The following publication by Regeneron scientists is a major breakthrough in conditional genomic engineering, though it will not have any impact on the stock near term, IMHO. Regeneron has used this unique technology, recombinase-generated null alleles, to determine gene function in rodents. I'll bet that this has been used in the novel targets that have resulted in mAbs against these targets. Then the question becomes what is the relevance of the animal models to the human pathologies. I am sure that Sanofi is blown away by all the good science being done at Regeneron (another good reason for SNY to increase its stake in REGN). I wonder what the undisclosed antibody targets are at Regeneron that have mAb clinical candidates as follows?
REGN846
REGN1154
REGN1500
Also, REGN stock breaks out to an all time high here.
BJ
pnas.org
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):E3179-88. doi: 10.1073/pnas.1217812110. Epub 2013 Aug 5.
Conditionals by inversion provide a universal method for the generation of conditional alleles.
Economides AN, Frendewey D, Yang P, Dominguez MG, Dore AT, Lobov IB, Persaud T, Rojas J, McClain J, Lengyel P, Droguett G, Chernomorsky R, Stevens S, Auerbach W, Dechiara TM, Pouyemirou W, Cruz JM Jr, Feeley K, Mellis IA, Yasenchack J, Hatsell SJ, Xie L, Latres E, Huang L, Zhang Y, Pefanis E, Skokos D, Deckelbaum RA, Croll SD, Davis S, Valenzuela DM, Gale NW, Murphy AJ, Yancopoulos GD.
Source: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
Abstract
Conditional mutagenesis is becoming a method of choice for studying gene function, but constructing conditional alleles is often laborious, limited by target gene structure, and at times, prone to incomplete conditional ablation. To address these issues, we developed a technology termed conditionals by inversion (COIN). Before activation, COINs contain an inverted module (COIN module) that lies inertly within the antisense strand of a resident gene. When inverted into the sense strand by a site-specific recombinase, the COIN module causes termination of the target gene's transcription and simultaneously provides a reporter for tracking this event. COIN modules can be inserted into natural introns (intronic COINs) or directly into coding exons as part of an artificial intron (exonic COINs), greatly simplifying allele design and increasing flexibility over previous conditional KO approaches. Detailed analysis of over 20 COIN alleles establishes the reliability of the method and its broad applicability to any gene, regardless of exon-intron structure. Our extensive testing provides rules that help ensure success of this approach and also explains why other currently available conditional approaches often fail to function optimally. Finally, the ability to split exons using the COIN's artificial intron opens up engineering modalities for the generation of multifunctional alleles.
From the text (for those who do not care to read the paper):
"To validate the COIN method, we engineered COIN alleles for 26 protein-coding genes whose inactivation would result in known or predicted phenotypes and scored them ( Table 1) using the following criteria: (i) normal Mendelian inheritance and wild type (WT) phenotype in mice either homozygous for the noninverted and thus, silent COIN allele (COIN/COIN) or compound heterozygous with the corresponding null allele (COIN/null); (ii) phenotypes and inheritance patterns identical to those of KO mice (null/null) in mice either homozygous for the inverted COIN allele (COIN-INV/COIN-INV) or compound heterozygous with the corresponding null allele (COIN-INV/null); (iii) normal target gene expression for the COIN allele compared with the unmodified gene; and (iv) COIN module reporter expression on inversion of the COIN. Where noted, phenotypes of some COIN alleles were studied in ES cells. Based on these criteria, nearly all of the COIN alleles were found to be completely WT before inversion and completely null postinversion ( Table 1)...+ |
