She Had Her Own Mutation, Sequencing Led to a Treatment and Major Genetic Discovery - Then She Died of COVID | Virus World | Scoop.it
From dnascience.plos.org - August 8, 2020 8:34 PM

It isn’t often that an investigation of a single patient who has a devastating, unrecognized disease leads to finding an existing drug that works, but also reveals something entirely new about gene function. A study from Dusan Bogunovic, PhD, Director of the Center for Inborn Errors of Immunity at the Icahn School of Medicine at Mount Sinai and colleagues just published in the journal Immunity, tells such a tale. The young woman was only 18 when the investigation began. Her death from COVID-19 tragically juxtaposes the challenges of treating an ultrarare genetic disease with those of a pandemic infectious disease. “We were so so sad when she passed. She was doing so well for the first time in her life for full 2 years. She was very happy, and her family was very happy to see her that way,” said Dr. Bogunovic.

An Immune Response in Overdrive - Problems started right away.

 

The patient was born with an oozing rash that striped the left side of her body – which would turn out to be a clue. At a year of age she developed persistent diarrhea and vomiting, and tests showed massive inflammation along her digestive tract. At age three she ballooned with sudden water weight as protein seeped into her urine from damaged kidney tubules. But her overactive immune system rejected a transplant, anti-rejection drugs weakened her, and she went on dialysis. Then asthma and food and environmental allergies kicked in. Her growth slowed. Although her condition didn’t have a name, it was clearly autoinflammatory. The innate immune response, the part that controls the signals that release cytokines, was always in overdrive, inflaming her own tissues. The researchers found the patient in an “undiagnosed disease program” at Mt. Sinai, one of several that the National Institutes of Health sponsors, where patients with unusual collections of signs and symptoms, many of them children who’ve been through grueling “diagnostic odysseys,” have their genomes searched for causative mutations. The programs help connect patients and researchers. The young woman had a previously unknown mutation in a well-studied gene called JAK1. Matching a mutation in a single gene to a disease is valuable because it can identify a specific glitch in a protein, and that can suggest therapeutic strategies – including existing treatments. In this case, a drug already available to treat two other autoimmune conditions, rheumatoid arthritis and psoriatic arthritis, made sense: tofacitinib, known from drug ads as Xeljanz. It’s a daily pill, a “JAK inhibitor.”

The researchers nailed down the mechanism using a powerful and increasingly prevalent technique, “custom single-cell RNA sequencing.” Scrutinizing one cell at a time better reflects molecular happenings than analyzing all the RNAs that fall out of a mashed up tissue sample consisting of more than one cell type. It’s a signal-to-noise issue. The four types of JAK genes – that stands for “Janus kinase” – encode enzymes (kinases) that turn on other genes. The JAK genes control production of cytokines, and the gene that was mutant in the young woman – JAK1 – controls more than 25 of them. Cytokines must be in precise, dynamic balance to prevent infections while not raging out of control and backfiring, which happens in the “cytokine storms” that kill during COVID.  The young woman’s mutation was unusual in several ways. First, instead of abolishing a gene’s function, it not only ramps it up, but affects cytokine types that JAK enzymes usually don’t. In genetics we call this a “toxic gain-of-function.” A second peculiarity is that the mutation was only in some of the young woman’s cells, making her a genetic mosaic. Perhaps the mutation had never been identified before because having it in every cell is unsurvivable. There’s precedent for a mosaic being a milder case. Jesse Gelsinger, the young man who died in a gene therapy trial in 1999, was a mosaic for a metabolic disorder; infants with the mutation in every cell die without treatment...

 

Original study published in Immunity (August 3, 2020):

https://doi.org/10.1016/j.immuni.2020.07.006