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1992.06.03 :  Gene Replacement -- Gaucher Disease

Contacts:  Jules Asher NIMH (301) 443-8956
Michaela Richardson NICHD (301) 496-5133
June 3, 1992
                                 
        For the first time, scientists have replaced a normal
gene with a defective one to replicate in mice the symptoms and
pathology of an inherited metabolic disease of humans.  The
scientists hope eventually to use such a genetically engineered
mouse to test new treatments for Gaucher Disease, the most common
disorder of fat storage.  
       Development of the animal model by investigators from the
National Institute of Mental Health, National Institute of Child
Health and Human Development, the Whitehead Institute,
Massachusetts Institute of Technology and Erasmus University is
reported in the June 4 issue of Nature.  
       Using a technique called "targeted disruption," the
researchers created a strain of mice that -- like human Gaucher
disease patients -- are born with a defective form of an enzyme
(glucocerebrosidase) that would normally break down fats in
certain body tissues.  As in the human illness, the mice inherit
and pass on to their progeny a mutant form of the gene that codes
for the enzyme.     The consequent buildup of a fatty waste
product in cells can cause brain abnormalities, enlarged spleen
and liver, bone deterioration and -- in its most severe forms --
death in infancy.   

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       "The gene replacement technique used to develop this
animal model is an important milestone in developing a genetic
replica of any human disorder that can be traced to a specific
mutation," said HHS Secretary Louis W. Sullivan, M.D. 
       Although it spares the brain, even the mildest and most
common form of Gaucher disease can produce incapacitating organ
and skeletal damage.  The mutation for this milder form is
carried by one in l3 Jews of Eastern European (Ashkenasic)
ancestry, making it the most common genetic illness among that
ethnic group.    
       Infusions of normal enzyme have recently become available
to alleviate symptoms.  However, this treatment can cost $200,000
per year/per adult patient.  The Gaucher mice represent a major
advance toward a model for testing new enzyme replacement and
gene therapy approaches.  The latter would correct the problem by
restoring the normal gene so that the body itself could
manufacture the missing enzyme.    
       To develop the model, Edward Ginns, M.D., of NIMH employed
a tracer to make it possible to find the rare (one in 10,000)
cultured cells that incorporated into their chromosomes a mutated
glucocerebrosidase gene.  These genetically altered stem cells,
developed by Victor Tybulewicz, Ph.D., and Richard Mulligan,
Ph.D., at the Whitehead Institute/MIT, were then injected into
mouse eggs by Michael Tremblay, Ph.D., of NICHD, and the eggs
reimplanted in female mice to breed a strain of transgenic
animals that carry the mutation.   

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       Paralleling the most severe form of Gaucher disease, 
this first variety of genetically altered mice die within a few
hours after birth.  Using detailed knowledge of mutations in the
human gene responsible for patients' symptoms, the investigators
hope to engineer animals with other specific mutations, leading
to milder symptoms and longer life spans, for testing new
therapies.
       Participating in the project were: Richard Mulligan,
Victor Tybulewicz and Keith Mintzer of Whitehead/MIT; Heiner
Westphal, Michel Tremblay and Sing-Ping Huang of NICHD; Edward
Ginns, Ellen Sidransky, Brian Martin, Mary LaMarca, Barbara
Stubblefield, Suzanne Winfield and Barbara Zablocka of NIMH; and
Rob Willemsen of Erasmus University.

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