< strong>▎WuXi Editor of Kangde Content Team< /h1>If you knew from a young age that you would eventually live beyond 40 due to incurable kidney disease, would you resign yourself to it?
Would you still choose to have children if you knew there was a 50% chance that this terrible disease would be passed on to the next generation?
Then if you know that you are not fighting alone, and that there are a group of people who are also working tirelessly to unravel the genetic curse tied to your body like you, will you have Different options?
Today’s story, we will unfold from a girl with a rare inherited kidney disease…
< strong>FatherDear Tommy CarrollDeath of ErOttom Steen (Autumn Steen) is an ordinary girl who grew up in Asheville, North Carolina, USA. Her life before the age of 17 was no different from that of her peers, with peaceful parents, rowdy but good relationships with her siblings. It wasn’t until one evening at the age of 17, when she came home from summer Bible school that she was greeted by her father’s icy corpse and her mother, leaning against the porch, sobbing uncontrollably.
She knew that her father had been on dialysis to maintain a normal life, and that more than half of his father’s 13 siblings suffered from the same The pain of her kidney disease, but she was not ready to accept that her father might leave at any time, all this was too sudden for her.
▲ span>autumwith her father on Park Avenue Group photo above (Courtesy Autumn Steen; Image source: Reference [1])
He is happy before going out tomorrow morning Why do people who are chatting about the sky suddenly say that they are gone? My father is only 50 years old!
Ottom ran wild to church, a fact she couldn’t accept. She even developed boundless anger towards religion, life and God: “Isn’t the doctrine that good people are rewarded? Father shouldn’t have this kind of terminal illness! It’s not fair!”
< /p>However, notOttom onlyparent< /strong>Dear brothers and sisters did not escape fate, autumsameNeither.
Finding Answers to Familial Kidney Disease Mystery Since father Tommy Carroll died in 2004, Ottom span>I have always wanted to find the answer to my family’s inherited kidney disease. To this end, she decided to go to college in Chapel Hill, North Carolina. She wanted to become a pharmacist. Maybe becoming a medical worker would have a chance to get closer to the answer? She was also the first in their family to do so. In college, although she could receive emails about the latest research on her family’s ailments, she didn’t get a few in a few years.
Actually, there are many other people in other corners of the world who suffer from the same predicament as the Carroll family. On a small island in the eastern Mediterranean called Cyprus, families are battling a rare genetic kidney disease with no cure. In Salt Lake City, USA, a large family was also found to suffer from the same disease, and each generation has a 50% chance of passing on the gene mutation to the next generation. The kidneys of these unfortunate patients who inherit the genetic mutation usually stop working in their 30s and 40s, requiring dialysis or a new kidney transplant to have a chance to survive.
Genetologists have done extensive genetic testing of these patients, but have never been able to find the cause of this inherited kidney disease. It wasn’t until 2001 that researchers at the Wake Forest School of Medicine identified the gene responsible for the disease in Carroll’s family mutation, and started a registry, hoping to find more families with the disease.
However, another mysterious genetic mutation that causes this inherited kidney disease was not identified until 2013 by Burrow, an MIT-Harvard co-founder Three scientists from the Broad Institute and Wake Forest School of Medicine found and published their findings in Nature Genetics.
This mutation was previously affected by massively parallel sequencing. The limitations of the detection technology could not be found, and scientists finally discovered the mutation caused by the insertion of a single “C” base in the MUC1 gene through capillary electrophoresis sequencing. But unfortunately, they also don’t know exactly how the mutation causes this catastrophic kidney disease, and naturally cannot help patients like Ottum to find a cure A cure for disease.
“Savior” is bornResearch progress on this rare disease seemed to have stalled until her appearance.
Anna GrekaAnna Greka isa physician and scientist. She was born into a medical family, her father was a nephrologist and her mother was a pathologist. Instilled by her parents, she has a strong interest in medicine and science since she was a child, and she aspires to become a doctor and a scientist when she grows up. Through tireless efforts, she eventually entered Harvard University to study neuroscience. In 2005, while Anna was browsing the Internet for the latest research on ion channels, her doctoral subject, a publication in the journal Science came to her attention.The ion channels in this study were linked to an inherited kidney disease Disease is highly correlated. Perhaps out of sadness and regret for the poor boy of the same age that his father treated when he was a child – the little boy was only 24 years old after suffering from kidney disease for more than ten years She passed away early; or perhaps she grew up in the 1980s. Since childhood, she has longed for the great scientists who effectively alleviated people’s panic about AIDS when AIDS was raging. After seeing this study, Anna resolutely changed her research direction and devoted herself to the research of kidney disease. She is desperate to find out which ion channels malfunctioning can lead to kidney failure.
The mystery of rare diseases is revealed, and the dawn is emergingIn January 2012, Anna established her first laboratory in Massachusetts. Although there were only her and a few staff members in the lab for a long time due to lack of funds, they still found ion channels associated with kidney failure and found evidence in mouse experiments.
