A number of cell and gene therapy researchers are attempting to shape regulatory guidance of the field on two critical issues. The first involves reducing FDA-mandated animal studies of biodistribution without increasing risk to patients through identification of well-characterized vector subtypes and dose ranges. The second issue relates to the effectiveness of mouse gene integration models and the possibility of reducing the number of these studies as well.
Terence R. Flotte, M.D., dean of the University of Massachusetts Medical School, is an expert on vector platforms. Dr. Flotte’s research has focused on gene therapy based on the adeno-associated virus (AAV) platform for pediatric genetic diseases including cystic fibrosis, alpha-1 antitrypsin (AAT) deficiency, type I diabetes, and disorders of fatty acid oxidation.
Dr. Flotte became involved in the “standardized pathways” idea through his role in a group that represented ASGCT on creating platforms to promote AAV vectors in diseases that were not yet being addressed, but which were similar enough to those under investigation. “We were looking for a route through which such trials could move forward quickly,” Dr. Flotte says.
For example, AAV vectors have established clinical efficacy in Leber's congenital amaurosis (LCA), a rare, recessive, single-gene disorder that leads to retinal dysfunction and visual impairment at an early age. For this disease the gene RPE65, when administered with the AAV vector at a certain dose through sub-retinal intraocular injection, restores vision. At least one company and several research groups are moving forward with this treatment.
“That’s great for LCA, but more than twenty similar, rare genetic diseases affect the retina,” explains Dr. Flotte. “Why not just plug in a different gene and attempt to treat them? [I want to help] facilitate parallel development of products for single-gene disorders.”
This would require a degree of transparency and cooperation among researchers, regulators, and funding agencies. The goal would be to create what Dr. Flotte refers to as a “clearly identified, relatively streamlined packet” of preclinical studies with which funders, regulators, and investigators would be comfortable, and which would grease the skids for parallel clinical studies on single-gene diseases. NIH, says Dr. Flotte, is “very interested in this concept.”
This approach has been somewhat inhibited by FDA’s oversight structure, which focuses more on approving or disapproving clinical projects, rather than providing carte blanche for conducting similar studies. Still, says Dr. Flotte, the agency could provide validity to this basic idea where sponsors can demonstrate similarity to either approved products or well-established clinical-stage treatments.
The comparison might be founded on the right combination of similar serotype, dosage, administration route, and gene delivery platform. “In other words, what would be the minimal package to get a treatment into the clinic, based on duplication of what appears to be a successful use of this platform,” adds Dr. Flotte.
What this represents is a standardized set of preclinical studies that demonstrate gene integration and lack of toxicity. To borrow from the small molecule pharmaceutical lexicon, the discovery and proof-of-concept phases are pared down significantly. Clinical development is expected to be similar in scope to current studies.