Inspired by a patient
Abstract
More than 50 leukodystrophies have been described. This group of inherited disorders affects myelin development and/or maintenance and can manifest from birth to adulthood. Neuroinflammation is a hallmark of some leukodystrophies, explaining in part the therapeutic benefit of hematopoietic stem cell transplantation (HSCT). Indeed, in addition to supplying the CNS with myelomonocyte donor cells expressing the deficient protein or enzyme, HSCT allows the restoration of normal microglia function, which may act on neuroinflammation. In this chapter, we explore the rationale, indication, and outcome of HSCT in Cerebral Adrenoleukodystrophy (CALD), Metachromatic Leukodystrophy (MLD), Krabbe Disease (KD), and Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), which are among the most frequent leukodystrophies. For these leukodystrophies, HSCT may modify notably the natural history and improve CNS-related deficits, provided that the procedure is performed early into the disease course. In addition, we discuss the recent development of ex vivo gene therapy for CALD and MLD as a promising alternative to allograft.
Metovic J, Li Y, Gong Y, Eichler F. Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials. Neurotherapeutics. 2024 Jul;21(4):e00443. doi: 10.1016/j.neurot.2024.e00443. Epub 2024 Sep 13. PMID: 39276676; PMCID: PMC11418141.
Abstract
Leukodystrophies are progressive single gene disorders affecting the white matter of the brain. Several gene therapy trials are in progress to address the urgent unmet need for this patient population. We performed a comprehensive literature review of all gene therapy clinical trials listed in www.clinicaltrials.gov through August 2024, and the relevant preclinical studies that enabled clinical translation. Of the approximately 50 leukodystrophies described to date, only eight have existing gene therapy clinical trials: metachromatic leukodystrophy, X-linked adrenoleukodystrophy, globoid cell leukodystrophy, Canavan disease, giant axonal neuropathy, GM2 gangliosidoses, Alexander disease and Pelizaeus-Merzbacher disease. What led to the emergence of gene therapy trials for these specific disorders? What preclinical data or disease context was enabling? For each of these eight disorders, we first describe its pathophysiology and clinical presentation. We discuss the impact of gene therapy delivery route, targeted cell type, delivery modality, dosage, and timing on therapeutic efficacy. We note that use of allogeneic hematopoietic stem cell transplantation in some leukodystrophies allowed for an accelerated path to clinic even in the absence of available animal models. In other leukodystrophies, small and large animal model studies enabled clinical translation of experimental gene therapies. Human clinical trials for the leukodystrophies include ex vivo lentiviral gene delivery, in vivo AAV-mediated gene delivery, and intrathecal antisense oligonucleotide approaches. We outline adverse events associated with each modality focusing specifically on genotoxicity and immunotoxicity. We review monitoring and management of events related to insertional mutagenesis and immune responses. The data presented in this review show that gene therapy, while promising, requires systematic monitoring to account for the precarious disease biology and the adverse events associated with new technology.
Khanal P, Patil VS, Bhattacharya K, Shrivastava AK, Bhandare VV. Exploring the globoid cell leukodystrophy protein network and therapeutic interventions. Sci Rep. 2024 Aug 5;14(1):18067. doi: 10.1038/s41598-024-66437-8. PMID: 39103379; PMCID: PMC11300594.
Abstract
Globoid cell leukodystrophy is a severe rare disorder characterized by white matter degradation, resulting in a progressive loss of physical and mental abilities and has extremely limited therapeutic interventions. Therefore, this study aimed to delve into the Globoid cell leukodystrophy associated intricate network of differentially expressed genes (p < 0.05, |Fc|> 1) to identify potential druggable targets and possible therapeutic interventions using small molecules. The disease-associated neuronal protein circuit was constructed and analyzed, identifying 53 nodes (minimum edge cutoff 1), among which five (FOS, FOSB, GDNF, GFRA1, and JUN) were discerned as potential core protein nodes. Although our research enumerates the potential small molecules to target various protein nodes in the proposed disease network, we particularly underscore T-5224 to inhibit c-Jun activity as JUN was identified as one of the pivotal elements within the disease-associated neuronal protein circuit. The evaluation of T-5224 binding energy (- 11.0 kcal/mol) from docking study revealed that the compound to exhibit a notable affinity towards Jun/CRE complex. Moreover, the structural integrity of complex was affirmed through comprehensive molecular dynamics simulations, indicating a stable hydrophilic interaction between T-5224 and the Jun/CRE complex, thereby enhancing protein compactness and reducing solvent accessibility. This binding energy was further substantiated by free binding analysis, revealing a substantial thermodynamics complex state (- 448.00 ± 41.73 kJ/mol). Given that this investigation is confined to a computational framework, we additionally propose a hypothetical framework to ascertain the feasibility of inhibiting the Jun/CRE complex with T-5224 against Globoid cell leukodystrophy, employing a combination of in vitro and in vivo methodologies as a prospective avenue of this study.
Coulombe B, Chapleau A, Macintosh J, Durcan TM, Poitras C, Moursli YA, Faubert D, Pinard M, Bernard G. Towards a Treatment for Leukodystrophy Using Cell-Based Interception and Precision Medicine. Biomolecules. 2024 Jul 17;14(7):857. doi: 10.3390/biom14070857. PMID: 39062571; PMCID: PMC11274857.
Abstract
Cell-based interception and precision medicine is a novel approach aimed at improving healthcare through the early detection and treatment of diseased cells. Here, we describe our recent progress towards developing cell-based interception and precision medicine to detect, understand, and advance the development of novel therapeutic approaches through a single-cell omics and drug screening platform, as part of a multi-laboratory collaborative effort, for a group of neurodegenerative disorders named leukodystrophies. Our strategy aims at the identification of diseased cells as early as possible to intercept progression of the disease prior to severe clinical impairment and irreversible tissue damage.
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