London-based Therexsys Ltd. said it has been granted a Europeanpatent for the use of locus control regions (LCR) to position genes inthe genome and enhance their expression, a technology the companysays will have broad implications for gene therapy.

However, Therexsys, which licensed the technology from theMedical Research Council, also of London, has numerouscompetitors and is not the only group with patents related to LCRs,which are DNA sequences involved in the regulation of geneexpression.

Roger Craig, general manager and chief scientific officer ofTherexsys, said the European patent identifies the LCR responsiblefor expression of genes in erythroid cells of the hemopoietic system.

But, he added, it could be more broadly applied to as yetundiscovered LCRs of other genes because the patent's inventor,Frank Grosveld, professor of cell biology and genetics at ErasmusUniversity in Rotterdam, described how to identify LCRs.

Craig said Therexsys has applied for a U.S. patent, but has notreceived one.

In the U.S., Irving London, a professor or medicine at HarvardUniversity and professor of biology at Massachusetts Institute ofTechnology in Cambridge, co-discovered the human erythroid-specific transcriptional enhancer, which is a specific portion of whatTherexsys has described as the LCR.

The discovery, London said, was the first time the hypersensitivesites of the LCR were located and patents have been issued to MITfor hypersensitive site 2 (HS2), which is the most importantregulatory site for expression of genes in erythroid cells.

The U.S. patent for HS2 was awarded in June 1992 and a Europeanpatent was granted in December 1994.

London and Philippe LeBoulch, a colleague at the Cambridge, Mass.-based Harvard-MIT Division of Health Sciences and Technology,have founded a company, Innogene Pharmaceuticals Inc., with theHS2 patent licensed from MIT.

Innogene is in the process of merging with Genetix Inc., ofTarrytown, N.Y., which has developed proprietary retroviralpackaging cell lines, to launch a gene therapy company aimed atcorrecting erythroid cell disorders, such as thalassemias (sickle cellanemia) and hemoglobinopathies.

In hemoglobin disorders, the beta-globin gene is abnormal and tocorrect the deficiency both a normal gene and the HS2 enhancer toboost the gene's expression are needed.

In making his sweeping claims for Therexsys' LCR patent, Craig saidthe technology has demonstrated how to overcome problems ofpositional effect of gene integration.

"Wherever you land in the genome," Craig said, "your expressionbecomes integration site independent." He added that Grosvelddemonstrated an LCR can contain two elements. The first involvesgetting the gene in the right position and the second is enhancing thegene's expression.

"[Grosveld] took the LCR and hooked it to the globin gene and itprecisely expressed in the right cell at the right level," Craig said. n

-- Charles Craig

(c) 1997 American Health Consultants. All rights reserved.