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Scientists have created new &#8220;molecular traps&#8221; that were able to improve survival in cell and fruit fly models of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) associated with mutations in the gene C9ORF72.
The traps bind to the toxic small proteins that arise from the mutated C9ORF72 gene and have a harmful effect on protein production and cell survival. The traps may offer a new approach to protect neurons from such damaging proteins, said researchers in &#8220;<a href="https://www.science.org/doi/10.1126/sciadv.adf7997">CLIP-Seq analysis enables the design of protective ribosomal RNA bait oligonucleotides against C9ORF72 ALS/FTD poly-GR pathophysiology</a>,&#8221; which was published in <a href="https://www.science.org/journal/sciadv">Science Advances</a>.
Mutations in the gene C9ORF72 are the most common known <a href="https://alsnewstoday.com/causes-of-als/#Genetics_of_ALS">genetic cause of ALS</a>. Disease-causing mutations in this gene lead to abnormal proteins called dipeptide repeat proteins, or DPRs, being produced, which are toxic to nerve cells.
DPRs can stick to other proteins in cells and it&#8217;s long been thought this is mainly what makes them toxic. But they also can stick to ribonucleic acid (RNA), scientists discovered here.
RNA is an intermediary molecule made when genes are &#8220;read&#8221; to create proteins. The genetic code is copied from a cell&#8217;s DNA into RNA, which is used as a template to make protein by ribosomes, the cell&#8217;s protein-making machines. Ribosomes also contain specialized RNA molecules that help them &#8220;read&#8221; RNA to create proteins.
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<h3>Making a better &#8216;molecular trap&#8217;</h3>
Through molecular testing, the researchers demonstrated that a specific DPR known as poly-glycine-arginine (poly-GR) can bind to the RNA inside ribosomes. The scientists figured out where the poly-GR protein and the ribosomal RNA molecules were interacting and showed that these interactions could interfere with ribosomes&#8217; job of making new proteins.
&#8220;We found that poly-GR directly binds to multiple [ribosomal] RNA species in cells and impedes ribosomal [normal functioning],&#8221; the scientists wrote.
This &#8220;interaction between Poly-GR and the [ribosomal] RNA is stronger than the interaction between the Poly-GR with other ribosomal proteins that had been previously described in other studies, and it tells us why these dipeptides have a high affinity for binding to ribosomes in cells,&#8221; Juan Alberto Ortega Cano, PhD, a co-author of the study at the University of Barcelona in Spain, said in a <a href="https://web.ub.edu/en/web/actualitat/w/new-therapeutic-strategy-to-reduce-neuronal-death-in-amyotrophic-lateral-sclerosis?tn=np">press release</a>.
Based on these findings, the scientists created &#8220;molecular traps,&#8221; the basic idea being to make an RNA molecule with a similar structure to the ribosomal RNA that could act as &#8220;bait&#8221; to draw away the toxic poly-GR.
In a lab model of human nerve cells carrying ALS-causing C9ORF72 mutations, treatment with the molecular traps led to significant improvements in cellular survival.
&#8220;It reduces the defects in ribosome biosynthesis in protein translation and toxicity in cells expressing Poly-GR, as well as death in motor neurons of ALS patients with mutations in the C9orf72 gene,&#8221; Cano said.
The molecular traps also improved survival outcomes in a fruit fly model of ALS caused by this mutation.
&#8220;Although more work is required to understand how the binding of [these molecular traps] to poly-GR alleviates its pathophysiology, the promising results we present here support the notion that using bait RNAs is useful not only to study RNA-protein interactions, but also to protect neurons from the detrimental effects of mutant or aberrant proteins,&#8221; the scientists said.

