Following 16 years in healthcare venture capital, Axel Bolte turned entrepreneur by founding Inozyme, a rare disease company committed to bringing novel treatments to diseases of abnormal mineralisation. Axel spoke to our digital editor Geoff Case about ENPP1 Deficiency and ABCC6 Deficiency (two closely related, rare genetic disorders) and their impact on individuals

Mineralisation disorders

The skeletons of mammals form through a specific process of mineralisation that has evolved in a unique way. The process depends upon enzymes catalysing pyrophosphate (PPi) to form calcium phosphate, the molecular building block for bone. “Mineralisation is absolutely fundamental to the human skeleton, and you don’t want to have a problem with it,” said Axel Bolte, MSc, MBA, Inozyme co-founder, president, and chief executive officer. “We want hard inorganic material to develop at the right place in the skeleton, and we don’t want calcification anywhere that should be soft. But, unfortunately, problems do arise.”

The problems that can occur in the biological pathways for mineralisation are well understood by scientists, but unfortunately few drugs have yet been developed to resolve them.

“ENPP1 Deficiency and ABCC6 Deficiency sit on a spectrum of related disorders of abnormal mineralisation. Historically, ENPP1 Deficiency has been described in different ways in the medical literature: Generalised Arterial Calcification of Infancy Type 1 (GACI) and Idiopathic Infantile Arterial Calcification (IIAC). Both terms highlight how the disease can begin in infancy, right after birth, or sometimes even before birth. Where the disease begins later, in adolescence, it is described in the literature as Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2). Likewise, ABCC6 Deficiency has been described in the literature as GACI Type 2.”

ENPP1 Deficiency

ENPP1 Deficiency is a rare and life-threatening genetic disorder, named after a mutation in the ENPP1 gene. The role of that gene is to produce the ENPP1 enzyme, which has a critical function in mineralisation because it maintains pyrophosphate at the right level. Without the pyrophosphate, there won’t be a proper mineralisation process, so the body’s soft tissues calcify, causing disease. The clinical signs of ENPP1 Deficiency may appear at any stage from before birth to adulthood. Even though the condition is ultra-rare, the symptoms that appear in infants are so clear that a diagnosis can typically be readily made.

“Calcifications in the vasculature can be detected in infants or even prenatally through simple techniques such as ultrasound, or by more sophisticated imaging techniques, such as X-rays or CT scans,” Bolte said.

Scans may reveal evidence of ectopic mineralisation: calcification of the arteries, organs and joints, resulting in stiffening, blocking and reduced function. “The most sensitive bodily system is the cardiovascular system, and calcification creates such heavy stress on the heart of newborns with ENPP1 Deficiency that many quickly die from cardiac failure,” Bolte explained. Natural history studies of ectopic mineralisation show a mortality rate of around 50 to 60% in the first 6 to 12 months.

“Patients who survive infancy mostly reach adulthood, but they will experience quite severe skeletal problems: they will have skeletal dysplasias (abnormalities of bone growth); generally, be very short owing to impaired bone growth; and experience permanent fatigue and considerable pain because of these skeletal issues,” said Bolte. “They will also have soft bones as a result of the imbalance in pyrophosphate. Frequently, patients don’t hear well, or at all, because the cilia in the ear are impaired.”

Unfortunately, patients may acquire significant comorbidities throughout their lives. Spinal stenosis (narrowing of the spaces within the spine) is common. Cardiovascular problems arise because the arteries may become blocked. Strokes are also a risk because the brain may calcify.

Sadly, there are currently no approved therapies specifically for ENPP1 Deficiency, and the standard treatments (drugs to assist cardiac function and bisphosphonates, intended to replicate pyrophosphate) do little to improve outcomes for patients.

ABCC6 Deficiency

ABCC6 Deficiency, caused by mutations in the ABCC6 gene, is another rare and life-threatening disorder of abnormal mineralisation. The ABCC6 enzyme is part of the same biological pathway for mineralisation as the ENPP1 enzyme, so the genetic mutations similarly lead to a low amount of pyrophosphate. In contrast to ENPP1 Deficiency, ABCC6 Deficiency has a slower onset, less severe symptoms and significantly less mortality. The prevalence is, however, much higher.

“ABCC6 Deficiency is progressively debilitating, and we could describe it as a slow-motion version of ENPP1 Deficiency,” noted Bolte. While, sadly, the infant population still has a mortality risk, the majority of patients don’t present with symptoms until their late adolescence or twenties, and in some cases, it is diagnosed but doesn’t affect life too much.”

Symptoms that may arise in adolescence and into the twenties include dermatologic changes, yellowish bumps called papules, ocular changes and angioid streaks (a retinal condition). By the third and fourth decades of life, calcifications may have accumulated in a range of soft tissues. This can potentially cause pain, peripheral arterial disease (which results in pain during walking), cardiovascular issues, stroke and skin calcification lesions (calcium deposits that appear as hard bumps).

“By the time patients affected by calcifications reach their 40s and 50s, many are extremely distressed by their symptoms and their disease progression,” said Bolte. “The skin is often affected, particularly in the extremities, and the majority have calcifications in the retina that can lead to blindness. For some, there is heavy implication of the cardiovascular system. They may be unable to walk short distances, and many need a heart valve replacement.”

As with ENPP1 Deficiency, there are currently no approved therapies to address the underlying cause of ABCC6 Deficiency 

The role of enzyme replacement therapy for ENPP1 Deficiency and ABCC6 Deficiency

Enzyme replacement therapy (ERT) is a medical treatment in which patients with conditions caused by enzyme deficiencies or malfunction receive a replacement enzyme. The replacement enzyme is derived from human DNA generated in genetically modified cells and processed before being given to the patient, usually by directly administering them into the bloodstream. After receiving these enzymes, the body can successfully perform the functions inhibited by the deficiency.

Biomarkers are vital in understanding a disease and how it responds to treatment because they are measurable alterations in tissue, cells or fluid. They may be used to confirm a diagnosis or help to show the severity of a disease. “Just as a high level of cholesterol is a biomarker for heart disease, a low level of pyrophosphate is a biomarker for calcification; the literature of the last three decades very clearly establishes that link,” explained Bolte. “Therefore, if a treatment produces a rise in pyrophosphate into the range found in healthy people, that very likely predicts that it is doing its job and has the potential to help patients with clinical symptoms.”

Axel explained how Inozyme’s first clinical trial for a modified version of the ENPP1 enzyme has been focusing on biomarkers and safety and has produced positive preliminary data.

“Data from the first cohort show a rapid, significant and sustained rise in levels of pyrophosphate, for all the participants,” he said. Ongoing validation is in progress, but it is hoped that the treatment, if successful, will be an at-home injectable administered by patients.

The company’s current focus is on enzyme replacement therapy, but gene therapy is a future possibility too. Theoretically, gene therapy would enable the patient’s body to create the enzyme needed for normal mineralisation.

 “While there is a lot of work to do, this is an important and encouraging result and a major step forward. Our goal would be for this therapy to be given immediately upon diagnosis, to save infants who would otherwise die.”

Links

website: inozyme.com

press release: Update for Phase 1/2 Clinical Trials in ABCC6 Deficiency and ENPP1 Deficiency

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