Autologous stem cell transplant with gene therapy for Friedreich ataxia

Abstract

We advance the overarching hypothesis that stem cell therapy is a potent treatment for Friedreich’s ataxia (FRDA). Here, we discuss the feasibility of autologous transplantation in FRDA, highlighting the need for the successful isolation of the FRDA patient’s bone marrow-derived mesenchymal stem cells, followed by characterization that these cells maintain the GAA repeat expansion and the reduced FXN mRNA expression, both hallmark features of FRDA. Next, we discuss the need for assessment of the proliferative capability and pluripotency of FRDA patient’s bone marrow-derived mesenchymal stem cells. In particular, we view the need for characterizing the in vitro differentiation of bone marrow-derived mesenchymal stem cells into the two cell types primarily affected in FRDA, peripheral neurons and cardiomyocytes. Finally, we discuss the need to test the application of bone marrow-derived mesenchymal stem cells as potent autologous donor cells for FRDA. The demonstration of the functional correction of the mutated gene in these cells will be a critical endpoint of determining the potential of stem cell therapy in FRDA. We envision a gene-based cell transplant strategy as a likely therapeutic approach for FRDA, involving stable insertion of functional human bacterial artificial chromosomes or BACs containing the intact FXN gene into stem cells, thereafter leading to the expression of frataxin protein in differentiated neurons/cardiomyocytes.

Safety and Efficacy of The Stem Cell Transplantation in Friedreich’s Ataxia: A Report of Three Cases

“…The other case continues to school and her life with various self-care skills. As Tajiri et al showed in MSC transplanted patients, differentiation into peripheral neurons and cardiomyocytes with their proliferative and pluripotency properties [11], MSCs constitute the leading cause of FA's death, myocardial fibrosis, cardiac failure, and neurodegeneration [12]. This suggests MSC could be effective in slowing down these pathologies with the combination of and clinical findings.…”

CRISPR/Cas9 system in hematopoietic stem cells: Basic research and clinical applications

“…Friedreich ataxia (FRDA) caused by genetic abnormalities in the FXN gene is an autosomal recessive disorder (47). Researchers who reported that the HSPC transplantation can be used for the treatment of FRDA carried out a study based on the gene correction on CD34+ cells from a patient's peripheral blood with FRDA by using CRISPR/Cas9 system.…”

Update on the Treatment of Ataxia: Medication and Emerging Therapies

“…Stem cell therapies for neurologic disease have had suggested mechanisms that range from neural replacement to nerve growth factor enhancement to use as a delivery vehicle for other therapy [40][41][42]. A phase 1/2a open-label study of intravenous adipose-derived mesenchymal stem cell treatment in 6 patients with spinocerebellar ataxia type 3 (ClinicalTrials.gov Identifier: NCT01649687) demonstrated good safety and tolerability over 1 year with plans to conduct a larger, controlled trial in the future [43].…”