Tag: inherited genetic disorders

Improving Diagnosis of Chronic Lung, Ear and Sinus Infections in Young Children

Young girl sneezing
Photo by Andrea Piacquadio on Unsplash

An international Task Force has recommended a method to help diagnose preschool age children with Primary Ciliary Dyskinesia (PCD), a rare, inherited condition that leads to chronic lung, ear and sinus infections. The Task Force’s findings were published in the European Respiratory Journal.

Children with PCD have a problem with mucus build-up, which leads to inflammation in the airways and infections in the lungs, nose, sinuses and ears. Most people with PCD have symptoms from birth or early childhood. But some children with PCD may not be diagnosed until much later.

Currently, a commonly used diagnostic test for PCD is measuring the nitric oxide (nNO) in the nose using a chemiluminescent analyser. This involves holding a sampling tube at the nostril, whilst the patient either holds their breath, or breathes out through their mouth against a resistance – but for young children such controlled breathing isn’t always practical. Furthermore, chemiluminescence analysers are extremely expensive, not portable, and not available in most countries.

Jane Lucas, Professor of Paediatric Respiratory Medicine at University of South Hampton, led an international Task Force to review existing studies and literature to establish whether there were more effective and accessible methods of diagnosis for PCD in younger children.

The task force concluded that although holding the breath or breathing against a resistor whilst using a chemiluminescence analyser was more reliable in older children and adults, adequate measurements could be achieved by measuring nasal nitric oxide whilst a pre-school child breathes normally and should be the standard way when diagnosing PCD in children under the age of five.

The Task Force also suggested that although chemiluminescence analysers are more reliable, the relatively inexpensive electrochemical devices have a role in healthcare systems with limited resources. They also recognised that the portability of electrochemical devices may be useful in countries where patients live long distances from a specialist centre, enabling the specialist to travel to the patient.

“We know that the earlier we can diagnose a condition, the better the chances are of implementing the best treatment plan for the patient,” Professor Lucas said. “But current guidelines and technical standards focus on nNO measurements in older, cooperative children using technology that is not widely available.

“Pre-schoolers often need different methods to be employed when measuring nNO, methods that are less invasive and adaptable. Without guidelines for younger children, and electrochemical analysers there is huge variability in how people take the measurements and interpret them.

“This paper is the first step towards standardising sampling, analysis, and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups including preschool-age children. We hope this will promote earlier diagnosis of PCD, and a standardised approach to interpreting and reporting results.”

The task force also recommends that future research is needed to ensure the technical standard is kept up to date.

Source: University of Southampton

Oil Exploration Software Reveals why Cystic Fibrosis Drugs Fail

Photo by WORKSITE Ltd. on Unsplash

Scientists have harnessed a computational approach usually used in oil exploration to search for cures for rare genetic diseases such cystic fibrosis. By using the method to analyse the spatial relationships between different variants of a protein, instead of the relationships between test wells across an oil field, the researchers can obtain valuable information on how disease affects a protein’s underlying shape and how drugs can restore that shape to normal.

The new method, detailed in the journal Structure, runs with just a few gene sequences collected from people with disease. Then, it determines how the structure of each corresponding variant protein is associated with its function, and how this functional structure can affect pathology and be repaired by therapeutics. To test the techniques, the researchers showed why existing drugs for cystic fibrosis fall short of curing the disease.

“This is an important step forward for treating rare diseases,” said senior author William Balch, PhD, professor of Molecular Medicine at Scripps Research. “The fact that we can get so much information from a few gene sequences is really unprecedented.”

Studies on inherited diseases often rely on the precise three-dimensional shape of a protein affected by disease. But genetic diseases can be caused by thousands of gene variants, some of which destabilise or change the protein shape in ways that make isolating the protein for further investigation much more difficult than usual.

Prof Balch, with Scripps Research senior staff scientist Chao Wang and staff scientist Frédéric Anglés, instead wanted to use natural variation to their advantage. So the group developed a method called variation-capture (VarC) mapping to analyse the natural array of gene sequences which exist in the human population and determine the mechanism by which they each changed a protein’s structure to cause disease.

Among other statistical tools, Prof Balch’s group integrated the methods that oil companies use to draw inferences about the location of an oil reservoir using only a small number of test wells. With only a few gene sequences, this let the researchers determine the most likely structural mechanisms driving function for each variant leading to disease, as well as model how drugs impacted those structural functions.

In the case of cystic fibrosis, disease is caused by genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), leading to a buildup of mucus in the lungs. More than 2000 variants of the CFTR gene have been identified, and many of these variants were known to have very different effects on the CFTR protein, but it has been difficult to compare and contrast these variants to guide how patients with different variants should be treated differently in the clinic.

“When you want to treat patients, you really have to appreciate that different therapeutics might target different variants in completely different ways, and that’s why our approach that looks at many different variants all at once is so powerful,” explained Wang. “Our approach not only reveals how these variants contribute to each patient’s biology, but also connects them in a way that each variant can inform how to manage the others.”

The researchers input about 60 genetic variants found in the cystic fibrosis population into their VarC program. The analysis captured how each amino acid residue talks to every other residue to generate function, and revealed that most of the cystic fibrosis patients had the same net effect on the protein: an unstable inner core.

When the program modelled how existing cystic fibrosis drugs impacted the structures, the researchers discovered that, despite the drugs’ effect on CFTR structure, none of them effectively stabilised the protein’s hidden inner core. This was like how the location of an oil reservoir in a complex landscape can be revealed by test wells.

Now that the researchers better understand the structural deficiencies in CFTR in cystic fibrosis patients, they say that the job of developing an effective drug to fix it is much easier. Potential compounds can be modelled in advance of lab experiments for their effect on the inner core of the CFTR protein.

“In most drug discovery, you throw thousands of compounds at a protein and see which ones change it, often without fully understanding the mechanism,” said Prof Balch. “To fix a thing, you must first understand the problem.”

Already, his team is applying the method to other rare genetic diseases, as well as pursuing new drugs to treat cystic fibrosis.

Source: Scripps Research Institute

Rapidly Correcting Genetic Disorders

Image source: Pixabay

Researchers have developed a new method to precisely and rapidly correct genetic alterations in cultured patient cells.

The genetically corrected stem cells are produced from a 2–3 mm skin biopsy taken from patients with different genetic diseases. The corrected stem cells are essential in the research and for the development of new therapies for the diseases in question.

The scientists based the new method on previous groundbreaking research in the fields of stem cells and gene editing; the first technique is the invention of induced pluripotent stem cells, iPSCs from differentiated cells, which won the Nobel in 2012. The other technique is the CRISPR-Cas9 ‘gene scissors’, which got the prize in 2020. The new method combines these techniques to correct gene alterations that cause inherited diseases, creating fully functional new stem cells.

The researchers aim to eventually produce autologous cells with therapeutic properties. The use of the patient’s own corrected cells could help in avoiding the immunological challenges hampering the organ and tissue transplantation from a donor. The new method was developed by PhD student Sami Jalil  and is published in Stem Cell Reports.

More than 6000 inherited diseases are known to exist, which are caused by various gene alterations. Currently, some are treated with a cell or organ transplant from a healthy donor, if available.

“Our new system is much faster and more precise than the older methods in correcting the DNA errors, and the speed makes it easier and diminishes also the risk of unwanted changes,” commented adjunct professor Kirmo Wartiovaara, who supervised the work.

“In perfect conditions, we have reached up to 100 percent efficacy, although one has to remember that the correction of cultured cells is still far away from proven therapeutic applications. But it is a very positive start” Prof Wartiovaara added.

Source: University of Helsinki