative colitis and Crohn’s disea...
Source
Photo-triggered release of biopharmaceutical drugs inside the cells is a challenging direction of modern science, which requires obtaining new polymeric systems. The interpolyelectrolyte complexes (IPECs) of poly-l-lysine with heparin capable of encapsulation of genetic constructions—such as model oligonucleotide, siRNA, and pDNA—were obtained. Poly-l-lysine to heparin ratios were optimized to provide the appropriate release kinetics of genetic material from the polyplex. In order to impart the ...
Source
#1Le-Le MaH-Index: 1
#2Ming-Xuan LiuH-Index: 1
Last. Lan HeH-Index: 14
view all 7 authors...
With the aim to develop a novel multifunctional gene delivery system that may overcome the common barriers of gene transfection, the near-infrared fluorescent triphenylamine-pyrazine was modified with DNA condensing moieties triazole-[12]aneN3 through the different length alkyl ester linkage to afford three new non-viral gene vectors, TDM-A/B/C. All compounds showed prominent solvatochromic fluorescent (stocks shift up to 383 nm), two-photon absorption properties (101 GM), and exhibited strong ag...
Source
#1Jason N. Belling (UCLA: University of California, Los Angeles)H-Index: 2
#2Liv K. Heidenreich (UCLA: University of California, Los Angeles)H-Index: 1
Last. Jae Hyeon Park (UCLA: University of California, Los Angeles)H-Index: 9
view all 19 authors...
Advances in gene editing are leading to new medical interventions where patients’ own cells are used for stem cell therapies and immunotherapies. One of the key limitations to translating these treatments to the clinic is the need for scalable technologies for engineering cells efficiently and safely. Toward this goal, microfluidic strategies to induce membrane pores and permeability have emerged as promising techniques to deliver biomolecular cargo into cells. As these technologies continue to ...
Source
#1Cui-Cui Ma (Sichuan University)H-Index: 5
#2Zhen-Ling Wang (Sichuan University)H-Index: 1
Last. WEIYuquan (Sichuan University)H-Index: 54
view all 5 authors...
Abstract With the improvement of gene vectors, the rise of chimeric antigen receptor T cell immunotherapy and breakthroughs in the genome editing technology, gene therapy had once again returned to the central stage of disease treatment. It had brought new choices to clinical therapy of diseases such as tumors and genetic diseases, and had changed the status quo of treatment for monogenic disorders and diffuse large B-cell lymphoma. Until August 2019, 22 gene medicines had been approved by the d...
3 CitationsSource
Source
A library of 83 structurally diverse cationic amino liposomes are rationally designed and parallelly synthesized for transfection of of plasmid DNA and siRNA. Our designed- and self-assembled- liposomes not only exhibit excellent transfection efficiency in HEK 293T cells and mouse embryonic stem cells, but also show low cytotoxicity.
Source
#1Mohammad-Masoud Zavvarian (U of T: University of Toronto)H-Index: 1
#2Amirali Toossi (UHN: University Health Network)
Last. Michael G. FehlingsH-Index: 96
view all 5 authors...
Spinal cord injury (SCI) leads to chronic and multifaceted disability, which severely impacts the physical and mental health as well as the socio-economic status of affected individuals. Permanent disabilities following SCI result from the failure of injured neurons to regenerate and rebuild functional connections with their original targets. Inhibitory factors present in the SCI microenvironment and the poor intrinsic regenerative capacity of adult spinal cord neurons are obstacles for regenera...
Source
#1Rajesh Yadav (AIIMS: All India Institute of Medical Sciences)H-Index: 2
#2Asgar Ali (AIIMS: All India Institute of Medical Sciences)H-Index: 16
Last. Sadhana Sharma (AIIMS: All India Institute of Medical Sciences)H-Index: 2
view all 9 authors...
Abstract The genetically engineered Chimeric Antigen Receptor bearing T-cell (CAR T cell) therapy has been emerged as the new paradigm of cancer immunotherapy. However, recent studies have reported an increase in the number of relapsed haematological malignancies. This review provides newer insights into how the efficacy of CAR T cells might be increased by the application of new genome editing technologies, monitoring the complexity of tumor types and T cells sub-types. Next, tumor mutation bur...
Source