Dexamethasone After Gene Therapy May Improve Effectiveness in Hem B

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by Marta Figueiredo PhD |

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Dexamethasone, a steroid with immunosuppressive and anti-inflammatory properties, may temporarily increase the efficacy of one-time gene therapy when given at later time points, a study in mice suggests.

Lab results showed that dexamethasone increased the levels of factor IX (FIX) — the missing clotting protein in hemophilia B — in a mouse model of the disease, when given four months after gene therapy designed to raise FIX levels. The effects were seen regardless of treatment duration.

However, a similar experiment in a dog model of hemophilia B failed to show the same effect, suggesting potential species-based differences.

Still, these findings suggest that administering short-term and intermittent dexamethasone after gene therapy may be an effective approach for improving the treatment’s efficacy — without the adverse events (side effects) associated with long-term steroid use — the researchers noted.

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The study, “Dexamethasone Transiently Enhances Transgene Expression in the Liver When Administered at Late-Phase Post Long-Term Adeno-Associated Virus Transduction,” was published in the journal Human Gene Therapy.

“Corticosteroids like dexamethasone, methylprednisolone and prednisone are frequently used in AAV-based human gene therapy protocols, but the optimal timing of such therapy has not been thoroughly studied,” Terence R. Flotte, MD, the journal’s editor-in-chief, said in a press release.

“This paper provides an interesting insight into the potential effects of short-duration steroid therapy,” Flotte added.

Gene therapy has the potential to treat diseases caused by mutations in a single gene by delivering a healthy version of that gene to a patient’s cells. This approach usually uses a modified and harmless version of an adeno-associated virus (AAV) to carry and deliver the relevant gene.

Virus-based gene therapies can only be given once, due to the body’s natural immune response against the viral carrier, which would be enhanced in subsequent exposures.

To suppress this anti-AAV immune response, which can limit the therapy’s effectiveness and cause liver damage — given that most AAVs tend to go to the liver — patients are often started on immunosuppressive treatment, typically steroids, before the gene therapy.

However, previous clinical trials showed that later treatment with prednisone, a steroid, rescued FIX production in hemophilia B patients who had reduced FIX levels at six to 10 weeks post-AAV-based gene therapy.

As such, it is possible that steroid treatment may improve gene therapy’s efficacy when given at later time points.

Now, a team of researchers at the University of North Carolina at Chapel Hill, provided evidence of just that by analyzing the effects of dexamethasone — a steroid six times more potent than prednisone — in the FIX levels of mice following AAV gene therapy.

This therapy was designed to deliver the F9 gene, which provides the instructions to produce FIX, to liver cells, the body’s main producers of clotting factors.

In healthy mice, a six-day dexamethasone treatment started two hours before gene therapy resulted in significantly higher FIX levels relative to no dexamethasone treatment.

A similar raise in FIX levels was observed when a seven-day dexamethasone treatment was given to mice only six weeks after gene therapy. Those findings suggest that dexamethasone administration at a late time point may increase the efficacy of gene therapy.

Comparable results were observed in a mouse model of hemophilia B. FIX levels were significantly increased after a six-day dexamethasone treatment that was started two hours before gene therapy, and after a one-week treatment period that began 16 weeks (about four months) after gene therapy, relative to no dexamethasone treatment.

Notably, re-administration of dexamethasone later on resulted in significantly higher FIX levels relative to those observed after the first, early treatment.

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Further experiments showed that this dexamethasone-induced FIX increase was temporary, lasting about a week after the last dose, and independent of the timing and duration of dexamethasone treatment.

The team also found that dexamethasone’s effects on FIX levels were not associated with changes in F9 gene activity or the amount of viral DNA in the mice’s liver. However, the immunosuppressive therapy was found to temporarily reduce pro-inflammatory molecules, suggesting that dexamethasone may promote an increase in FIX levels by suppressing the immune system and potential responses against the viral carrier.

Interestingly, a three-day treatment with dexamethasone at one-year post-gene therapy failed to increase FIX in a dog model of hemophilia B. Administration of a higher dose of dexamethasone 16 weeks (about four months) after the first regimen also had no impact on the dogs’ FIX levels.

This suggested that there may be some differences between species in terms of dexamethasone’s mechanisms.

Still, these findings “provided valuable information to design an effective approach for application of dexamethasone in future clinical studies with AAV vector liver targeted gene therapy, such as short term and intermittent administration of steroids,” the researchers wrote.

“This may decrease the toxicities from long term application of steroids and also avoid liver damage from high doses of AAV vector seen in clinical trials,” they added.

Future studies are needed to determine when and how long-term treatment with steroids, as well as which steroid, should be administered “to exert the best liver protection with the least complications,” the team concluded.