Doing the monogenic mambo

Shire, Sangamo to develop therapies for hemophilia, other monogenic diseases

Kelsey Kaustinen
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RICHMOND, Calif.—Shire PLC and Sangamo BioSciences Inc. havejoined forces in a collaboration and license agreement for the development oftherapeutics for hemophilia and other monogenic diseases based on Sangamo'szinc finger DNA-binding protein (ZFP) technology platform. 
Per the agreement, Shire will be granted worldwide rights toZFP 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 forhemophilia A and B, and will also have the right to designate three additionalgene targets. For its part, Sangamo will be responsible for all activities upto the filing of an IND or European Clinical Trial Application for each of theseven targets, while Shire will be funding Sangamo's related internal andexternal work. After that point, Shire will be responsible for clinicaldevelopment 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 willenable us to expand our therapeutic pipeline into therapies for other geneticdisorders such as hemophilia," Sylvie Grégoire, president of Shire's HumanGenetic Therapies business, said in a press release. "While still early in theclinical development process, this DNA-binding protein technology is alignedwith 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 platformcan be applied to virtually any monogenic disease, many of which Sangamo isalready working on, such as sickle cell anemia, X-linked severe combinedimmunodeficiency and beta-thalassemia.
Sangamo's approach utilizes its proprietary ZFP nuclease andZFP transcription factor (ZFP TF) technology, and its ZFPs can be engineered torecognize 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 generegulation. We engineer ZFPs to recognize a DNA sequence close to or within agene 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 ZFPTF that can regulate the expression of the target gene up or down."
In a mouse model of hemophilia B, which is caused by adefect in clotting Factor IX, ZFN-mediated genome editing proved to be possiblein vivo and was curative in the animal.Researchers demonstrated the production of stable levels of the correctedFactor IX that are clinically meaningful, restoring clotting times to normalafter a single administration. The results were published in the June 2011edition of Nature.
Lanphier says the partnership with Shire fits well withSangamo's plans to move the company and its technology platform forward, giventhat 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 currentprojects in human genetics include treatments for Fabry disease, Duchennemuscular dystrophy and metachromatic leukodystrophy.
"Culturally, there's a great fit between our organizationsin terms of their growth strategy, their entrepreneurial environment and reallybeing very focused on bringing, as they characterized it, genetic cures topatients using our ZFN technology," Lanphier says. "Shire has a strongbackground or experience in the whole area of human gene therapy or human genetechnologies, which makes them a very sophisticated partner."
He believes the nature of this collaboration, seeking acurative approach rather than simply trying to treat or ameliorate symptoms, isa trend that is likely to continue in the industry, pointing to initiativessuch as the Michael J. Fox Foundation and the Juvenile Diabetes ResearchFoundation, 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 thatcauses the disease in a permanent way, so that not only at the DNA level,genotypically, but also at the protein level, phenotypically, there is apermanent cure for the disease," Lanphier notes. "I think that's really thegoal and expectation of both of our parties about this collaboration."

Shire, arGEN-X collaborate on human antibodies for rarediseases
ROTTERDAM, the Netherlands—Shire PLC also announced lastmonth that it has partnered with arGEN-X, a biopharmaceutical company focusedon the discovery and development of human monoclonal antibodies, to createnovel therapeutic antibody products against multiple targets submitted byShire. 
Using its Superior Immunodiversity with Minimal Protein LeadEngineering (SIMPLE) Antibody discovery technology, arGEN-X will isolate andcharacterize human antibodies against the targets that Shire has identified andthat are known to contribute to the pathophysiology of severe, rare geneticdiseases. arGEN-X will also bring its state-of-the-art antibody capabilities tothe collaboration for the preclinical characterization of therapeutic leads. Shirehas the option to license the most promising leads for further preclinical andclinical development and commercialization worldwide.
Under the terms of the agreement, arGEN-X will receive anupfront technology access fee, research funding and preclinical successpayments. In return for its option to develop and commercialize products on anexclusive basis, Shire will pay fees, milestones and royalties on productsales. 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 ofpatients," stated Philip J. Vickers, senior vice president of research anddevelopment at Shire Human Genetic Therapies (HGT). "Monoclonal antibody therapyis an underutilized approach to the treatment of rare diseases, and this novelplatform has the potential to bring multiple drug candidates into ourearly-stage pipeline. Partnerships such as this one with arGEN-X are animportant part of our strategy to bring new therapies to those suffering fromrare diseases worldwide."

Kelsey Kaustinen

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