Gene And Cell Therapy Products Community

Hi colleagues,
I am relatively new to supporting gene therapy and when reading about AAV shedding I pictured it as a biomarker for safety, even if it uses the same PCR method as for PK.  Am I incorrect? Is it a PK assessment? Are you collecting PK data in other tissues?  The reason I am asking is because I want to ensure clear roles and responsibilities between the bioanalytical (PK and immunogenicity) and the Translational Leads (biomarkers).  How is your company doing it?

Tagging @Amanda Hays and @Russell Soon @Justin Smith to add some insights here. 

Hi colleagues,
I am relatively new to supporting gene therapy and when reading about AAV shedding I pictured it as a biomarker for safety, even if it uses the same PCR method as for PK.  Am I incorrect? Is it a PK assessment? Are you collecting PK data in other tissues?  The reason I am asking is because I want to ensure clear roles and responsibilities between the bioanalytical (PK and immunogenicity) and the Translational Leads (biomarkers).  How is your company doing it?

Hi colleagues,
I am relatively new to supporting gene therapy and when reading about AAV shedding I pictured it as a biomarker for safety, even if it uses the same PCR method as for PK.  Am I incorrect? Is it a PK assessment? Are you collecting PK data in other tissues?  The reason I am asking is because I want to ensure clear roles and responsibilities between the bioanalytical (PK and immunogenicity) and the Translational Leads (biomarkers).  How is your company doing it?

Hi Johanna,

You are raising a very good point here. While the assay reagents can be the same as the ones used for other assays for the AAV vector (such as Biodistribution or Identification Assay) the main aim of the shedding assay is environmental protection. In my experience shedding data is not used as a PK endpoint, which is usually defined as the concentration or activity time-profile of the expressed therapeutic protein. 

Shedding in AAV gene therapies has a unique context of use. The shedding results describe how the vector product is excreted or released from the patient's body, which raises the possibility of transmission from treated to untreated individuals (e.g., close contacts and health care professionals). The FDA's industry guidance can be found here: "Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products"; 2015; https://www.fda.gov/media/89036/download.  

In the FDA guidance it says that they don't expect shedding assays to be validated, instead the assays should be qualified to meet minimal performance capabilities and be suitable for the intended purpose. In reality, the method requires full validation because you need a robust and reliable method due to the impact of the sample collection on the volunteers during the trial. The sampling often involves weekly collection of invasive samples of blood, faeces, semen, urine and saliva, which are collected at the trial site. This also means that the turnaround time at the lab has to be fast because after 3 consecutive results below the LOD the sample collection should stop and you don't want to collect invasive patient samples for longer than necessary.

For the shedding assay the sensitivity of the assay, the limit of detection (LOD) and the turnaround time are the key parameter which gives this assay a unique set of operational challenges.

I hope this answer is helpful and I'd be happy to share more details and best practice on how we do it at Celerion. 

Best wishes

Hi colleagues,
I am relatively new to supporting gene therapy and when reading about AAV shedding I pictured it as a biomarker for safety, even if it uses the same PCR method as for PK.  Am I incorrect? Is it a PK assessment? Are you collecting PK data in other tissues?  The reason I am asking is because I want to ensure clear roles and responsibilities between the bioanalytical (PK and immunogenicity) and the Translational Leads (biomarkers).  How is your company doing it?

Hi colleagues,
I am relatively new to supporting gene therapy and when reading about AAV shedding I pictured it as a biomarker for safety, even if it uses the same PCR method as for PK.  Am I incorrect? Is it a PK assessment? Are you collecting PK data in other tissues?  The reason I am asking is because I want to ensure clear roles and responsibilities between the bioanalytical (PK and immunogenicity) and the Translational Leads (biomarkers).  How is your company doing it?

Hi Johanna,
That is correct.  VS data is used to inform on safety aspects, not PK.
However, since the same method (PCR) is used both for bio-distribution (PK) and vector shedding, it makes practical sense for us to keep it all in one team.  I hope this helped.  
Thanks,
Uma.

Hi colleagues,
I am relatively new to supporting gene therapy and when reading about AAV shedding I pictured it as a biomarker for safety, even if it uses the same PCR method as for PK.  Am I incorrect? Is it a PK assessment? Are you collecting PK data in other tissues?  The reason I am asking is because I want to ensure clear roles and responsibilities between the bioanalytical (PK and immunogenicity) and the Translational Leads (biomarkers).  How is your company doing it?