Prof. Annemieke Aartsma-Rus is taking on a challenge by reading and commenting on a paper a day. She shares her insights, findings and thoughts via her @oligogirl Twitter account. See below the overview of February 2023.
Prof. Aartsma-Rus reads and comments on the paper titled: Evaluation of rAAVrh74 gene therapy vector seroprevalence by measurement of total binding antibodies in patients with Duchenne muscular dystrophy.
#apaperaday This pick is from Therapeutic Advances in Neurological Disorders by Goedeker et al on the seroprevalence of AAVrh74 antibodies in Duchenne patients (aka how many patients have preexisting immunity to AAV type 74?). Spoiler: not many DOI: 10.1177/17562864221149781
Adeno associated viral vectors (AAV) are used to deliver transgenes to skeletal muscle. For Duchenne AAV9 and AAV74 are used to deliver microdystrophin. When individuals have encountered those AAVs before, they will have preexisting immunity (the immune system remembers). This is a problem, because the antibodies can neutralize the AAV with the microdystrophin so it cannot reach the muscles, but can also result in a massive inflammatory response which is a safety risk.
How do people get exposed to AAV9 and AAV74? They can be infected by the regular AAVs (those existing in ‘the wild’ as it were), but also with the viral vectors used in clinical trials (e.g. when a brother is treated with AAV gene therapy). Result will be the same…
Individuals with preexisting immunity for a certain AAV serotype are excluded from participating in gene therapy trials that use that serotype (so AAV9 preexisting immunity –> no AAV9 trials and likely no AAV9 gene therapy treatment)
Authors explain there are 2 ways to assess preexisting immunity. One can look at neutralizing antibodies specifically. The titer is defined here as the highest dilution of serum that can result in a 50% reduction of transduction of cultured cells. An easier way is to look at all the antibodies against a specific serotype (so not only those that bind to the vector and prevent transduction). This can be done with an ELISA. Here authors used the latter approach to test how many Duchenne patients had antibodies against AAV74.
This is the AAV used by Sarepta in Duchenne and Limb Girdle patients – authors assessed 101 Duchenne patients aged 4-18 (most 8-18) years old. 14% had preexisting immunity to AAV74 at titers ranging from 1:400 (threshold) to 1:3200.
Authors discuss that the relatively low number of patients with preexisting immunity likely is because the AAV74 virus was isolated from monkeys rather than humans (e.g. AAV2, 6, & 9). They indicate that a limitation is that they only studied patients in the USA. And that most patients were white (>70%). I expect more individuals will be seropositive in countries where there are monkeys. A nice aspect of the study is that patients/families could indicate whether they preferred blood to be taken in the hospital or at home!
More work will be needed to study the seroprevalence in other cohorts (other diseases, other regions, other age ranges etc). However, the fact that seroprevalence is low at least in this cohort is encouraging.
Prof. Dr. Annemieke Aartsma-Rus is a professor of Translational Genetics at the Department of Human Genetics of the Leiden University Medical Center. Since 2013 she has a visiting professorship at the Institute of Genetic Medicine of Newcastle University (UK).
Her work currently focuses on developing antisense-mediated exon skipping as a therapy for Duchenne muscular dystrophy. In addition, in collaborative efforts she aims to bridge the gap between different stakeholders (patients, academics, regulators and industry) involved in drug development for rare diseases.
In 2013 she was elected a member of the junior section of the Dutch Royal Academy of Sciences (KNAW), which consists of what are considered the top 50 scientists in the Netherlands under 45. From 2015 to 2022, she was selected as the most influential scientist in Duchenne muscular dystrophy by Expertscape.