Viral gene therapy (scientific)

By: Eunice Lozada-Delgado

Gene therapy is a promising technique that is being studied to treat different diseases related to gene mutations. Some diseases such as muscular dystrophy or cancers are caused by gene mutations, thus the most effective way of treating them would be by correcting said mutations. Gene therapy focuses on the delivery of a specific gene(s) to targeted cells with a mutation or loss of this gene so that the gene product can be restored. Furthermore, since direct insertion of genes to a cell generally does not function, a carrier for this gene should be used. Carriers being studied today are viral vectors. Viral vectors because viruses are known to infect target cells and insert their genomic information into the host cell successfully. Therefore, viral vectors are currently being genetically engineered to carry the desired gene without causing disease.

There are different viruses being used in studies as viral vectors. Most are of retroviruses and adenoviruses but also adeno-associated viruses, herpes viruses, lentiviruses, among others also being studied for gene delivery. The difference between all of them lies in: whether they alter the target cells genetic material temporarily or permanently, how well they transfer the genes, and how they infect their target cell (genetherapynet.com). Some examples of related recent studies and their possible applications are going to be briefly discussed next.   

First, in a study by Lostal et al. they were trying to use an Adeno-associated viral vector (AAV-vector) to carry the dystrophin gene into Duchene muscular dystrophy (DMD) mice (Lostal et al., 2014). The problem they found was that this carrier viral vector has small packaging capacity of carrying  up to 5kb while the dystrophin cDNA is >11kb. Therefore, they engineered various sets of what they call tri-AAV vectors, where they split the dystrophin cDNA into three pieces independently packed into three recombinant AAV- vectors.  Then they tested their efficacy of insertion and expression of the full dystrophin gene after injecting DMD mice with all three vectors together. They found that even with low reconstitution efficiency, expression of the full dystrophin gene was found in the muscle tissue. In essence, they were able to successfully express a split recombinant gene carried by AAV-vectors into DMD mice. This also brings light into the possible use of the delivery of large genes using tri-AAV-vectors. Now, further studies have to be made to optimize these findings as well as evaluate disease progression.

A similar study in DMD follows in a video: 
https://www.youtube.com/watch?v=S7gFK6w_3Q0

Furthermore, another study by Tardieu et al. focuses on a Phase I/II trial of Mucopolysaccharidiosis type IIIA  patients using Adeno-associated viral vector (AAV-vector) (Tardieu et al., 2014). Mucopolysaccharidiosis type IIIA is a degenerative disease caused by a mutation on the gene encoding the N-sulfoglycosamine sulfohydrolase (SGSH) which is activated by a sulfatase-modifying factor (SUMF1). In this study they chose 3 patients of 5.5-6 years old and one of 2 years and 8 months old. These patients received intracranial injection of AAV-vector encoding both human SGHS and SUMF1 cDNAs together with immunosuppressive treatment for better response, and where followed up for 1 year. At this point they already have data of the use of this vector in mice and dogs, thus now are going to this phase I/II trial in humans. After injection, they were evaluating if these patients had any immunological response, secondary effects as well as cognitive benefits due to the treatment. What they found was that the treatment was relatively safe for that year, the largest symptoms in the patients where diarrhea that was able to be controlled. In terms of the cognitive benefits they were most observed in the youngest patient that didn’t have brain atrophy as the other three older patients before treatment. They conclude that in this first clinical trial they observed some improvement together with safety which could lead to further clinical trials with increased vector dosage and additional injection sites to test.

In summary, in this entry we have discussed various recent studies in human viral gene therapy being used for the treatment of diseases as Duchene muscular dystrophy and Mucopolysaccharidiosis type IIIA. As demonstrated, these studies are currently being done not only at the animal model level but also some have made it to human clinical trials. Even though great advances have been made recently, more research is needed to optimize these promising efforts to be able to efficiently and safely treat mutation based diseases with these viral gene vectors.

References used:

LOSTAL, W.  et al. Full-length dystrophin reconstitution with adeno-associated viral vectors. Hum Gene Ther, v. 25, n. 6, p. 552-62, Jun 2014. ISSN 1557-7422. Disponível em: < http://www.ncbi.nlm.nih.gov/pubmed/24580018 >.

TARDIEU, M.  et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum Gene Ther, v. 25, n. 6, p. 506-16, Jun 2014. ISSN 1557-7422. Disponível em: < http://www.ncbi.nlm.nih.gov/pubmed/24524415 >.

Viral vectors information, recovered 3/29/15 <http://www.genetherapynet.com/viral-vectors.html>