I’ve been doing some research to try to get my head around CRISPR, gene editing and the potential use of PYC’s FPP platform technology in this field.
There is no doubt that this is a “hot” area - gene editing platforms are attracting a great deal of interest, including a $3 billion headline value deal last month between Gilead's Kite Pharma and Sangamo Therapeutics. There seems to be competition between three main gene editing platforms, with each having already received pharma backing. The current contenders are CrispR/Cas9 (Novartis, Juno, Kite), TALEN (Cellectis – Pfizer, Servier) and ZFN (Sangamo – Pfizer, Gilead/Kite) (1).
CRISPR/Cas9 is regarded as the next-generation technology in gene-editing. CRISPRs are specialized stretches of DNA and the protein CAS9 is an enzyme that can cut strands of DNA.(2) CRISPR is apparently easier, cheaper and faster to design and produce than earlier gene-editing technologies. But it also seems to have more off-target effects, is largely untested in human clinical trials (first human trials of CRISPR in the US are still to commence) and there is a patent ownership spat which makes licensing of this technology problematic. (3, 4) ZFN (a Sangamo proprietary technology) is an older gene-editing technology than CRISPR but has already been tested in hundreds of patients in early-stage clinical trials with no significant safety issues. ZFN has also recently passed the landmark of being used for the first time for in-vivo gene-editing in a human patient. (5)
Efficient intracellular delivery appears to remain a major obstacle to therapeutic use of gene-editing technology. In a 2016 interview with the ABC, Dr Marco Herold, the laboratory head at the CRISPR facility at the Walter and Eliza Hall Institute of Medical Research in Melbourne, said that the efficiency of current technology for bringing the gene into the cell was “very, very low”. (6)
There is no doubt that there has been strong interest in solving this problem. Using the search request “intracellular gene delivery” on Pubmed turned up more than 6000 published research articles. I note that Sangamo says on its website that it currently uses both adeno-associated virus (AAV) and mRNA to deliver its therapeutics and continues to develop and refine these platforms. (7) Sangamo’s recent in-vivo gene-editing trial used an AAV vector to ferry DNA encoding the ZFNs and new gene into the liver cells.
Reading more widely on the use of AAVs in therapeutics, I note that its use in gene delivery has been hampered by relative inefficiency in both cell membrane penetration and endosome escape. One proposed method of improving the efficacy of AAV-mediated gene transfer into cells is to use CPPs. (8)
Consequently, I can see where PYC’s CPP platform might be useful in gene-editing therapeutics.
What I don’t understand at this point is how PYC’s offering stacks up against other potential intracellular delivery technologies for genes, including other CPPs. I note that FPP1746 has performed more efficient delivery than TAT in PYC’s recent experiments. But I do wonder how PYC’s FPPs compare with other CPPs out there, including poly-Arg(R9), MPG, Pep-1, cR10, R12, Pep42, Antp and LAH4.
A personalised tool to help users track selected stocks. Delivering real-time notifications on price updates, announcements, and performance stats on each to help make informed investment decisions.
(20min delay)