‘Molecular traps’ may help fend off nerve damage from gene mutations

<a href="https://arrowheadpharma.com/">Arrowhead Pharmaceuticals</a> has filed an application in Australia seeking the green light to launch the first clinical trial of ARO-SOD1, its RNA-based therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The therapy is designed to reduce SOD1 protein levels in ALS patients carrying SOD1 mutations, which are estimated to account for about 2% of <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a> cases and up to 20% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic cases</a>.
Pending clearance from the Australian Department of Health and Aged Care, Therapeutic Goods Administration, ARO-SOD1 may become the first candidate developed with Arrowhead&#8217;s proprietary <a href="https://arrowheadpharma.com/science/">Targeted RNAi Molecule (TRiM) platform</a> for delivery to the brain and spinal cord to enter clinical studies.
The AROSOD1-1001 Phase 1 trial is designed to assess the safety, tolerability, and pharmacological properties of ARO-SOD1 in people with ALS-SOD1. It is expected to enroll 24 adult patients who will receive ascending doses of the medication or a placebo.
“The ARO-SOD1 program entering clinical studies represents the further expansion of our proprietary TRiM platform, which now includes product candidates addressing a multitude of diverse disease areas that target the liver, lung, muscle, and CNS [central nervous system],” Chris Anzalone, PhD, president and CEO of Arrowhead, said in a <a href="https://www.businesswire.com/news/home/20230627815548/en/Arrowhead-Pharmaceuticals-Files-for-Regulatory-Clearance-to-Initiate-a-Phase-1-Study-of-ARO-SOD1">company press release</a>.
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<h3>ARO-SOD1 is designed to target SOD1 messenger RNA</h3>
Mutations in the SOD1 gene lead to the production of an abnormal SOD1 protein prone to aggregate and form clumps in nerve cells, which causes nerve cell death and contributes to ALS progression.
ARO-SOD1 is an RNA interference (RNAi) therapy designed to target the SOD1 messenger RNA (mRNA), an intermediate molecule that&#8217;s produced when the gene is read and serves as a template for protein production.
RNAi is a natural process of gene silencing in which small RNA molecules, called interfering RNAs, bind to a specific mRNA and target it for destruction, ultimately preventing protein production. Thus, by binding to SOD1 mRNA molecules, ARO-SOD1 can significantly lower the production of toxic SOD1 proteins.
The therapy is injected into the spinal canal — called an intrathecal administration — allowing the therapy to reach the CNS where it is expected to prevent the buildup of the abnormal SOD1 protein, and, consequently, slow disease progression.
<a href="https://alsnewstoday.com/news/arrowhead-will-seek-ok-test-rna-therapy-aro-sod1-clinical-trial/">Preclinical data</a> showed ARO-SOD1 was highly active against SOD1 mRNA across multiple different models. In a SOD1-ALS rat model, a single injection into the spinal canal was sufficient to reduce SOD1 mRNA by 95% in the spinal cord.
Also, studies with nonhuman primates showed the therapy has sustained effects, with 80% of SOD1 mRNA remaining depleted for three months after a single intrathecal dose.
According to Arrowhead, these findings suggest ARO-SOD1 may require four or less annual injections, much fewer than the monthly intrathecal injections required for <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen), an RNA-based therapy that recently <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/">gained conditional approval</a> in the U.S. for the treatment of ALS patients with SOD1 mutations.

