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There are two main gene therapy approaches, namely ex vivo and in vivo. In ex vivo gene therapy live cells are taken from a patient and treated in the laboratory to carry the new transgene (transduced cells). Transduced cells can then be finally re-introduced into the patient. Once in the patient, the treated cells are expected to form part of the same tissue the sample was originally taken from. Although this technique showed high success in recent applications, it has some limitations. Often the tissue affected is made of cells unable to survive outside the body or the engraftment of treated cells is not efficient enough to compensate for the rest of mutated cells present in that tissue.
In this scenario, in vivo gene therapy is used instead. This technique is based on the delivery of the healthy gene directly into the affected tissue of the patient (e.g. direct injection in the muscles, nervous system etc.). Since a DNA sequence injected in vivo is not efficient in entering the cells, modified viruses known as viral vectors are used to carry the transgene directly into the patient cells. Viruses are considered machines highly specialized in the penetration of the cell and the introduction of DNA sequences into the host cell. Viral vectors used in gene therapy retain the property of introducing DNA sequences into the cells but are unable to replicate and cause damage to the body since the viral DNA sequence is removed and replaced with the transgene. Viral vectors are therefore used as efficient carriers for the transgene. Depending on the kind of viral vector used, disadvantages such as strong immune response by the organism towards the viral vector can be present. To overcome these drawbacks non-viral methods for transgene delivery have been developed but they are often characterized by a limited efficiency in the delivery of the transgene into cells, therefore the vast majority of gene therapy protocols under current development are based on the use of viral vectors.
An important issue to consider when designing gene therapy vectors is the fate of the transgene once delivered into the patient cells. Since the transgene is unable to replicate, cells that replicate will eventually lose the transgene. In order to have a stable transgene maintenance in the transduced cells, two approaches can be utilized, namely vector integration into the cell chromosomes and extrachromosomal maintenance. In the first approach, integrating viral vectors (such as retroviruses and lentiviruses) insert their vector DNA sequence and, thus, the transgene into the host cell DNA material (genome). As a result, the transgene has become part of the patient cell genome and will be replicated at each cell division and kept indefinitely in the transduced cell. In spite of being an efficient way of retaining the transgene, integrating viral vectors could insert the transgene in the wrong site of the genome, thus disrupting other genes and causing cell transformation (tumour). Extrachromosomal vector maintenance describes instead the presence of the transgene as a DNA sequence physically independent from the patient cell genome but still capable of replication. When the transduced cell replicates, the extrachromosomal transgene will replicate too and persist in the cell, providing the protein missing in the affected patient tissue. This approach overcomes the risks associated with integrating vectors but allows at the same time transgene retention in the transduced cell over time.
Different gene therapy approaches designed for Friedreich’s ataxia are currently being tested in cells and animal models of Friedreich’s ataxia (animals showing the characteristic symptoms of Friedreich’s ataxia). One study using integrating vectors carrying the healthy Frataxin transgene, showed the Frataxin gene could be efficiently delivered to cells by the viral vectors, however these vectors showed toxicity probably due to unregulated high production of frataxin. Vectors based on the non-integrating herpes simplex 1 virus proved able to induce a healthy phenotype in animal models resembling Friedreich’s ataxia. New viral vectors are being developed based on herpes simplex 1 virus which are able to provide a regulated production of the Frataxin protein, which seems essential for long term production of Frataxin.
Gene therapy offers great promise in the treatment of neurodegenerative diseases such as Friedreich’s ataxia. The possibility of permanently treating patients by introducing the healthy version of the Frataxin gene in affected tissues represents a clean and powerful approach for designing treatments for Friedreich’s ataxia. Current limitations in vector design and delivery to the affected tissues will need to be overcome but the advantages that gene therapy can offer greatly outnumber its limitations.
Dr Michele Lufino is a young research scientist working in Oxford in the Molecular Neurodegeneration and Gene Therapy Laboratory, headed by Richard Wade-Martins. Dr Lufino is currently developing vectors designed both for the study of Friedreich’s ataxia and for the development of gene therapy applications.
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The life of Marie Schlau, a German Jewish girl born in 1833 hides great unsolved mysteries: accidents, disappearances, enigmas, unknown diagnoses, disturbing murders, love, tenderness, greed, lies, death ... alternatively a different story unfolds every time and takes us closer to the present. Thus, there are two parallel stories unravelling, each in a different age and place, which surprisingly converge in a revelatory chapter.
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Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:
1) Gene Therapy for Friedreich's Ataxia research project:
The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.
2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.
The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.