Contents

#### **Preface XI**


and Shuji Terai

Chapter 2 **Gene Therapy for Cystic Fibrosis: Hurdles to Overcome for Successful Clinical Translation 21**

Myriam Sainz-Ramos, Nuseibah AL Qtaish, Idoia Gallego, Ilia Villate-Beitia, Tania López, Gustavo Puras and José Luis Pedraz

Chapter 3 **Mechanisms for Controlling HIV-1 Infection: A Gene Therapy Approach 41**

> Katherine Ognenovska, Vera Klemm, Scott Ledger, Stuart Turville, Geoff Symonds, Anthony D. Kelleher and Chantelle L. Ahlenstiel


Preface

modified *ex vivo.*

indications including infections and diabetes.

coming a treatment modality in the next 5-10 years.

Gene therapy constitutes a unique class of advanced biological therapy, which works by transferring genetic materials with the aim of regulating, repairing, replacing, adding, or de‐ leting a genetic sequence of interest. This class encompasses nucleic acids transferred using non-viral systems, recombinant viruses that were modified to express a therapeutic gene of interest, genome editing interventions, and genetically engineered human cells that were

Over the past decades, gene therapy has seen a massive transformation from a proof-of-con‐ cept approach to a clinical reality culminating in the regulatory approval of state-of-the-art products in the European Union and in the United States. These included *in vivo* gene thera‐ py approaches based on recombinant adeno-associated viruses for the treatment of rare in‐ herited genetic disorders such as: lipoprotein lipase deficiency (Glybera®, a replicationdeficient adeno-associated virus serotype 1 (AAV1) expressing S447X variant of human lipoprotein lipase (LPL) gene) and retinal dystrophies caused by mutations in the retinal pigment epithelium-specific 65 KDa (RPE65) gene (Luxturna®, a replication-deficient AAV2 expressing human RPE65 gene). Cancer gene therapy has also dominated the scene, with the approval of cutting-edge gene therapy products. These include the first oncolytic virothera‐ py for melanoma based on attenuated non-integrating Herpes Simplex Virus-1 (HSV-1) modified not only to efficiently replicate within tumors, but also to express the immune stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF). Non-sol‐ id tumors, notably B-cell acute lymphoblastic leukaemia (ALL), diffuse large B-cell lympho‐ ma (DLBCL), and primary mediastinal large B-cell lymphoma (PMBCL) have also seen progress in their therapeutic management with the approval of a new generation of *ex vivo* autologous genetically modified T-cell based cancer immunotherapies (Kymriah® and Yes‐ carta®, autologous T-cells genetically engineered with a lentiviral vector (used during Kym‐ riah® manufacturing)/retroviral vector (used during Yescarta® manufacturing) to express anti-CD19 chimeric antigen receptor (CAR)). The clinical and marketing authorization suc‐ cesses of these gene/genetically modified cell-based technologies in cancer and rare genetic diseases have now opened up the pathway for gene therapy application in other new target

Gene therapy is continuously shaping and revolutionizing the field of medicine, with more cutting-edge therapies including genome editing-based medicines entering the clinic and be‐

