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Diseases of Abnormal Mineralization
Inozyme Pharma is developing novel therapeutics for the treatment of diseases of abnormal mineralization impacting the vasculature, soft tissue, and skeleton. Mineralization is a biological process by which an organism deposits calcium salt crystals, typically calcium polyphosphates, onto an organic extracellular matrix that gives rise to essential structures, such as bone and teeth. In humans, this normal mineralization process begins as early as in fetal development and continues throughout life. Diseases of abnormal mineralization have high levels of morbidity and mortality and can have a genetic and non-genetic basis.
The Mineralization Pathway
Mineralization in the human body is regulated by a metabolic pathway that has been conserved throughout evolution in higher organisms. Multiple enzymes and other proteins perform sequential reactions in this key pathway as part of a normal mineralization process.
In a properly functioning mineralization pathway, the protein encoded by the ABCC6 gene located on the cellular membrane is responsible for transporting adenosine triphosphate, or ATP, from inside a cell to outside the cell. The enzyme encoded by the ENPP1 gene then cleaves ATP into pyrophosphate, or PPi, and adenosine monophosphate, or AMP. PPi is a potent regulator of mineralization and, in particular, controls the rate of calcium crystal deposition in bone. AMP is further metabolized into adenosine, a potent regulator of cellular proliferation that, in particular, modulates a blood vessel’s response to injury and is responsible for preventing neointimal proliferation, or the overgrowth of smooth muscle cells inside blood vessels.
This key mineralization pathway normally functions as illustrated below:
Any alteration or disturbance to the key mineralization pathway can result in both genetic and non-genetic conditions involving abnormal mineralization. These genetic conditions include ENPP1 and ABCC6 deficiencies, both of which are systemic, progressive, and continuous diseases occurring over the course of a patient’s lifetime, starting as early as during fetal development and extending into adulthood.
Genetic mutations affecting ENPP1, a critical enzyme in the mineralization pathway, result in low levels of PPi and AMP, a precursor of adenosine. Genetic mutations affecting ABCC6, a critical protein in the mineralization pathway, decrease the availability of extracellular ATP required for proper ENPP1 function and give rise indirectly to low levels of PPi and AMP.
Low levels of PPi lead to abnormal mineralization and pathological calcification in areas of the body where it should not occur. This condition, known as ectopic calcification, occurs in the vasculature and soft tissue, including multiple organ systems, and results in disease affecting the heart, kidneys, and skin. When ectopic calcification occurs in blood vessels inside bones, it can also interfere with normal skeletal mineralization.
ENPP1 Deficiency Leads to Calcification of the Vasculature of the Arteries and the Bones
Low levels of adenosine lead to the narrowing and obstruction of blood vessels caused by neointimal proliferation, potentially resulting in cardiovascular disease.
Neointimal Proliferation is a Second Consequence of ENPP1 Deficiency
The consequences of genetic mutations affecting ENPP1 and ABCC6 are depicted in the figure below.
ENPP1 is a Key Regulator of Biological Mineralization and Cell Proliferation