The filtration function of the kidneys is to retain essential proteins while removing wastes from the body. When the filtration barrier is damaged, proteinuria and urine The presence of albumin is also a marker of cardiovascular disease and renal failure. Ana and her staff found that when TRP ion channels (an ion channel that Ana had focused on during her graduate studies) were overactive, the influx of calcium ions into cells caused podocytes, the visceral epithelial cells of the renal capsule, to be the The cellular structure of one of the tissue structures that constitute the glomerular hemofiltration barrier) is destroyed, and the filtration barrier is damaged. Inhibiting a subtype of the channel called TRPC5 prevented the disintegration of these key cells.
▲ span>TRPC5 regulates kidneyModel of dirty filter function (picture from reference [3])< /p>
It’s no coincidence that, in 2013, researchers at the Broad Institute discovered a genetic mutation associated with inherited kidney disease, and its director, Eric Lander ) Ph.D. is also interested in this field. At a scientific meeting in 2014, Eric happened to be sitting with Anna, and after learning about Anna’s research, he hit it off and invited Anna to the Broad Institute for targeted research in January 2015.
After coming to the Broad Institute, Anna soon achieved results. With the help of a diverse team, she finally uncovered the cause of this rare kidney disease reason. The researchers found that mutations in the MUC1 gene discovered in 2013, resulting in the insertion of a single “C” base, resulted in a horde of malformed misfolds that could not be broken down by lysosomes of a protein called MUC1-fs, accumulation of this toxic protein causes autosomal dominant tubulointerstitial disease-MUC1 (ADTKD-MUC1).
The mystery of a rare familial inherited kidney disease that has plagued Ottom for years is also being solved. The hereditary nephropathy in their family is caused by the accumulation of a sister protein of MUC1, proteinuria-modulating protein (UMOD), called ADTKD-UMOD, which belongs to the same toxic protein accumulation disease as ADTKD-MUC1 discovered by Anna’s team. In fact, toxic protein accumulation diseases are not uncommon in daily life, such as some dementias, amyotrophic lateral sclerosis, Parkinson’s disease, etc., are caused by different types of toxic protein accumulation.
Image source: 123RF
More exciting than the discovery of the cause is that through the Broad Institute’s Center for Drug Repurposing database, Anna and staff also discovered BRD4780, a potential drug for this toxic protein buildup. Researchers have discovered that a specific molecule called TMED9 plays an important role in BRD4780’s treatment of toxic protein build-up disease. When TMED9 interacts with Binding of MUC1-fs can prevent MUC1-fs from being sent to lysosomes for degradation, and when using BRD4780 to bind to TMED9, MUC1-fs is released, redirected to lysosomes and then degraded and cleared, preventing kidney cell death. The research results were published in the internationally renowned journal “Cell” in July 2019.
▲Roscoe Nelson, Patriarch of the Nelson Family (Roscoe Nelson) 100-year-old family photo (Courtesy Nelson family, the picture comes from reference [1])
Another patient, Marcia Ann Ludlow, a devout Christian, survived 10 years on dialysis after a failed kidney transplant in 2007. A few months after her death, her brother and son founded the Rare Kidney Disease Foundation. Dr. Anna encouraged them to organize a party once a year and bring together patients with the same mutation.
EndThis is the end of the whole story . So, back to the question at the beginning of the story, do you have an answer?
At least, autum has its own answer.
It took her three years to screen embryos that did not carry this gene through in vitro fertilization, and finally gave birth to a lovely daughter, Eva, who is currently Already two years old.
Although the clock hanging over Ottum is still counting down, maybe in the not-too-distant future she will have to visit every three months Nephrologist, weeklyHad to spend three days on dialysis or, alternatively, have a kidney transplant and be on medication all the time. But at least she now has another possibility.
Since the discovery of that potential drug, Autum has conducted annual consultations with physicians at Wake Forest School of Medicine. More than one call. And since these meetings included not just the Carroll family, but hundreds of people from all over the world, she was comforted that autum would no longer be alone.
Autum said, “I just want to enjoy the sweet times right now because it’s not always easy.”
It is hoped that BRD4780 can successfully pass the follow-up clinical trials and that patients with such rare kidney diseases will have medicines for treatment as soon as possible. From this story, we can get a glimpse of the difficulties in rare disease treatment and drug development. Perhaps for rare diseases, being able to be correctly diagnosed and discovered is already a major problem, and subsequent cause exploration and drug development require a combination of efforts and opportunities. But we can also find that whether it is clinicians, scientists, various social organizations, or patients and their families, the small efforts of innumerable individuals can be combined into a powerful force, making the impossible possible! Although the development of a rare kidney disease drug is full of hardships and ups and downs, with the advancement of technology and the unremitting efforts of human beings, we can still see the hope of conquering this kind of disease!
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