Ongoing research for the treatment of GACI/ARHR2
Early-stage research is ongoing to develop an enzyme therapy to normalize levels of PPi. This experimental therapy has been demonstrated to be an effective treatment in multiple mouse models of ENPP1 Deficiency (GACI type 1 Phenotype). In one set of experiments, this therapy elevated PPi levels and prevented mortality and vascular calcifications2. Additional experiments have also shown this therapy to improve blood pressure and cardiovascular function3. This enzyme therapy is currently being developed as a potential treatment for ENPP1 Deficiency and ABCC6 Deficiency (GACI type 2 phenotype) and the company developing it started adult clinical trials in late 2021. Infant and pediatric clinical trials should follow soon.
Age-dependent manifestations of ENPP1 Deficiency (GACI type 1 and ARHR2)
Depending on age, ENPP1 Deficiency can manifest as two phenotypes due to the interaction between low plasma PPi and age-dependent normal or compensatory physiological changes. In infants with ENPP1 Deficiency (GACI type 1 phenotype), the ability to inhibit ectopic calcification is lost due to low PPi levels, resulting in pathological soft tissue calcification, including mineralization of the arteries, heart, kidneys, and joints. This process of ectopic calcification usually begins in utero or within the first few weeks of life. Infants who survive the first 6 months have a much lower risk of death1, likely due to reduced arterial blood flow resistance as infants age.
Infants with ENPP1 Deficiency who survive GACI type 1 will almost all develop ARHR2, usually beginning between ages 2–8 years. ARHR2 is a skeletal disorder that is characterized by rickets, bone and muscle pain, bowing of the legs, short stature, and an increased risk of fractures. It is hypothesized that children with ENPP1 Deficiency develop a state of low phosphate in their serum, known as hypophosphatemia, as a compensatory mechanism for the state of low PPi in order to inhibit or decrease ectopic calcification1. This hypophosphatemia leads to rickets in affected children.
Age-dependent manifestations of ABCC6 Deficiency (GACI type 2 and PXE)
ABCC6 Deficiency disorder is also characterized by low PPi levels and may sometimes manifest as GACI type 2 in infants. In infants with ABCC6 Deficiency (GACI type 2 phenotype), the ability to inhibit ectopic calcification is lost due to low PPi levels, resulting in pathological soft tissue calcification, including mineralization of the arteries, heart, kidneys, and joints. This process of ectopic calcification usually begins in utero or within the first few weeks of life. Infants who survive the first 6 months have a much lower risk of death1, likely due to reduced arterial blood flow resistance as infants age.
ABCC6 Deficiency is most likely manifest as Pseudoxanthoma Elasticum (PXE) in the post-infancy stage. PXE is a disorder that causes select elastic tissue in the body to become mineralized due to calcium and other minerals being deposited in the tissue. This can result in changes in the skin and eyes.
The role of pyrophosphate in preventing pathogenic mineralization
ENPP1 Deficiency is caused by loss of function mutations in the ENPP1 gene that leads to decreased levels or activity of ENPP1 enzyme. ENPP1 enzyme cleaves adenosine triphosphate (ATP) to generate adenosine monophosphate (AMP) and inorganic pyrophosphate (PPi), a molecule essential for preventing harmful soft tissue calcification and for regulating bone mineralization5,6. Therefore, a decrease in PPi levels causes a disease state exhibiting both ectopic (especially vascular) calcification in infants (GACI phenotype) and defects in bone mineralization (ARHR2 phenotype) post-infancy.
There is a substantial body of evidence that documents PPi as an endogenous inhibitor of calcification5,6. Specifically, PPi potently inhibits the ability of calcium to crystallize with phosphate to form hydroxyapatite (HA), the main mineral component of bone, in soft tissue. PPi prevents the initiation of mineralization in soft tissue by binding strongly to the surface of HA crystals and blocking HA crystals from growing, thereby preventing the initial mineralization and further harmful soft tissue calcification. Therefore, it is the low level of PPi that permits pathological mineralization in vascular smooth muscle tissue. The ability of PPi to inhibit calcification and its essential role in preventing harmful soft tissue calcification is highlighted in ENPP1 Deficiency where low PPi levels allow for ectopic calcification. Low levels of plasma PPi are linked with abnormalities in bone microstructure7,8 leading to ARHR2 (rickets)1.
