Like other viral and non-viral gene delivery methods, biological properties of bacteria, particularly their tendency to naturally colonize tumor sites, have allowed them to be exploited for DNA delivery to cells or tissues. The concept of exploiting bacteria as gene delivery vectors has existed for some time, however the field is still new, particularly as mechanisms by which bacteria colonize tumor sites is still largely unknown.
With the field growing, the FDA has stepped in to update their previous guidances on microbial vectors for gene therapy by issuing an updated version which introduces more control over the manufacturing of such delivery vectors for therapeutic processes that are proceeding to IND submission and approval.
It must be mentioned that, in their current form, the guidances are intended to cover only initial IND submissions, not products in advanced stages.
In the updated guidelines, the FDA recommends that IND sponsors provide detailed information about product manufacturing and characterization of microbial vectors in their submission documents.
Thise guidances, “Recommendations for Microbial Vectors used for Gene Therapy,” include recommendations for both Manufacturing and Testing of the material. Specifically:
- Description of the MVGT bacterial strain, including its growth and storage conditions, the reagents used to grow it, and details about the bacterial and inserted genetic material.
- Description of how the MVGT Drug Product is produced, isolated, purified and formulated for administration to humans;
- Description of the product containers;
- Manufacturing process qualifications (such as current Good Manufacturing Processes (cGMP) requirements) for Phase 1, Phase 2 and Phase 3 clinical trials, as appropriate.
- Results from appropriate product testing for identity, purity, viability and potency at each stage of production, including safety, purity, potency, presence of DNA plasmids, viability, and cell number, stability, residual moisture content, and more.
- In vivo biological activity studies, safety and biodistribution profiles
In relation to this information, which significantly expands on previously published guidelines in terms of information required by IND sponsors and drug manufacturers, the FDA provides recommendations to ensure the safety in therapies where microbial vectors are used.
Of particular note is the FDA’s new focus on requiring data from in vivo studies. In vivo data must include, among others:
- Analysis whether the microbial vector for gene therapy (MVGT) can continue to replicate and spread in the body after treatment, including to non-target tissues, and
- MVGT activity and distribution with and without antibiotics to guide antibiotic use in human trials.
Additional guidance points include design of trials and selection of vector, to ensure appropriate data is collected and appropriate subjects and vectors are chosen to minimize risk and increase safety.