In memory of Litsa Krinos (1939-2020)

This past April, researchers from St. Jude Children’s Research Hospital reported in the New England Journal of Medicine on the success of their early-stage clinical trial involving a lentiviral gene therapy for the treatment of infants with X-linked severe combined immunodeficiency (SCID-X1). SCID-X1 is a rare life-threatening genetic disorder of the innate and adaptive immune systems caused by mutations in the IL2RG gene, a cytokine receptor subunit shared by multiple cytokine receptors. This leads to a deficiency in the production of T lymphocytes and natural killer (NK) cells. Characterized by the onset of persistent and serious infections that are often fatal, most SCID-X1 patients do not live past infancy. Children must live in isolation to avoid any contact with pathogens, and because it is an X-linked recessive disease and therefore most prevalent in males, SCID-X1 is also referred to as the “bubble boy” disease.

The St. Jude study showed that of the eight newly diagnosed infants with SCID-X1 included in the Phase 1/2 clinical trial, which used a lentiviral vector to transfer IL2RG cDNA to bone marrow stem cells, all were able to clear their previous infections after treatment and all have been reported to be continuing to grow normally at a median follow-up of 16.4 months.

While long-term follow-up will be necessary to assess the durability of the immune reconstitution and persistence of the transferred gene in hematopoietic and immune cells, as well as to monitor patients for potential late effects of the busulfan conditioning used and the gene therapy itself, the efficacy and safety demonstrated in the Phase 1/2 trial are very promising and could point to a curative treatment that will allow these children to grow up and live normal lives.

This study is also exciting because it highlights a major advancement in gene therapy safety over recent years, in this case spurred by scientists who were courageous enough to push forward the development of safer vectors to overcome serious adverse events (SAEs) that were resulting from the previous generation of gene therapies developed for SCID-X1.

Early Setbacks Lead to Better Outcomes
With the recent approvals of several new gene therapies, it might be easy to forget that gene therapy has initially been considered a failure. In the case of SCID-X1, the first gene therapy clinical trials conducted in the early nineties demonstrated that gene-corrected cells could in fact effectively reconstitute immune competence, but also found that the treatment caused leukemia in several treated pediatric patients. The γ-retroviral vector used to deliver the therapeutic transgene inserted itself into a stretch of DNA in or near a tumor-promoting gene, inducing its transcriptional activation and childhood leukemia. The trials were halted when this adverse event resulting from insertional oncogenesis was discovered.

Although the adverse events were disheartening, the trials did trigger further research by scientists who firmly believed that gene therapy was a valid option to cure SCID-X1. At a time when many had written gene therapy off, these persistent researchers worked with dedication to improve the safety profile of vectors used for SCID-X1 gene therapy so that patients could fully reap the initially demonstrated benefits of the treatment – restoration of T-cell immunity – and regain their health to lead a normal life.

Nearly a decade of intensive research later, in 2010, a modified version of the above γ-retroviral vector was developed to create a self-inactivating (SIN) γ-retrovirus and used in an international study of nine SCID-X1 patients. Early immune recovery occurred quickly as in previous trials, and the vector caused significantly less clustering within proto-oncogenes and genes that had been involved in the serious adverse events of the previous trials. These safety gains were promising, and after a 48 month follow up, eight of the nine patients were alive and well – although treatment efficacy was not as expected.

Forging Ahead to Enable New Breakthroughs
Research has continued by dedicated scientists like the late Dr. Brian Sorrentino who was involved in the recent gene therapy study for SCID-X1 at St. Jude. He and other scientists throughout the world focused on developing novel insulated viral vectors designed to reduce the risk of activating host genes adjacent to the integration site, as well as self-inactivating (SIN) vectors, therefore preventing the accidental induction of oncogenes in the host genome.

This work led to the tremendously promising results of the approach implemented in the St. Jude trial, leveraging a lentiviral vector with a preconditioning course of busulfan. Busulfan is approved as a conditioning agent prior to bone marrow transplantation in patients with leukemias and other immune-related cancers. In this study, long-term replenishment of all affected lymphocyte lineages in infants with newly diagnosed SCID-X1 was demonstrated. Not only have the infant patients shown no immediate side effects from the treatment, but they are showing engraftment of crucial immune cells, including T cells, B cells and natural killer (NK) cells, indicating the gene therapy’s ability to fully restore the immune system.

A Bright Future Thanks to Scientific Tenacity
Constant innovation is rapidly expanding the spectrum of diseases that can be treated and possibly even cured by gene therapy. Oftentimes this research involves the modification of the gene delivery vehicle or the development of a novel approach to gene transfer. Those scientists that dedicate themselves to overcoming known treatment challenges, even when considered too complex, are the ones that are giving new hope to patients that had none before.

At BioAgilytix, our mission is to enable the breakthroughs of tomorrow, today. We are committed to continually enhancing our expertise and capabilities to advance your research, applying scientific ingenuity to address complex bioanalytical challenges and give your drugs the best chance to reach patients who need them. When it comes to gene therapy, we are applying some of the most innovative methods like qPCR, ddPCR, and high parameter flow cytometry in our new, state-of-the-art genomics laboratory to facilitate the advancement of your innovative treatments. I welcome you to reach out to me with questions on how BioAgilytix can support your gene therapy program.