Gene Therapy for Genetic Syndromes: Understanding the Current State to Guide Future Care

Abstract

Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, β-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost–benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.

Navigating equity in global access to genome therapy expanding access to potentially transformative therapies and benefiting those in need requires global policy changes

“…These regulatory and ethical issues are not unique to sickle cells, but looms over potentially transformative gene therapies for clinic care. These include etranacogene dezaparvovec (Hemgenix) for the treatment of adult hemophilia B, voretigene neparvovec (Luxturna) for retinal dystrophy treatment, onasemnogene abeparvovec (Zolgensma) for pediatric spinal muscular atrophy, and tisagenlecleucel (Kymriah) for treating acute lymphoblastic leukemia (ALL), follicular lymphoma, and B-cell lymphoma, for instance ( Henderson et al, 2024 ).…”

Gait Characterization in Duchenne Muscular Dystrophy (DMD) Using a Single-Sensor Accelerometer: Classical Machine Learning and Deep Learning Approaches

“…DMD is present from birth but early detection through pilot newborn screening programs is becoming increasingly common [ 7 ]. At the same time, multiple new therapies for DMD have achieved market approval with more in the development process, providing clinicians with potential options for early intervention [ 8 ]. The availability of early diagnosis, potential therapies, and increasing emphasis on the use of community-based measures of mobility as clinical trial outcome measures and clinical monitoring tools has led to new efforts to develop unobtrusive and quantitative wearable tools for the evaluation of patients with DMD across their lifespans [ 9 , 10 , 11 ].…”