Researchers from the Children’s Hospital of Philadelphia (CHOP; PA, USA) have developed a gene therapy lentiviral vector that can achieve significantly more hemoglobin production than those currently used in trials for the treatment of blood disorders such as sickle cell disease and beta-thalassemia.

Their research was recently published in Molecular Therapy.

“These results have many potential benefits for the successful treatment of patients affected by beta-globinopathies like sickle cell disease and beta-thalassemia, including a better dose response, a minimized chance of clonal expansion and tumorigenesis, a reduced cost of therapy, and a potentially reduced need for chemotherapy or radiation before beginning gene therapy,” commented Laura Breda, a professor at CHOP and first author of the paper.

“All of us in the CuRED Frontier Program at CHOP are dedicated to finding new and improved curative therapies for blood disorders, and we look forward to taking steps to move this vector into clinical trials.”

Beta-globinopathies are disorders caused by mutations in the beta-globin gene, which is responsible for the production of hemoglobin. This essential protein is composed of globin and four iron-containing subunits, and transports oxygen throughout the body. The newly developed vector works by delivering functional copies of the beta-globin gene to correct the genetic abnormality seen in these blood disorders.

In order to achieve this, the team developed a new vector using an engineered lentivirus – the same retrovirus used to create gene therapy vectors in other trials for beta-globinopathies.

In these previous trials, the lentiviral vectors contained the human beta-globin gene along with its promoter; three hypersensitive sites that are important for gene transcription; and a condensed version of intron 2, which does not code for proteins.

Now, the team have hypothesized that including the full intron, rather than the condensed version, will enhance beta-globin – and therefore the expression of hemoglobin.

Of the five novel lentiviral vectors created, one called ALS20 was significantly more powerful than the rest – expressing up to 157% more adult hemoglobin when compared to benchmark vectors. Additionally, ALS20 viral particles did not contain any unwanted genomic RNA by-products, and mice treated with ALS20 exhibited normal physiology – implying that the novel therapy will be safe to use.

“Considering the body of evidence presented in this work, we believe that ALS20 is an outstanding candidate for the successful treatment of beta-globinopathies,” concluded senior author Stefano Rivella (CHOP). “Our vector may not only provide safer therapy with a reduced probability of genome toxicity and milder conditioning requirements, but it may also improve the efficacy and offer a competitive product for the gene therapy market.”

Link:https://www.regmednet.com/novel-lentiviral-gene-therapy-vector-improves-hemoglobin-production-in-blood-disorders/