Nonviral CRISPR ocular gene therapy: two programs to INTERACTActive
UW–Madison CRISPR Vision Program · Regulatory advisor and U.S. Agent
Two LNP-formulated, subretinally administered genome-editing products for inherited retinal dystrophies: an adenine base editor directed to KCNJ13 for Leber congenital amaurosis 16, and an SpCas9 nuclease directed to the mutant BEST1 allele in autosomal-dominant Best disease. Crawling Stone serves as regulatory advisor and U.S. Agent to the program, authored both INTERACT briefing documents, and chaired both meetings with CBER.
The questions placed before the Agency encompassed novel-excipient and LNP CMC strategy, off-target assessment, potency assurance, the use of patient-derived iPSC-RPE as proof of concept in the absence of an animal model, a platform approach to product variants differing only in guide RNA sequence, and eligibility for the Agency's rare-disease evidence pathways. Both meetings established alignment on the preclinical model, the scope of the nonclinical package, and the CMC development strategy; the work proceeds toward Pre-IND for both programs.
GD2-targeted CAR-T: regulatory and CMC oversight through INDActive
Academic sponsor · Client-side oversight of CDMO automated manufacturing
An academic program with completed preclinical work and technology transfer to an automated CDMO manufacturing platform, directed toward IND submission on a fixed date. Crawling Stone provides the sponsor-side oversight that an academic team and a nascent CDMO do not otherwise possess between them: the process control strategy and critical quality attributes, a tiered potency assurance strategy, the stability protocol and allocation of retain samples, release specifications, master batch record review, person-in-plant presence during process qualification, and CBER-compliance review of the Module 3 and Module 4 drafts.
The organizing principle is that every decision defining what the qualification runs must demonstrate has to be settled before those runs execute. The governing risk is not a missed submission date but a filing that draws a clinical hold.
CAR-T manufacturing platform strategy in an allogeneic transplant setting
Commercial-stage cell therapy company · CMC and manufacturing scope
The sponsor sought to introduce a CAR-T component into an established allogeneic transplant product, a setting in which donor collection logistics and the infusion schedule impose a fixed manufacturing window. Crawling Stone conducted a comparative assessment of viral transduction, transposon, CRISPR-mediated knock-in, and nonviral mRNA platforms against five criteria: process dwell time, GMP and release-testing burden, intellectual property landscape, regulatory pathway, and compatibility with the sponsor's donor-derived starting material, evaluated under an explicit mandate for cost and speed of development.
The analysis identified a rapid nonviral mRNA process as the preferred near-term platform and recommended early engagement with CBER in view of the absence of regulatory precedent for the proposed combination. The program was structured as a standalone IND, preserving the sponsor's licensed product from the change-reporting obligations of 21 CFR 601.12.
Investigator-sponsored TIL program: path to an industry-sponsored registrational trial
Health-system venture and innovation group · Regulatory, CMC, and investment diligence
An academic tumor-infiltrating lymphocyte product had completed Phase 1 under an investigator-sponsored IND and was under evaluation for spin-out and an industry-sponsored Phase 2 trial. Crawling Stone defined the route to BLA and the nonclinical, CMC, and clinical requirements for licensure, and assessed the extent to which the existing Phase 1 data package could support a standalone entity.
The practice advised on a potency assurance strategy constructed to current CBER expectations, pairing a reporter-cell co-culture cytotoxicity assay with a tumor-intrinsic biomarker as a candidate companion diagnostic, and on the elements of the TIL process that attract Agency scrutiny: clearance of irradiated feeder cells, provenance and testing of starting and ancillary materials, shipment under quarantine with release at the clinical site, and prospective change control. It further set out a staged CMC build-out from investigator-sponsored to industry-sponsored manufacture and the operating model for extending a resection-to-infusion process across multiple clinical sites. The analysis underpinned the investor's decision on whether to advance the asset.
