NATIONAL HARBOR, Maryland — “Technology is running ahead of regulatory understanding, but science fueled by genomics will drive it and address close to 80% of rare diseases,” Mo Heidaran, PhD, vice president of technical and regulatory consulting at Parexel International Biotech, said in a session at the 2021 World Orphan Drug Congress.

The majority of rare diseases are caused by single point mutations, with 47.1% of point mutations occurring in A-T to G-C base pairs. These mutations are addressed either by ex vivo or in vivo technologies that replace or insert transgenes using nucleases or other technologies.

Dr. Heidaran explained the difference between in vivo and ex vivo technologies for gene editing. In vivo gene therapy entails direct transfer of the transformative agent into the patient via intravenous infusion. Ex vivo techniques involve changing the patient’s genetic materials outside of the patient’s body and then reinfusing the altered material back into the patient intravenously.

Both ex vivo and in vivo therapies utilize viral and nonviral platforms, including adeno-associated viruses and/or lipid nanoparticles, to deliver the altered genetic materials to the proper organelles for transcription and translation into the therapeutic proteins that are missing in the patient carrying the rare disease.

The blood-brain barrier poses a particular challenge to in vivo administration of gene therapy, the speaker said, as these agents may not be able to cross this barrier to reach target sites directly within patients’ brains.

Areas of concern regarding gene editing include strong immune-mediated patient responses to vector-mediated delivery using bacterial nucleases, sustainability of therapeutic benefits of in vivo gene editing, the possibility of germline mutations, and off-target effects in sites other than the intended gene alteration target site.

Products that do not utilize nucleases may reduce the likelihood of patient rejection of treatment. Long-term, rigorous follow-up of patients is required to assess for oncogenesis as a possible side effect of gene editing.

“Analysis for off-target effects currently is not well-defined,” Dr. Heidaran said. More precise assays are required to define parameters used to assess off-target effects.

He said the most important advance in gene editing is base editing, which does not require a double-stranded break to insert altered material and carries a low risk of off-target effects.

CRISPR, TALEN, and ZFN are all clinical trials studying gene editing. “This is not science fiction. Some of these studies are in phase 2 [of development],” Dr. Heidaran remarked.


Genome editing: the future is now. Presented at: World Orphan Drug Congress USA 2021: August 26, 2021; National Harbor, MD.