Three Decades of Clinical Gene Therapy: From Experimental Technologies to Viable Treatments

Main Text

Genetic modifications and corrections are effective treatments for inherited human diseases; gene therapies offer durable and possibly curative clinical benefit following a single treatment. Although the transition from the lab to the clinic has been long and arduous, multiple gene therapies have now achieved regulatory approval and are considered viable treatments in multiple fields of medicine. This special issue of Molecular Therapy on the topic of clinical gene therapy reviews the critical discoveries that led to the development of successful gene therapies for both genetic disorders and cancers, provides critical commentaries on issues that remain to be solved, and publishes original research papers that illustrate the current state of patient treatment.

Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million patients in the US alone. Although the few drug-based treatments approved for these diseases may manage or improve symptoms, they do not correct the underlying genetic causes. Hematopoietic stem cell transplantation (HSCT) had been the best strategy to resolve inherited disorders until the advent of integrating vectors portended a new age. The possibility to achieve genetic correction of autologous hematopoietic stem and progenitor cells (HSPCs) by integration of a functional copy of the mutated gene allows permanent correction of genetic disorders and eliminates the need for treatments involving allogenic HSCT. The success of preclinical studies rapidly led to the clinical application of gamma retroviral vector-based autologous HSCT gene therapy (HSCT-GT) for the correction of primary immunodeficiency, but it revealed at the same time the potential limitations of the approach due to insertional mutagenesis. In this context, the introduction of lentiviral vectors improved both the efficacy and safety of autologous ex vivo HSCT-GT, allowing a higher level of transduction accompanied by a safer integration profile, thus expanding application to correction of several inherited metabolic disorders. Gene editing strategies will further improve the outstanding results achieved so far by autologous HSCT-GT approaches by preserving physiological gene regulation and potentially avoiding the issue of insertional mutagenesis. In this issue of Molecular Therapy, Tucci et al.¹ review clinical applications of reinfusion of ex vivo gene-modified/corrected HSPCs for primary immunodeficiencies, hemoglobinopathies, and lysosomal storage disorders from the early trails to registration of advanced medicinal products and highlight current challenges. Sharma et al.² review gene correction using the CRISPR-Cas9 system.

Another therapeutic approach for genetic diseases employs direct delivery of therapeutic gene(s) to relevant cells or tissues (in vivo gene therapy). Adeno-associated virus (AAV) vectors are among the most promising in vivo gene therapy vectors due to their low immunogenicity compared to other virus-based vectors (e.g., adenovirus) in humans. Mendell et al.³ review current clinical applications of in vivo gene therapy using AAV vectors for different types of genetic disorder. They further discuss the potential issue of toxicity in some patients following delivery of high doses of AAV. Maguire et al.⁴ review clinical outcomes in patients with retinal dystrophy using US Food and Drug Administration (FDA)-approved Luxturna (AAV2 expressing human RPE65) and discuss how Luxturna studies led to additional gene therapy-based treatments for retinal diseases. Antisense oligonucleotides (ASOs) can specifically silence mutated gene(s) and/or affected downstream gene(s) at the transcriptional level, and Scharner and Aznarez⁵ and Herkt and Thum⁶ review applications of ASOs to a wide range of diseases as well as current clinical development.

In the field of cancer, immunotherapy has led to remarkable achievements with the induction of durable clinical responses in tumors traditionally associated with poor outcomes. In particular, blockade of T cell inhibitory checkpoint molecules can unleash anti-tumor T cell activity and lead to long-term clinical responses. However, the benefit of immune checkpoint therapies remains limited to a subset of patients.

Three distinct steps must be achieved to mount effective anti-tumor immunity. To initiate immunity, antigen-presenting cells (e.g., dendritic cells) must sample tumor antigens, which can be ingested in situ or delivered exogenously as a therapeutic cancer vaccine. Shemesh et al.⁷ review current strategies of tumor vaccination that aim to elicit new or strengthen existing CD8⁺ cytotoxic T cell lymphocyte responses using different platforms. Upon antigen encounter, dendritic cells must receive a suitable activation signal, allowing them to differentiate extensively to promote immunity as opposed to tolerance. In addition to modulation of splicing and target knockdown for genetic disorders, ASOs can also be employed to stimulate dendritic cells as vaccine adjuvants, and Scharner and Aznarez⁵ and Herkt and Thum⁶ also review the use of ASOs as boosters for anti-tumor and anti-viral responses to co-administered vaccines. Finally, genetically modified viruses (oncolytic viruses [OVs]) specifically or preferentially replicate in and lyse cancer cells (thereby spreading cancer antigens), and the host recognizes virus infection through pattern-recognition receptors to stimulate an immune response (adjuvant effect). OVs thus represent an ideal therapeutic platform because OVs can be additionally modified to express additional immunostimulatory molecules, such as cytokines. Watanabe et al.⁸ review clinically tested OVs and how investigators in the field have improved OVs and combined them with other regimens (e.g., immune checkpoint inhibitors) to enhance host anti-tumor immunity.

Although these approaches significantly enhance the development of anti-tumor immunity and improve outcomes, presentation of tumor antigen on major histocompatibility complex (MHC) is required for cancer cell recognition and elimination by endogenous T cells. However, persistent cancers often downregulate MHC to overcome naturally occurring immune responses. One method to overcome cancer cell escape is the use of T cells genetically engineered to express chimeric antigen receptors (CARs) that recognize cancer cells independent of MHC. CAR T cells have had resounding clinical success against certain lymphoid malignancies. Leick et al.⁹ discuss the recent results of FDA-approved CAR T cells for aggressive B cell lymphomas. While CAR T cells have had remarkable success in patients with hematologic malignancies, effective CAR T cell therapy for solid tumors has required that strategies overcome tumor-defense mechanisms, such as immunosuppression, antigen escape, and physical barriers to entry. Watanabe et al.⁸ discuss how investigators modify CAR T cells and/or combine other regimens (e.g., radiotherapy) to enhance anti-tumor activity for solid tumors. In addition, Sharma et al.² review strategies using CRISPR-Cas9 technology to develop and advance T cell therapy products.

In the last three decades, extensive research and new technologies contributed to the emergence of gene therapy as a promising platform to treat many human diseases, resulting in remarkable successes and treatment options for diseases that were previously thought untreatable. Nonetheless, several challenges remain, including understanding and preventing genotoxicity from integrating vectors, improving gene transfer, preventing immune responses that limit the therapeutic efficacy of systemically administered vectors, and overcoming manufacturing and regulatory hurdles. The ability of gene therapies to provide durable benefits to human health, exemplified by clinical successes over the past several years, justifies increasing efforts toward making these products the new standard for human disease.