- Rutsch F, Böyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, Weissen-Plenz G, Fischer RJ, Mughal Z, Gregory JW, Davies JH, Loirat C, Strom TM, Schnabel D, Nürnberg P, Terkeltaub R; GACI Study Group. “Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.” Circ Cardiovasc Genet. 2008 Dec;1(2):133-40. View Link.
- Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, Covo MS, Tehan M, Yang G, Cheng Z, Bouchard K, Yu ZX, Thorn S, Wang X, Folta-Stogniew EJ, Negrete A, Sinusas AJ, Shiloach J, Zubal G, Madri JA, De La Cruz EM, Braddock DT. “ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy.” Nat Commun. 2015 Dec 1;6:10006. View Link.
- Khan T, Sinkevicius KW, Vong S, Avakian A, Leavitt MC, Malanson H, Marozsan A, Askew KL. “ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy.” Dis Model Mech. 2018 Oct 8;11(10). View Link.
- Orriss, IR, Arnett TR, Russell RG. “Pyrophosphate: a key inhibitor of mineralisation.” 2016 Curr Opin Pharmacol 28:57-68. View Link.
- Fleisch H, Russell RG, Straumann F. “Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis.” Nature. 1966 Nov 26;212(5065):901-3. View Link.
- Mackenzie, NC, Huesa C, Rutsch F, MacRae VE. “New insights into NPP1 function: lessons from clinical and animal studies.” 2012 Bone 51 (5):961-8. View Link.
- Hajjawi, M O, MacRae VE, Huesa C, Boyde A, J. Millan JL, Arnett TR, and Orriss IR. “Mineralisation of collagen rich soft tissues and osteocyte lacunae in ENPP1(-/-) mice.” 2014 Bone 69:139-47. View Link.
Patients and Parents IRB Approved Survey
“Understanding the Spectrum of ENPP1 Deficiency and ABCC6 Deficiency (GACI and ARHR2) Through the Eyes of Patients and Parents Survey”.
We are excited to share the news that GACI Global has partnered with Inozyme, a biotechnology company developing novel medicines to treat rare and life-threatening mineralization disorders, to investigate the burden of disease from a patient/family perspective.
Families who are affected by GACI/ARHR2 know firsthand that it is a life-changing diagnosis. Your life, your world, is never the same again. When your child is diagnosed, you are not just a parent anymore. You become a researcher, a therapist, an advocate, a cheerleader, a caregiver. You learn more about this condition than most doctors will ever know. Children who survive GACI typically go on to develop ARHR2. Adults living with ARHR2 know better than anyone that it is a condition that affects them every single day of their lives.
This is an opportunity for patients or parents to share what it is like living with this ultra-rare disease. The goal of this study is to improve understanding of the experiences of patients with GACI/ARHR2 (ENPP1 Deficiency or ABCC6 Deficiency). Participants in this study, which is completed via a telephone survey, will receive a $100 honorarium. You may choose to have the honorarium paid by check in US dollars OR in the form of an Amazon e-gift card.
Your involvement would consist of filling out an RSVP survey, providing a document that shows proof of disease, and participation in a 40 minute telephone interview, which can be conducted in English, German, or French. Engage Health has been enlisted to conduct the interviews for this study.
There is no preparation required for you to participate. If you would like to participate in the research interviews, please:
- Click here to RSVP with dates and times that you are available. Please note that times outside of standard business hours are available.
- At the screen, please check the box that says “Check if you have no code” to proceed to the RSVP.
- If you are unable to access the RSVP from the link above, please copy and paste the following URL into your browser bar to access the RSVP:
https://www.engagehealth.com/survey/TakeSurvey.aspx?SurveyID=8252n62# or visit www.clincaltrials.gov, using the identifier NCT04372446.
Hidden at the moment:
Click here to read our official letter seeking participants in this study.
Read the official press release regarding this study here: link