Successes and challenges in clinical gene therapy

Abstract

Despite the ups and downs in the field over three decades, the science of gene therapy has continued to advance and provide enduring treatments for increasing number of diseases. There are active clinical trials approaching a variety of inherited and acquired disorders of different organ systems. Approaches include ex vivo modification of hematologic stem cells (HSC), T lymphocytes and other immune cells, as well as in vivo delivery of genes or gene editing reagents to the relevant target cells by either local or systemic administration. In this article, we highlight success and ongoing challenges in three areas of high activity in gene therapy: inherited blood cell diseases by targeting hematopoietic stem cells, malignant disorders using immune effector cells genetically modified with chimeric antigen receptors, and ophthalmologic, neurologic, and coagulation disorders using in vivo administration of adeno-associated virus (AAV) vectors. In recent years, there have been true cures for many of these diseases, with sustained clinical benefit that exceed those from other medical approaches. Each of these treatments faces ongoing challenges, namely their high one-time costs and the complexity of manufacturing the therapeutic agents, which are biological viruses and cell products, at pharmacologic standards of quality and consistency. New models of reimbursement are needed to make these innovative treatments widely available to patients in need.

Toward a cure – Advancing HIV/AIDs treatment modalities beyond antiretroviral therapy: A Review

“…Clinical trials are ongoing to assess the safety and effectiveness of this therapy, evaluating approaches like T cell, HSC, and immune cell gene alteration. [41] Future research could focus on refining vector design, enhancing delivery techniques, and exploring combination strategies with additional antiviral treatments or immunomodulatory drugs.…”

Reprogramming tendon healing: a guide to novel molecular tools

“…Tailoring the ncRNA-based strategies to individual patient profiles may improve the efficacy of the treatments. Moreover, even when the possibility for off-target effects is still a concern when working with ncRNAs, they offer superior specificity to the traditional gene manipulation methods ( Kohn et al, 2023 ). Additionally, they can be integrated into various biomaterials and scaffolds to achieve enhanced regeneration capacity.…”

A novel functional gene delivery platform based on a commensal human anellovirus demonstrates transduction in multiple tissue types

“…Although viruses such as herpes simplex virus 1 (Vyjuvek for the treatment of epidermolysis bullosa) [Epstein 2023] and retroviruses (chimeric antigen receptor [CAR]-T cell therapies for cancer) [Charitidis 2023] have been used and even approved for various gene therapy applications, adeno-associated virus (AAV) has been the primary vector employed for the treatment of inherited monogenic disorders [Zhao 2021], which are individually rare but collectively affect >30 million Americans [Mendell 2021]. Several AAV-based gene therapies have been approved by the U.S. Food and Drug Administration (FDA) [Kohn 2023]. AAV vectors are engineered by removing the viral protein-coding sequences and substituting the therapeutic gene of interest as a payload [Wang 2019].…”