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A biomarker test that identifies abnormal protein fragments called cryptic peptides may help detect <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and frontotemporal dementia (FTD) in the early stages, a study found.
Cryptic peptides from the HDGFL2 protein were elevated in fluid samples from people with ALS/FTD, including in those who had disease-causing mutations but no evident symptoms, according to the study, &#8220;<a href="https://www.nature.com/articles/s41591-023-02788-5">A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD</a>,&#8221; published in Nature Medicine.
&#8220;We believe we’ve discovered a biomarker that could potentially be used to detect ALS and FTD in their earliest stages — even before symptoms appear,&#8221; Philip Wong, PhD, professor at Johns Hopkins University School of Medicine and the study&#8217;s senior author, said in a <a href="https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/03/johns-hopkins-medicine-led-team-develops-fluid-biomarker-for-early-detection-of-degenerative-diseases-als-and-ftd">university press release</a>.
The team is collecting samples from ALS and FTD patients around the world to continue evaluating their approach and moving it toward the clinic.
“We hope to support the effectiveness, reliability, and sensitivity of our biomarker by testing it on thousands of patient samples, and once validated, encourage its use as a clinical tool,” said the study&#8217;s first author, Katie Irwin, a graduate student at Johns Hopkins.
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<h3>Protein accumulates where it shouldn&#8217;t</h3>
Toxic accumulation of the TDP-43 protein is evident in most ALS cases and is believed to contribute to nerve cell damage. While the protein is usually found in the cell&#8217;s nucleus, the core where DNA is contained, TDP-43 aberrantly clumps outside the nucleus in ALS and FTD.
TDP-43’s usual role is to help in the proper formation of messenger RNA (mRNA), a genetic template produced when the information in DNA is being used to make a protein.
When the protein wrongly accumulates where it shouldn’t, this process becomes corrupted. Some mRNA templates will contain problematic sequences called cryptic exons, which affect the production of proteins important for brain health.
Because the presence of these cryptic sequences in some proteins reflects TDP-43 dysfunction, the researchers had the idea that protein fragments (peptides) containing them could be possible biomarkers of the early stages of ALS or FTD.
Prior to this study, TDP-43 pathology could only be seen during a postmortem tissue analysis, so it wasn&#8217;t known to what degree these types of abnormalities might be seen early on.
[quote=”center”]Pathogenic mechanisms often begin years before the emergence of clinically relevant symptoms.[/quote]
The team sought to develop antibodies that could bind to cryptic sequences in a blood or spinal fluid sample and be visualized in the lab. They decided to focus on the one protein that seemed the most reliable: HDGFL2.
“Of all the cryptic peptides for which we made &#8230; antibodies, the one that worked best was the one designed for the cryptic HDGFL2 protein,” Irwin said. “We used that &#8230; antibody to develop an extremely sensitive detection test for the cryptic HDGFL2 protein in body fluids.”
The researchers evaluated their approach by measuring levels of cryptic HDGLF2 in cerebrospinal fluid (CSF) — the fluid surrounding the brain and spinal cord — and blood samples from people with <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>/FTD caused by mutations in the C9orf72 gene, <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a>/FTD without any known mutations, and presymptomatic patients with mutations in C9orf72.
Cryptic HDGLF2 was detectable across all patient groups in both types of bodily fluids, including in those who did not yet have any symptoms of the disease. Samples from all ALS/FTD patients had higher levels of the cryptic peptide than samples from healthy people or people with other brain diseases.
“Our test found cryptic HDGFL2 in the presymptomatic stages of patients who were genetically predisposed to ALS and FTD, and were expected to go on to develop the diseases, giving the method credibility as a potential preclinical biomarker for predicting risk of ALS and FTD,” Irwin said.
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<h3>Disease drivers may appear years before symptoms</h3>
Based on their findings, the researchers believe that cryptic HDGFL2 levels might peak before symptom onset and then decrease as the disease progresses.
The study highlights a &#8220;common theme of neurodegenerative diseases — that pathogenic [disease-driving] mechanisms often begin years before the emergence of clinically relevant symptoms,&#8221; the researchers said.
When compared with neurofilament light chain (NfL), an established biomarker across multiple neurodegenerative diseases that reflects the degree of nerve damage, increases in HDGFL2 followed a similar trajectory, but appeared to rise earlier than NfL levels.
The scientists believe the two markers could be used together to help understand the trajectory from presymptomatic to symptomatic disease, noting that more extensive and long-term studies are need to clarify those dynamics.
Such knowledge could guide clinical trial enrollment, helping patients access therapies sooner, &#8220;at a time when it might truly make a difference,&#8221; said Wong.
Irwin said the team will explore whether the biomarker test can be used to determine the effectiveness of therapies &#8220;by looking for reductions in cryptic HDGFL2 levels — and restoration of TDP-43 function — after treatment.”

