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Doing the monogenic mambo
March 2012
by Kelsey Kaustinen  |  Email the author


RICHMOND, Calif.—Shire PLC and Sangamo BioSciences Inc. have joined forces in a collaboration and license agreement for the development of therapeutics for hemophilia and other monogenic diseases based on Sangamo's zinc finger DNA-binding protein (ZFP) technology platform.
Per the agreement, Shire will be granted worldwide rights to ZFP Therapeutics designed to target four genes (for blood clotting Factors VII, VIII, IX and X), which will be used in the search for curative therapies for hemophilia A and B, and will also have the right to designate three additional gene targets. For its part, Sangamo will be responsible for all activities up to the filing of an IND or European Clinical Trial Application for each of the seven targets, while Shire will be funding Sangamo's related internal and external work. After that point, Shire will be responsible for clinical development and commercialization of projects that result from the partnership. Sangamo will receive $13 million up front, as well as research, regulatory, development and commercial milestone payments and royalties on product sales.
"Sangamo's groundbreaking ZFP gene-editing technology will enable us to expand our therapeutic pipeline into therapies for other genetic disorders such as hemophilia," Sylvie Grégoire, president of Shire's Human Genetic Therapies business, said in a press release. "While still early in the clinical development process, this DNA-binding protein technology is aligned with our focus of developing new treatments that can add value for physicians, patients and their families and the healthcare community overall."  
While the agreement is initially focused on hemophilia, Edward Lanphier, president and CEO of Sangamo, says the ZFP technology platform can be applied to virtually any monogenic disease, many of which Sangamo is already working on, such as sickle cell anemia, X-linked severe combined immunodeficiency and beta-thalassemia.
Sangamo's approach utilizes its proprietary ZFP nuclease and ZFP transcription factor (ZFP TF) technology, and its ZFPs can be engineered to recognize any specific DNA sequence in a gene. As noted on the company's site, ZFP TFs are "novel transcription factors that mimic the natural mode of gene regulation. We engineer ZFPs to recognize a DNA sequence close to or within a gene of choice. By attaching a functional domain such as a naturally occurring 'gene activation' or a 'gene repression' domain to that ZFP, we generate a ZFP TF that can regulate the expression of the target gene up or down."
In a mouse model of hemophilia B, which is caused by a defect in clotting Factor IX, ZFN-mediated genome editing proved to be possible in vivo and was curative in the animal. Researchers demonstrated the production of stable levels of the corrected Factor IX that are clinically meaningful, restoring clotting times to normal after a single administration. The results were published in the June 2011 edition of Nature.   Lanphier says the partnership with Shire fits well with Sangamo's plans to move the company and its technology platform forward, given that Shire "has a long and significant history in the area of rare diseases" and "really is a specialty pharma in this space." Some of Shire's current projects in human genetics include treatments for Fabry disease, Duchenne muscular dystrophy and metachromatic leukodystrophy.
"Culturally, there's a great fit between our organizations in terms of their growth strategy, their entrepreneurial environment and really being very focused on bringing, as they characterized it, genetic cures to patients using our ZFN technology," Lanphier says. "Shire has a strong background or experience in the whole area of human gene therapy or human gene technologies, which makes them a very sophisticated partner."  
He believes the nature of this collaboration, seeking a curative approach rather than simply trying to treat or ameliorate symptoms, is a trend that is likely to continue in the industry, pointing to initiatives such as the Michael J. Fox Foundation and the Juvenile Diabetes Research Foundation, both of which are looking for cures rather than just standard treatments.  
"I think that's really the theme of this collaboration, going beyond just treatment but actually repairing the mistake in the gene that causes the disease in a permanent way, so that not only at the DNA level, genotypically, but also at the protein level, phenotypically, there is a permanent cure for the disease," Lanphier notes. "I think that's really the goal and expectation of both of our parties about this collaboration."

Shire, arGEN-X collaborate on human antibodies for rare diseases
ROTTERDAM, the Netherlands—Shire PLC also announced last month that it has partnered with arGEN-X, a biopharmaceutical company focused on the discovery and development of human monoclonal antibodies, to create novel therapeutic antibody products against multiple targets submitted by Shire.
Using its Superior Immunodiversity with Minimal Protein Lead Engineering (SIMPLE) Antibody discovery technology, arGEN-X will isolate and characterize human antibodies against the targets that Shire has identified and that are known to contribute to the pathophysiology of severe, rare genetic diseases. arGEN-X will also bring its state-of-the-art antibody capabilities to the collaboration for the preclinical characterization of therapeutic leads. Shire has the option to license the most promising leads for further preclinical and clinical development and commercialization worldwide.  
Under the terms of the agreement, arGEN-X will receive an upfront technology access fee, research funding and preclinical success payments. In return for its option to develop and commercialize products on an exclusive basis, Shire will pay fees, milestones and royalties on product sales. Specific details of the financial terms were not disclosed.
"As a leader in innovative therapies for rare diseases, Shire is continuing to apply new technologies to address the needs of patients," stated Philip J. Vickers, senior vice president of research and development at Shire Human Genetic Therapies (HGT). "Monoclonal antibody therapy is an underutilized approach to the treatment of rare diseases, and this novel platform has the potential to bring multiple drug candidates into our early-stage pipeline. Partnerships such as this one with arGEN-X are an important part of our strategy to bring new therapies to those suffering from rare diseases worldwide."
Code: E031218



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