Cell therapy for diverse central nervous system disorders: inherited metabolic diseases and autism

Abstract

The concept of utilizing human cells for the treatment of medical conditions is not new. In its simplest form, blood product transfusion as treatment of severe hemorrhage has been practiced since the 1800s. The advent of hematopoietic stem cell transplantation (HSCT) began with the development of bone marrow transplantation for hematological malignancies in the mid-1900s and is now the standard of care for many hematological disorders. In the past few decades, HSCT has expanded to additional sources of donor cells, a wider range of indications, and the development of novel cell products. This trajectory has sparked a rapidly growing interest in the pursuit of innovative cell therapies to treat presently incurable diseases, including neurological conditions. HSCT is currently an established therapy for certain neurologically devastating inherited metabolic diseases, in which engrafting donor cells provide lifelong enzyme replacement that prevents neurological deterioration and significantly extends the lives of affected children. Knowledge gained from the treatment of these rare conditions has led to refinement of the indications and timing of HSCT, the study of additional cellular products and techniques to address its limitations, and the investigation of cellular therapies without transplantation to treat more common neurological conditions, such as autism spectrum disorder.

Autologous, Gene-Modified Hematopoietic Stem and Progenitor Cells Repopulate the Central Nervous System with Distinct Clonal Variants

“…While additional studies are required to determine whether a subset(s) of CD34 + cells with CNS potential can be isolated, these results raise the exciting possibility that, in addition to perivascular macrophages, gene-modified microglia could also be exploited for HSPC-based gene therapies for CNS pathologies. Such an approach would have immediate implications in LSDs such as adrenoleukodystrophy or metachromatic leukodystrophy, and possibly other CNS disorders including stroke (Borlongan et al., 2011, Boy et al., 2011), multiple sclerosis (Scolding et al., 2017), and autism (Dawson et al., 2017, Sharma et al., 2013, Sun and Kurtzberg, 2018).…”

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

“…While delivery of stem cells for the treatment of neurological diseases has been achieved via both intravenous and intracerebral administration techniques, only the latter could be applicable for the treatment of POLR3-HLD. Intravenous stem cell therapy, including bone marrow transplantation or hematopoietic stem cell transplantation, has been used in treating other monogenic neurological diseases based on the notion that monocytes could migrate through the blood-brain barrier to the CNS tissue and secrete active enzyme for cellular uptake by dysfunctional host cells, as well as differentiate into microglia and/or astrocytes that could inherently provide trophic support for diseased cells or regulate inflammation (Krivit et al, 1995;Priller et al, 2001;Asheuer et al, 2004;Sun and Kurtzberg, 2018). While this approach has been used in leukodystrophies that are associated with enzyme deficiencies [e.g., globoid cell leukodystrophy or Krabbe disease (Escolar et al, 2005;Wright et al, 2017;Laule et al, 2018), adrenoleukodystrophy (Peters et al, 2004;Mahmood et al, 2007;Matsukawa et al, 2020), and metachromatic leukodystrophy (Martin et al, 2013;Musolino et al, 2014;Boucher et al, 2015;Groeschel et al, 2016)], it is not applicable for treatment of the hypomyelinating phenotype associated with POLR3-HLD as neither the POLR3 enzyme complex nor its subunits are secreted extracellularly for reuptake, and myelination would be dependent on the delivery of functional OPCs or earlier lineages.…”

The Challenge of Gene Therapy for Neurological Diseases: Strategies and Tools to Achieve Efficient Delivery to the Central Nervous System

“…Of importance, there is evidence that stem cells are not only replacing dying cells, but are also regulating inflammation and immune responses and have proneurogenic effects. 180 Numerous studies support the notion of using stem cells as a treatment for inherited diseases like LSDs, 179 HD, and also for complex diseases like AD, PD, and amyotrophic lateral sclerosis. 181,182 Further preclinical and clinical studies are needed to ensure the safety and efficacy of these treatment options.…”