Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease

Abstract

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.

Mesenchymal Stromal Cells’ Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

“…In the study of Li et al ( 2018 ), the neuroprotective action of MSC was linked with the upregulation of the insulin-like growth factor 1/heat shock protein 70 (IGF-1/HSP70) pathway. In our study, we demonstrated that MSC protected GABAergic and Glutamatergic neurons, as by proton magnetic resonance spectroscopy (1H-MRS) we detected an increased expression of Gaba and the complex Glutamine-Glutamate upon a treatment, along with increased levels of mRNA for the receptors Gabrb2 and Grm1 in the cerebellum, denoting a higher synaptic activity (Oliveira Miranda et al, 2018 ).…”

“…However, the regression of some patients to the status before the treatment was reported (Dongmei et al, 2011 ; Jin et al, 2013 ; Miao et al, 2015 ; Tsai et al, 2017 ; summarized in Table 2 ). This was also following the need for performing several treatments suggested by some of the pre-clinical studies (Chang et al, 2011 ; Li et al, 2018 ; Oliveira Miranda et al, 2018 ). Nonetheless, in the clinical context, periodic MSC injections may not be feasible as they could lead to unwanted side effects.…”

“…Consistently with these results, no adverse effects were reported so far in any of the pre-clinical studies. Moreover, in our study, we assessed for the levels of hepatic aminotransferases, which were not increased when compared to non-treated or WT mice, denoting the absence of liver toxicity in mice treated repeatedly with MSC (Oliveira Miranda et al, 2018 ).…”

“…Our group has recently demonstrated that mouse BM-MSC transplantation can ameliorate both phenotypical and neuropathological MJD symptoms in Machado–Joseph disease (MJD)/SCA3 (Oliveira Miranda et al, 2018 ). In agreement with the previous study, our investigation showed that the administration of several consecutive IV injections of BM-MSC sustainably ameliorated motor impairments, when delivered post-symptomatically.…”

“…In our study, we demonstrated that after ICV transplantation, despite cells surviving up to 8 weeks after transplantation, the SPION-labeled MSC signal was drastically reduced from 1 to 8 weeks in vivo . Moreover, BM-MSC delivered IV was detected in the brain of mice 30 min after transplantation, but completely disappeared from circulation before completion of 7 days (Oliveira Miranda et al, 2018 ). Similarly, other studies in HD animal models also observed that MSC remained only for a short time in the lesion site (Snyder et al, 2010 ), or in other cases, although the authors could detect cells in the brain, only a small percentage of the implanted cells could survive (Lee et al, 2009 ; Im et al, 2010 ; Snyder et al, 2010 ; Lin et al, 2011 ; Yu-Taeger et al, 2019 ).…”