Cryptic protein fragments may detect ALS in early stages: Study

Treatment with <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> was found to significantly delay disease progression and prolong survival, by more than 1.5 years, among adults with early-stage <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in the RESCUE-ALS trial and its open-label extension phase.
That&#8217;s according to two different statistical analyses, which overall showed that patients who received CNM-Au8 had a 70% lower risk of death over two years of follow-up compared with those never given the medication.
Indeed, the new analyses revealed a &#8220;19.3 month significant survival difference for CNM-Au8 treated participants versus [those on a] placebo,&#8221; <a href="https://clene.com/">Clene Nanomedicine</a>, the company developing CNM-Au8, stated in a <a href="https://www.globenewswire.com/news-release/2023/08/29/2733238/0/en/Clene-Reports-Significantly-Improved-Survival-Benefit-of-19-3-Months-and-Significantly-Delayed-Clinical-Worsening-in-Rescue-Als-Open-Label-Extension-Two-Year-Follow-Up.html">press release</a>.
“The data that continues to be received from the RESCUE-ALS open label extension study is truly impressive, and now shows consistently significant decreased risk of death greater than 70% using two different long-term analysis models,” said Matthew Kiernan, PhD, of the University of Sydney, one of the trial&#8217;s clinical advisors.
“The survival benefit across treatment arms is linked to less worsening of disease, as experienced by ALS patients. At the same time, the further safety data confirms that CNM-Au8 is well tolerated in ALS patients,” Kiernan added.
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<h3>Main trial of CNM-Au8 failed to meet primary, secondary goals</h3>
The oral therapy is a suspension of gold nanoparticles that&#8217;s intended to slow ALS progression by preventing the death of the motor nerve cells that are progressively lost in the disease.
CNM-Au8 is believed to promote nerve cell survival by boosting energy production and protecting against a type of cellular damage, called oxidative stress, that&#8217;s implicated in ALS .
The Phase 2 <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">RESCUE-ALS trial (NCT04098406)</a>, sponsored by Clene and launched in late 2019, enrolled 45 adults with early ALS at two sites in Australia. All had developed their first symptoms of the progressive disorder in the prior two years.
The participants were randomly assigned to receive CNM-Au8, at a dose of 30 mg, or a placebo, given as a liquid suspension once daily for 36 weeks, or about eight months. The therapy was given in addition to <a href="https://alsnewstoday.com/als-treatment/">standard ALS medications</a>.
Following the main trial, most participants (90%) entered into an <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension (NCT05299658)</a>, in which all would be given CNM-Au8 for up to 120 weeks, or more than two years.
The main trial had <a href="https://alsnewstoday.com/news/cnm-au8-failed-primary-rescue-als-goals-top-line-trial-data/">failed to meet its primary and key secondary goals</a> of improving motor nerve cell health and slowing lung function declines after 36 weeks.
However, additional analyses spanning the trial and its extension have indicated a <a href="https://alsnewstoday.com/news/early-cnm-au8-treatment-als-continues-show-survival-benefits/">survival benefit</a> and <a href="https://alsnewstoday.com/news/slower-progression-experimental-als-treatment-cnm-au8/">slower disease progression</a> among patients who started the therapy eight months earlier relative to those who switched from the placebo in the extension phase.
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<h3>Survival benefits with CNM-Au8 still being seen in extension trial</h3>
Now, Clene has reported that the survival benefits of CNM-Au8 are still being observed as of July 2023 — after two years in the extension trial.
