#apaperaday: Use of plasmapheresis to lower anti-AAV antibodies in nonhuman primates with pre-existing immunity to AAVrh74

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Use of plasmapheresis to lower anti-AAV antibodies in nonhuman primates with pre-existing immunity to AAVrh74

Duchenne themed special again. Today’s pick is from Potter et al from @MolTherapy methods and clinical development on ways to allow retreatment with AAV in nonhuman primates. DOI: 10.1016/j.omtm.2024.101195

Disclosure: this work is from Sarepta and I am on their scientific advisory board. However, I was in no way involved in this study. Gene therapy for Duchenne involves adeno-associated viral vectors (AAV) and a micro-dystrophin gene code.

Because very high doses of AAV are given, it is pertinent that individuals do not already have antibodies against AAV. For them, a massive immune response to AAV after gene therapy could lead to very serious side effects and even death.

However, once injecting a patient with AAV gene therapy, they will have an immune response. As such, retreatment with AAV is currently not an option. Still, we know that micro-dystrophin levels will go down with time as micro-dystrophin is not fully functional.

The unknown is how long this will take. However, it is good to already study whether retreatment would be an option. Authors tested different approaches in nonhuman primates with AAV74-microdystrophin.

They tried to avoid monkeys from eliciting an immune response to AAV by a strong immune suppression regimen involving rituximab (anti B-cells) and sirolimus (reducing adaptive immune response) on top of steroids. Other monkey groups were only treated with steroids.

The monkeys treated with strong immune suppression showed side effects from this (a rash that did disappear). After the second dose monkeys showed a very strong immune response to the gene therapy, with weight loss, no appetite, nose bleeds. All monkeys survived.

The other monkeys were treated with plasmapheresis before retreating. Plasmapheresis involves ‘cleaning of the blood’ by removing all large proteins. In humans, plasma is replaced with donor plasma – as this is not available for monkeys, they received human albumin.

The procedure removes blood from a large vein, you get your red and white blood cells back but receive donor plasma. It takes 1-3 hours each time and multiple sessions may be needed. This is because IgG antibodies no all reside in the blood but also in tissue.

The primates receiving plasmapheresis and then the second dose of AAV did not have the severe problems the monkeys with the (failed) immune suppression experienced. I say the immune suppression failed because these monkeys did have an antibody response after the first treatment.

Interestingly, in one monkey, AAV74 treatment did not result in an antibody response after the first treatment. Also, for some monkeys, plasmapheresis was not possible as no accessible veins were present. In none of the monkeys was complement activation seen.

This is a common event for AAV9 but not for AAV74 – also not after repeated treatment in monkeys. Microdystrophin expression was seen in muscles and the heart for all treated monkeys. Authors discuss that they know so far micro-dystrophin persists in humans for at least 4 years.

An immune suppression regimen has been proposed to avoid an immune response and allow retreatment. At least in monkeys, this does not seem to be successful, likely due to the high amounts of viruses injected. The plasmapheresis approach did work in monkeys.

Authors also showed that in some monkeys with low antibody titers where plasmapheresis was not possible, redosing was possible without severe side effects. Learned at @Parent_Project meeting that Sarepta is now planning a trial for patients with preexisting immunity.

This study has not yet been initiated and is not yet registered in http://clinicaltrials.gov, but it was mentioned on a poster. Here plasmapheresis will be done for individuals who have AAV74 antibodies and then they will receive AAV micro-dystrophin gene therapy.

Hopefully, it is also possible to do this safety in humans. Note that if so, the step to retreating is still more challenging as the titers after gene therapy are much higher than after natural exposure to AAV. However, it would be something for patients with preexisting immunity.