Cell and Gene Therapy for Friedreich Ataxia: Progress to Date

Evans-Galea, Marguerite V.; Pébay, Alice; Dottori, Mirella; Corben, Louise A.; Ong, Sze Hwee; Lockhart, Paul J.; Delatycki, Martin B.

doi:10.1089/hum.2013.180

Cited by 29 publications

(25 citation statements)

References 140 publications

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“…To date, gene therapy of Friedreich's ataxia has been explored with only a few types of vectors . It is important that the development and evaluation of all of these continue to be supported because different aspects of the same disease may be better treated by different vector types and delivery strategies.…”

Section: Discussionmentioning

confidence: 99%

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector

Ventosa

Lim

2017

The Journal of Gene Medicine

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Section: Discussionmentioning

confidence: 99%

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector

Ventosa

Lim

2017

The Journal of Gene Medicine

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“…Demonstration of differentiation into neurons and cardiomyocytes, arguably the two major cell populations necessary for gene- and cell-based therapy, will establish the relevance of an autologous transplantation regimen for the treatment of FRDA. As noted above, FRDA is accompanied by neurodegeneration and cardiomyopathy [3], with progressive cell death in the spinal cord, peripheral nerves, and the cerebellum associated with the early clinical symptom of gait ataxia [17,18], and heart diseases, such as hypertrophic cardiomyopathy, myocardial fibrosis, and cardiac failure, as the major underlying cause of death [19,20]. With this in mind, treatment of FRDA should be approached by abrogating both neurodegeneration and cardiomyopathy.…”

Section: Discussion Of the Hypothesismentioning

confidence: 99%

Autologous stem cell transplant with gene therapy for Friedreich ataxia

Tajiri¹,

Staples²,

Kaneko³

et al. 2014

Medical Hypotheses

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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.

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“…Gene therapy is the ultimate target for the complete treatment of both TM and FA [146,147] . However, such experimental therapies have been tried in many diseases with no optimistic outcome so far [146,147] .…”

Section: Future Prospects In the Treatment Of Thalassaemia And Friedrmentioning

confidence: 99%

“…However, such experimental therapies have been tried in many diseases with no optimistic outcome so far [146,147] . In all cases of the proposed introduction of new protocols or new treatments for FA or TM patients, a risk/benefit assessment is necessary for comparison of the existing and the new treatments.…”

Section: Future Prospects In the Treatment Of Thalassaemia And Friedrmentioning

confidence: 99%

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

Kolnagou

Kontoghiorghe

Kontoghiorghes

2014

WJM

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Author contributions: Kolnagou A reviewed the organisational health structure of thalassaemia and Friedreich ataxia in Cyprus; Kontoghiorghe CN contributed the literature background on recent developments on thalassaemia and Friedreich ataxia and critically reviewed the clinical and other aspects of the manuscript; Kontoghiorghes GJ designed, wrote and edited the manuscript including the mechanisms of iron chelation therapy and iron metabolism and toxicity. AbstractThalassaemia major (TM) and Friedreich's ataxia (FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients.Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Thalassaemia; Friedreich ataxia; Prenatal diagnosis; Survival; Chelation therapy; Deferiprone; Deferoxamine; Cyprus Core tip: Thalassaemia major (TM) and Friedreich's ataxia (FA) are inherited diseases related to iron toxicity, with high morbidity and mortality rates. Cyprus has the highest frequency of TM and FA worldwide. Prenatal diagnosis and other health policies almost abolished the birth of TM and FA patients in Cyprus. Deferiprone has increa...

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Cell and Gene Therapy for Friedreich Ataxia: Progress to Date

Cited by 29 publications

References 140 publications

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector

Autologous stem cell transplant with gene therapy for Friedreich ataxia

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

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