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Dihydropyrimidine Dehydrogenase Deficiency:

 In Search of a Cure

  Disease Background

 Dihydropyrimidine dehydrogenase (DPD) deficiency is a genetic disorder which prevents normal metabolism of uracil and thymine (components of RNA and DNA).  The enzyme is also involved in the breakdown of a chemotherapy drug called 5-flurouracil (5-FU).  Full or partial DPD deficiency is estimated to be present in about 3%-5% of the population. Screening tests are not common and it often takes several months to several years before a diagnosis is confirmed.  Patients with DPD deficiency undergoing treatment with 5-FU are at high risk for severe and sometimes fatal toxic reactions due to accumulation of the drug in the body.  Half of all unexpected severe toxic reactions to 5-FU are associated with decreased DPD activity. Research in DPD deficiency is largely focused on developing strategies to mitigate adverse reactions in patients undergoing chemotherapy.  However, research activities in treatment of primary DPD deficiency remains a significant unmet medical need. 

DPD deficiency is associated with a range of symptoms and in some cases, the condition can be asymptomatic.  Symptoms, which usually present early in life, include seizures, psychomotor retardation, increased muscle tone and retardation of mental and physical development.  Patients with DPD deficiency may exhibit some or all of these symptoms.  In most cases, the quality of life for patients and caregivers is significantly affected.  Individuals with asymptomatic DPD deficiency are vulnerable to severe, potentially fatal reactions to certain chemotherapeutic drugs called fluoropyrimidines which include 5-FU and capecitabine.

 Strategies for Drug Development 

DPD plays a critical role in the degradation of certain molecules known as uracil and thymine (collectively called pyrimidines).  The neurological symptoms associated with DPD deficiency may be a result of the impairment of the pyrimidine degradative pathway resulting in toxic levels of uracil and thymine and/or a deficiency of degradative products such as beta-alanine which may function as a neurotransmitter in the brain.  In DPD deficient patients, a genetic error results in either insufficient synthesis of DPD or rapid breakdown of the enzyme.  Hence, a key objective in development of drugs for this condition is to ensure that there are sufficient and sustained levels of this enzyme in the blood.  These include (but not limited to) administration of a recombinant DPD enzyme (enzyme replacement therapy).  The objective of this approach is to increase DPD activity in circulation to lower toxic levels of uracil and thymine or 5-FU in patients receiving chemotherapy.  In DPD deficient patients, providing a sink for the rest of the tissues and central nervous system. A growing number of enzyme replacement therapies have been developed to treat genetic diseases resulting in enzyme deficiencies such as Gaucher disease, Fabry disease, Pompe disease, and Muccopolysaccharidosis I, II and VI.  .  While enzyme replacement therapy may be a promising approach to treating DPD deficiency and preventing severe toxic reactions to 5-FU in cancer patients, this approach has not been tested in animal models.  Key next steps to developing a treatment for DPD deficiency include generating a DPD deficient animal model (i.e., DPD knock out mouse model) and recombinant human DPD which can be used for in vivo proof of concept studies.

 Development of treatments for any disease is a time consuming process with a hefty financial commitment.  A treatment hypothesis which includes previously untested drugs is required to follow stringent development protocols.  Drug candidates are first tested in different animal species to ascertain safety and effectiveness before initiation of human studies. Government and traditional foundations tend to fund basic research while pharmaceutical companies and venture capitalists favor supporting late-state research and late-stage clinical trials. It is our goal to fill the funding gap by supporting the critical translational research of academic or industry scientists.   

Currently, we are seeking to raise $350,000 as seed money to generate proof of concept in animal models.  Based on the results, we hope to generate sufficient interest from industry and major foundations to fund further pre-clinical and clinical development.

 It is Important to Act Now

 Availability of effective treatments for DPD deficiency emerging from research initiated today can take anywhere between 5-8 years.

 Therefore, it is important for families and friends of patients suffering from DPD deficiency to drive awareness and work with the government and industry to fund and initiate development of viable treatments.  It is disheartening to see little children deprived of a normal life and their parents and physicians helplessly hanging on to a hope that someday there will be solution to control or cure this disease. 


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