Specifically, patients who started CNM-Au8 eight months earlier had a median survival of 34.2 months, or almost three years, compared with 24.1 months, or about two years, among those who switched from placebo. That&#8217;s a survival benefit of 10.1 months, and it amounts to a 46% lower risk of death among those originally assigned to CNM-Au8.
Investigators also conducted another survival analysis wherein the data were adjusted to subtract the potential survival benefits received by those who started on a placebo and then switched to CNM-Au8.
Essentially, the analysis estimated survival in this group if the patients had remained on a placebo and never switched over. That survival was determined to be 14.9 months, or about 1.2 years.
Here, the survival benefits of those always on CNM-Au8 were even more pronounced, with patients living about 19.3 months longer relative to those on a placebo. This was associated with a 75% lower risk of death in participants on continuous CNM-Au8.
[quote=&#8221;center&#8221;]A median survival improvement of 19.3 months provides people living with ALS, their families, and caregivers more time that is so invaluable, and adds to the totality of data we are seeing in our ALS clinical program.[/quote]
The researchers then compared the survival of individuals treated with CNM-Au8 with historical placebo-treated patients — controls whose data were contained in the PRO-ACT ALS patient database. In that analysis, treatment with CNM-Aug was associated with a 70% lower risk of death.
Patients initially assigned the experimental therapy in the main trial also were found to be at a 52% lower risk of clinical worsening compared with those who started treatment eight months later. Clinical worsening was defined as the occurrence of one of several outcomes: death, breathing tube placement, assisted ventilation, or feeding tube placement.
Among open-label participants treated with CNM-Au8, 42% are still alive up to 3.5 years after their enrollment in RESCUE-ALS — and up to 6.6 years after their ALS symptom onset — according to Benjamin Greenberg, MD, head of medical at Clene.
Greenberg called this finding &#8220;a profoundly meaningful milestone for people living with this devastating disease.&#8221;
“A median survival improvement of 19.3 months provides people living with ALS, their families, and caregivers more time that is so invaluable, and adds to the totality of data we are seeing in our ALS clinical program,” Greenberg said.
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<h3>CNM-Au8 also shows benefit in ALS platform trial</h3>
Similar findings also were observed in the CNM-Au8 arm of <a href="https://clinicaltrials.gov/ct2/show/NCT04297683">HEALEY ALS (NCT04297683)</a>, a platform trial that is investigating multiple ALS therapies simultaneously as a way to reduce costs and accelerate treatment development.
In that platform trial arm, treatment with 30 mg CNM-Au8 for six months lowered the risk of death by <a href="https://alsnewstoday.com/news/cnm-au8-found-lower-risk-death-als-healey-platform-trial/">more than 90%</a>. Moreover, <a href="https://alsnewstoday.com/news/cnm-au8-delayed-clinical-worsening-als-patients-healey-trial/">significant reductions also were observed</a> in the risk of needing a feeding tube, assisted ventilatory support, or being hospitalized.
Additionally, in more than 475 collective years of CNM-Au8 exposure in patients with several neurodegenerative disorders — ALS, <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a> — no safety signals have been identified, according to researchers. Most reported side effects have been mild to moderate in severity, and temporary.
Side effects reported in RESCUE-ALS include nausea, bruising, abdominal discomfort, and aspiration pneumonia, or inflammation caused by food or liquids inhaled into the airways.
Clene has reported plans to launch a Phase 3 trial of CNM-Au8 called RESTORE-ALS. Should results be positive, the data may support regulatory applications for the therapy&#8217;s approval.

Tag: early stage ALS

Cryptic protein fragments may detect ALS in early stages: Study

CNM-Au8 seen to extend survival by more than 1.5 years in ALS trial