Etidronate for Arterial Calcifications Due to Deficiency in CD73 (ACDC)
Condition: Arterial Calcification; CD73 Deficiency
MeSH terms: Arteriosclerosis; Calcinosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

        -  Arterial Calcifications due to Deficiency in CD73 (ACDC) is a rare genetic disease.
           People with ACDC develop calcification in the arteries of the lower extremities as well
           as calcium deposit in the joints of the fingers, wrists, ankles and feet. The lower
           extremities calcification causes claudication because of severe ischemia requiring at
           time revascularization procedures. the calcium deposits in the joints causes severe
           debilitating pain in the hands and feet. Currently, there are no standard treatments for
           ACDC.

        -  Etidronate is a bisphosphonate that interferes with bone metabolism. It is approved to
           treat Paget's disease, a condition in which the bones are soft and weak and may be
           deformed, painful, or easily broken. It is also used to treat high blood calcium levels.
           Researchers want to see if it can be used to treat the calcifications of ACDC and
           improve pain and blood flow in the lower extremities and arthritic pain of the hands and
           feet.

      Objectives:

      - To see if etidronate is a safe and effective treatment for ACDC.

      Eligibility:

      - People between 18 and 80 years of age who have been diagnosed with ACDC.

      Design:

        -  Participants will be screened with a physical exam and medical history. They will also
           have imaging studies, including CT scan of the lower extremities, x-rays and DEXA bone
           scans, before starting treatment. Blood and urine samples will be collected. An exercise
           tolerance test will also be given and ABI (ankle brachial index will be measured.

        -  Participants will take etidronate by mouth once a day for 14 days every 3 months. They
           will be assigned an individualized 6- month drug schedule to follow.

        -  Participants will have regular study visits throughout the treatment period. These
           visits will involve imaging studies, full dental exams, and blood and urine tests.
           Participants will also have exercise tolerance tests and ABIs measured.

        -  Participants may also provide tissue samples for further study.

        -  Treatment will continue for up to 3 years as long as the side effects are not severe and
           the condition does not become worse. Participants will have a final follow-up visit
           after stopping treatment.
    

Detailed description: 
      We have recently identified a novel genetic disease affecting nine known adults in whom de
      novo vascular calcifications develop in the lower extremity arteries and juxta-articular
      joint capsules of the fingers, wrists, ankles and feet. This rare disease results from
      bi-allelic mutations in the gene ecto-5-prime-nucleotidase (NT5E), encoding the CD73 protein.
      CD73, an enzyme involved in the extracellular ATP metabolic pathway, converts extracellular
      AMP to adenosine and inorganic phosphate. The clinical symptoms of this rare disease, termed
      ACDC (Arterial Calcifications due to Deficiency in CD73), include claudication of the calves,
      thighs, and buttocks, chronic ischemic pain of the feet at rest with threat of potential limb
      loss, and debilitating rheumatoid pain in the wrists and hands. Radiological and histological
      evaluations do not resemble classic atherosclerotic vascular calcification, since the
      calcification and dysplasia in ACDC occur in the medial portion of the arterial blood vessel
      wall. Data from patient-specific cell lines indicate increased activity of tissue
      non-specific alkaline phosphatase (TNAP), a key mediator of pathological ectopic tissue
      calcification, and thus reveals a potential therapeutic target.

      To date, no effective therapy exists for ACDC patients. However, since bisphosphonates are
      potent competitive inhibitors of TNAP activity and are widely used to modulate bone
      metabolism, they may beneficially alter vascular calcification. In addition, our preliminary
      in vitro studies demonstrate the effectiveness of etidronate, a nitrogen-containing
      bisphosphonate, in lowering TNAP activity in cells isolated from ACDC patients. Etidronate,
      and bisphosphonates in general, have proven safe and are well tolerated by most patients.

      This protocol provides for the administration of etidronate to ACDC patients, for whom no
      alternative treatment is available. Patients will be examined at the NIH Clinical Center
      bi-annually for 3 years. The primary objective of this clinical study is to test the
      effectiveness of etidronate in attenuating the progression of lower extremity arterial
      calcification and vascular blood flow based on CT calcium score and Ankle Brachial Index
      (ABI).
    

Intervention name(s): Etidronate; MRI Scan
Intervention type(s): Drug; Device
Intervention description(s): Didronel (etidronate disodium)- Didronel tablets contain either 200 mg or 400 mg of etidronate disodium, the disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also known as EHDP. regulates bone metabolism. It is a white powder, highly soluble in water. The 400 mg tablets are white capsule-shaped tablets with ED 400 on one side and G on the other side.; Visit on day 0 and visit at 36 month - Exploratory MRI studies may be employed to evaluate the lumen of the artery and degree of collateral vessels, given that the high degree of calcification is precluding that evaluation by CT.
Other intervention name(s): Etidronate disodium; Didronel
Intervention MeSH terms: Etidronic Acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: NT5E; Bisphosphonates; Vascular Calcifications; Joint Capsule Calcifications; Inherited Disease