Application filed in Australia to launch first trial of ARO-SOD1

A sizable portion of people with sporadic <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) carry a genetic mutation known to cause other neurological disorders, a new study shows.
&#8220;This suggests shared risk factors among these diseases, shared mechanisms that cause nerves to die – and perhaps shared therapeutic strategies in the future,&#8221; Kelly Williams, PhD, associate professor at Macquarie University in Sydney and co-author of the study, said in a <a href="https://lighthouse.mq.edu.au/for-media/study-finds-some-mnd-and-dementia-patients-share-genetic-defects">press release</a>. &#8220;While the causes of sporadic [ALS] and FTD [frontotemporal dementia] remain unknown, this is an important step in a long-term effort to identify the risk factors for developing one of these diseases.&#8221;
The study, &#8220;<a href="https://www.science.org/doi/10.1126/sciadv.ade2044">Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia</a>,&#8221; was published in <a href="https://www.science.org/journal/sciadv">Science Advances</a>.
ALS is characterized by the gradual death and dysfunction of motor neurons, the nerve cells that control movement. While <a href="https://alsnewstoday.com/als-and-genetics/">some mutations</a> have been linked to ALS, the vast majority of people with <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> have no known mutation associated with the disease.
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<h3>STR expansion can disrupt gene function, cause disease</h3>
Within a person&#8217;s DNA, many genes contain short tandem repeats (STRs) — sequences where a few nucleic acids (the building blocks of DNA) are repeated over and over again. These repetitive regions are important for regulating gene activity.
Sometimes, the repetitive region in STRs will duplicate or expand, so the repeat becomes much longer than normal. This type of mutation, called an STR expansion, can disrupt gene function and cause disease. In fact, the most common ALS-causing mutation is an STR expansion in the gene C9ORF72.
STR expansions in other genes have been shown to cause other neurological disorders. For instance, an STR expansion in the gene HTT is the cause of <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington&#8217;s disease</a>, while STR expansions in the genes ATXN1, ATXN2, and ATXN8 cause a group of movement disorders known as spinocerebellar ataxias.
Research on STR expansions has historically relied on time-consuming laboratory tests, but with the recent development of whole-genome sequencing — technologies that can determine the entirety of a person&#8217;s genetic code — it is now much easier to look for these expansions in large groups of patients.
In this study, scientists based in Australia used whole-genome sequencing data to look for STR expansions in people with ALS or the related condition frontotemporal dementia (FTD).
The study included data on 608 people with sporadic ALS, 68 with sporadic FTD, and 4,703 control subjects with no known neurological disease. The researchers specifically looked for 21 STR expansions that have been linked with other neurological disorders.
Among the sporadic ALS patients, 48 carried a mutation that had previously been connected with the disease; 41 had an STR expansion in C9ORF72, three had a mutation in the SOD1 gene, and four had mutations in the TARDBP gene.
Among all 676 ALS and FTD patients, 119 (17.6%) harbored an STR repeat expansion in a gene that&#8217;s traditionally been associated with another disease. There were 12 patients (less than 2%) with expansions in more than one of these genes.
&#8220;We found almost 18 per cent of sporadic [ALS] and FTD patients carried a DNA repeat expansion thought to be involved in other degenerative diseases,&#8221; said Lyndal Henden, PhD, a co-author of the study at Macquarie University. &#8220;Finding this genetic connection between [ALS] and FTD offers a fresh opportunity to uncover common risk factors for neuron death, and it will have implications for understanding both diseases.&#8221;
<h3>Diagnoses consistent with ALS despite other mutations</h3>
In most cases, the detected mutations were intermediate expansions — that is, the STR region contained more repeats than normal, but not so many as to be disease-causing. However, a handful of patients were found to have known disease-causing repeat expansions in genes including the spinocerebellar ataxia genes ATXN8 and ATXN1, as well as FMR1, which causes <a href="https://fragilexnewstoday.com/what-is-fragile-x-syndrome/">fragile X syndrome</a>.
Despite having mutations shown to cause other diseases, clinical data from all these patients &#8220;were consistent with a diagnosis of ALS,&#8221; the researchers wrote.
STR expansions also were seen in more than 1 out of every 10 patients without the disease. However, when including all genes assessed, the overall rate of STR expansions was significantly higher among the patients with ALS or FTD compared with controls (23.2% vs. 16.3%). The researchers stressed further studies will be needed to verify whether and how these mutations influence the development of disease.
&#8220;Rare repeat expansions, such as these identified in this study, may be truly associated with disease risk; however, larger ALS and FTD patient cohorts will be required to determine their significance to disease,&#8221; they wrote.

Tag: gene mutations

‘Molecular traps’ may help fend off nerve damage from gene mutations

Application filed in Australia to launch first trial of ARO-SOD1

Some sporadic ALS patients have mutation causing other diseases