Abstract:Krabbe disease, or globoid cell leukodystrophy, is a rare disorder caused by deficient galactosylceramidase activity and loss of myelin‐forming oligodendrocytes, resulting in progressive demyelination and severely impaired motor function. Disease symptoms in humans appear within 3–6 months of age (early infantile) and manifest as marked irritability, spasticity, and seizures. The disease is often fatal by the second year of life, with few effective treatment options. Herein we evaluated the therapeutic potenti… Show more
“…In a second study, a singular 4-week-old Krabbe rhesus received 4 injections of allogeneic mesenchymal stem cells targeted to the caudate nucleus [ 42 ]. There was a transient post-treatment improvement in nerve conduction and motor scores.…”
Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning
Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by si
x
months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the to
x
ic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in presymptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies.
“…In a second study, a singular 4-week-old Krabbe rhesus received 4 injections of allogeneic mesenchymal stem cells targeted to the caudate nucleus [ 42 ]. There was a transient post-treatment improvement in nerve conduction and motor scores.…”
Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning
Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by si
x
months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the to
x
ic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in presymptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies.
“…The utility of this macaque model was demonstrated by a study exploring the therapeutic potential of intracranially administered mesenchymal stem cells (MSCs) to treat early onset Krabbe disease. The treatment elicited transient improvements in coordination, ambulation, cognition, and large motor skills, providing preliminary support for further study of MSCs for the treatment of lysosomal storage diseases [ 99 ]. Fig.…”
Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.
“…A few other studies invested further therapies with MSC in KD 79‐81 . In one of these studies, the authors evaluated the potential of adipose or bone marrow‐derived MSC treatment in Twitcher neonatal pups.…”
Section: Msc As Therapeutic Agents For Lsds and Polyglutamine Diseasesmentioning
confidence: 99%
“…53 A few other studies invested further therapies with MSC in KD. [79][80][81] In one of these studies, the authors evaluated the potential of adipose or bone marrow-derived MSC treatment in Twitcher neonatal pups. Cells were administered by stereotaxic injections in the striatum and behavioural tests were performed.…”
Section: Kd May Present Clinical Advantagesmentioning
confidence: 99%
“…Finally, a group of investigators performed a single‐case study in a rhesus monkey. It was included in the severe early‐onset KD phenotype, showing similar cognitive and motor symptoms as humans, and was treated at 1 month‐old with allogeneic MSC intracranially 81 . After transplantation, the primate showed: (1) transient improvements in coordination, ambulation, cognition and large motor skills that correlated with better peripheral nerve conduction measurements; (2) more pronounced myelination on the injected vs. contralateral hemisphere in several brain regions (occipital white matter, cortical region of the brain, corpus callosum, caudate nucleus and putamen).…”
Section: Msc As Therapeutic Agents For Lsds and Polyglutamine Diseasesmentioning
Background
Mesenchymal stem cells' (MSC) therapeutic potential has been investigated for the treatment of several neurodegenerative diseases. The fact these cells can mediate a beneficial effect in different neurodegenerative contexts strengthens their competence to target diverse mechanisms. On the other hand, distinct disorders may share similar mechanisms despite having singular neuropathological characteristics.
Methods
We have previously shown that MSC can be beneficial for two disorders, one belonging to the groups of Lysosomal Storage Disorders (LSDs) – the Krabbe Disease or Globoid Cell Leukodystrophy, and the other to the family of Polyglutamine diseases (PolyQs) – the Machado‐Joseph Disease or Spinocerebellar ataxia type 3. We gave also input into disease characterization since neuropathology and MSC's effects are intrinsically associated. This review aims at describing MSC's multimode of action in these disorders while emphasizing to possible mechanistic alterations they must share due to the accumulation of cellular toxic products.
Results
Lysosomal storage disorders and PolyQs have different aetiology and associated symptoms, but both result from the accumulation of undegradable products inside neuronal cells due to inefficient clearance by the endosomal/lysosomal pathway. Moreover, numerous cellular mechanisms that become compromised latter are also shared by these two disease groups.
Conclusions
Here, we emphasize MSC's effect in improving proteostasis and autophagy cycling turnover, neuronal survival, synaptic activity and axonal transport. LSDs and PolyQs, though rare in their predominance, collectively affect many people and require our utmost dedication and efforts to get successful therapies due to their tremendous impact on patient s' lives and society.
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