The What and the How
October 9, 2018
I tend to multi-task, thanks to a little help with some modest technology. During any given day I will have a long to-do list on my computer desktop, supplemented by calendar reminders that pop up in the nick of time during the day. I am vast. I contain multitudes.
If something unexpected happens that demands my attention, some of those things may go unchecked and neglected. A single disruption can create problems with seemingly unrelated tasks.
Some genes can be this way too. Though we often associate a single function with a gene involved in a genetic disease, a disruption to a gene can affect someone in ways that may seem otherwise unrelated. Some genes can do more than one thing at a time.
I make this point because when it comes to diagnosing a rare condition, a symptom that to an untrained eye may seem unrelated to a certain problem can be a telltale sign to the right expert.
Consider the condition distal renal tubular acidosis (dRTA), a condition that occurs when the kidneys fail to properly remove acids from blood and push them out through urine. The resulting acid overload causes the pH of the blood to become unbalanced and results in a range of effects including failure to thrive and rickets, a condition characterized by weak bones. dRTA causes recurring kidney stones, can lead to impairment of the kidneys, and ultimately kidney failure.
But one of the other consequences of dRTA is that it can cause hearing loss leading to deafness. It turns out the gene that plays a role in the tubulars in your kidneys, also plays a role in the tubulars in your ears.
There’s no approved therapy for dRTA, but people with the condition try to address it by countering the acidity in the blood by ingesting alkalizing agents, such as sodium bicarbonate, sodium citrate, or potassium citrate. This is true for people who have the genetic form or the acquired form of dRTA, which can be caused by autoimmune disease.
When Estela Zarate’s son Diego was born, he wasn’t growing as he should, and doctors used the term “failure to thrive.” It began a three-month diagnostic odyssey for Diego and his parents.
“For us, it seemed like a very long time,” his mother said. “He wasn’t growing. There were some initial development delays.”
Diego had a severe presentation. His body was weak. He had poor muscle tone. He didn’t make eye contact. Once a nephrologist was brought on to the case, a diagnosis quickly followed. Diego had dRTA. He was the first case of dRTA his pediatrician had seen and only the second case for the nephrologist.
Caring for Diego’s dRTA was challenging. At first, his parents fed him every two hours. Six times a day, using a syringe, they would shoot awful-tasting compounds into his mouth to lower the acidity of his blood.
Today, Diego is 10 and he swallows capsules four times a day to counter the pH imbalance of his condition. Even with the treatments, he has had to contend with kidney stones and had one episode where doctors had to place a stent until a stone could be dissolved. Calcification of the kidney is an ongoing concern. He is also developing hearing loss. Right now, his hearing loss is considered mild to moderate in both ears, but his audiologist has told his parents that the hearing loss will continue to worsen.
One of the problems for Diego is the compounds he uses don’t stay in his system long enough to last through the night while he sleeps. Instead, the acidity of his blood rises as these compounds leave his system. And his doctor has warned his mother that as he moves to his teen years, getting him to comply with his dosing regimen will grow harder.
Right now, Estela Zarate is trying to enroll her son in a clinical trial being run by Advicenne that the company hopes will lead to an approval of its experimental dRTA drug ADV7103. The active ingredients are similar to what patients like Diego use every day, but its value to patients is in the formulation.
The pivotal phase 3 study is expected to enroll about 40 patients in the United States to evaluate the safety and efficacy of ADV7103 compared to a placebo in preventing the development of metabolic acidosis in pediatric and adult patients with dRTA.
Ludovic Robin, chief business and strategy officer for Advicenne, said the formulation allows patients to take a dose once every 12 hours. The drug is in the form of tiny tasteless granules that can be used by children or adults. It avoids the bad taste. And the coating allows the active ingredients to be released slowly in the gastrointestinal tract rather than in the stomach, where these substances can cause a problem with gas.
“It will have a major impact on compliance,” said Robin. “It will also avoid the peaks and valleys in the blood.”
This may fall short of a lot of the gee-whiz science driving the rare disease pipeline these days, but it does have the potential to greatly improve the quality of life and management of the disease for patients like Diego. Sometimes innovation is not about the what, but the how.
Which brings me back to my to-do list and calendar reminders that have become so essential to keeping me functioning during the day. It’s not that I’m incapable of remembering what I need to do but using my computer to take care of this takes a lot of strain off my brain and let’s me manage my day with much greater efficiency and effort. I can meet deadlines and avoid jumping on conference calls late.
Of all the things my computer does, this function is among the most easily replaced with pen and paper. It is perhaps the least bit of high-tech wizardry I call on all of this hardware to perform on any given day, but I’ve learned to appreciate how valuable it can be.
October 9, 2018
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