I’m very far from an expert on ENPP1 (a chronic disorder involving phosphate metabolism, with a different cause from XLH), so I apologize in advance for any errors I may make in discussing it. I think it’s worth our at least trying to understand the basics, because of the exciting ENPP1 research that’s happening, with potential benefits for all patients with calcification issues.
ENPP1 was previously known as autosomal recessive hypophosphatemic rickets type 2. You know how much I hate including “rickets” in the name of hypophosphatemic disorders (including ENPP1) that are so much more than rickets, so I’m happy to see the work being done to popularize a more accurate name, based on the root cause of the phosphate wasting. (As an aside, one of the speakers at NIH’s Rare Disease Day events mentioned that he expects a lot of conditions to be renamed to better reflect their genetic roots as gene therapy begins to dominate new treatments, so my advocacy for a more accurate name for the hypophosphatemias is ahead of the curve!)
As I understand it from Medline Plus (you may need to sign up for a free subscription to access that link), ENPP1 refers to both the relevant gene location (sort of like PHEX in the XLH context) and the enzyme regulated by that gene. The enzyme is needed to produce “pyrophosphates” (you can see the phosphate aspect of the disorder there), which in turn are needed to prevent abnormal calcium deposits. The gene is located on a non-sex-determining chromosome (unlike XLH), that transmits in a recessive manner (also unlike XLH).
Unlike most cases of XLH and the other disorders caused by FGF23 excess, the ENPP1 mutation can have directly fatal consequences. During infancy, ENPP1 deficiency can cause Generalized Arterial Calcification (GACI), which, since it affects heart function, has a high mortality rate. Thereafter, I believe the symptoms are much like those of XLH, with bone growth issues in childhood, and widespread musculoskeletal issues throughout life, except that the calcifications are even more pronounced and have an even earlier onset.
To learn more about ENPP1, check out the patient advocacy group, GACI Global, or the pharmaceutical company, Inozyme Pharma.
And now for the exciting aspects of ENPP1 research. Inozyme is working on a treatment (INZ-701) that essentially replaces the missing ENPP1 enzyme. It’s currently recruiting ENPP1 patients for a combined Phase 1 and 2 clinical trial (the safety and dosage phases), and they hope to release data from the trial in the first half of 2022. They’re also hopeful that the same enzyme will treat several related conditions that will eventually have their own clinical trials. Inozyme is also doing preliminary work for gene therapy for patients with calcification disorders, and are preparing to do a natural history study of ENPP1 and a related condition (ABCC6 deficiency), which will gather information to support future applications for gene therapy approval, as well as the current enzyme therapy.
While much of this research is specific to the ENPP1 enzyme, it’s also likely to shed more light on calcification disorders in general. It always surprises me how little the medical community knows about some basic organic processes, like calcification, where there isn’t even a good model of the biochemical pathways that lead to that calcification. We need to know that biochemistry in order to disrupt it.
The medical community generally doesn’t (yet) think of XLH as a calcification disorder, since our enthesopathy is a secondary effect in adults, not the one most associated with the disorder (phosphorus and bones, especially during childhood). But patients know that the calcification issues rank high in degree of debilitating consequences in adulthood, comparable to the effects of bone pain and osteoarthritis. So the more we understand about how calcification works and how it can be interrupted, the better the chance of finding treatments that, like INZ-701 is intended to do, prevent calcification and work across several different disorders.
I remember when Ultragenyx first became involved in developing burosumab (Crysvita), and were transitioning from studying the limited and very abstract scientific research in journals to talking to actual patients. There was so much Ultragenyx didn’t know about the patients living with XLH then, and fortunately they recognized the limits of their knowledge. They did what amounts to a sort of rough precursor to a natural history study, with the results later published as “The Lifelong Impact of X-Linked Hypophosphatemia: Results From a Burden of Disease Survey.” It was, at the time, the largest collection of data on XLH patients, especially adults. That data gave Ultragenyx insights that they could then build on during the burosumab clinical trials instead of working in the dark, and the understanding of the XLH patient experience began to grow exponentially.
I’m hoping that Inozyme will likewise gain that kind of exponential growth in understanding of ENPP1 and calcification in general from their clinical trials and natural history study. And the scientific knowledge that benefits one of the phosphate-based metabolic disorder likely benefits us all. There’s already been one journal article about ENPP1 that briefly mentions a comparison of symptoms to those of XLH, “Musculoskeletal Comorbidities and Quality of Life in ENPP1-Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models.” The abstract notes, ” Residual pain, similar in magnitude to that identified in adult patients with X-linked hypophosphatemia, was experienced by the majority of [ENPP1] patients ….” I only have access to the abstract, not the full article, where there may be a more detailed comparison, but even what’s described in the abstract is immediately recognizable as matching the XLH experience.
Maybe someday GACI Global and all the XLH patient groups will work together to get a bunch of patients from the two disorders together to compare our experiences. I’ve met other patients with TIO but never one with ENPP1 (at least not in person, although I’ve corresponded with one online). Wouldn’t it be great to be able to share our stories, see what the main similarities are and where the significant differences are? Throw in a few TIO and autosomal dominant hyophosphatemia patients, maybe a few with non-phosphate-wasting bone disorders, like OI and fibrous dysplasia, and just imagine what we could learn!
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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