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TPN-101, an investigational oral molecule developed by <a href="https://www.transposonrx.com/">Transposon Therapeutics</a>, reduced multiple biomarkers of neuroinflammation and neurodegeneration, and slowed respiratory decline in some people with <a href="https://alsnewstoday.com/what-is-als/https:/alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and/or frontotemporal dementia (FTD).
That’s according to an interim analysis of a <a href="https://clinicaltrials.gov/study/NCT04993755?cond=Amyotrophic%20Lateral%20Sclerosis&amp;intr=TPN-101&amp;rank=1">Phase 2a clinical trial (NCT04993755)</a> that&#8217;s testing TPN-101 in people with ALS/FTD caused by C9orf72 gene mutations. The analysis was conducted after all the patients completed the six-month randomized period.
The treatment also showed meaningful benefits in biomarker and clinical outcomes in a completed <a href="https://clinicaltrials.gov/study/NCT04993768?cond=Progressive%20Supranuclear%20Palsy%5C(PSP%5C)&amp;intr=TPN-101&amp;rank=1">Phase 2a trial (NCT04993768)</a> in people with progressive supranuclear palsy (PSP), a progressive condition that results from damage in brain areas that control body movements, coordination, or cognitive functions.
Researchers plan to advance TPN-101 to a Phase 3 study that might support its approval in PSP. Pending positive final results from the ALS/FTD trial, a Phase 3 trial might also launch for this indication.
&#8220;Based on the groundbreaking study results shown by TPN-101 in both PSP and ALS/FTD, we plan to rapidly advance TPN-101 into a Phase 3 registration study for the treatment of PSP, and potentially ALS/FTD as well, pending final confirmatory study results,&#8221; Dennis Podlesak, chairman and CEO of Transposon, said in a <a href="https://www.prnewswire.com/news-releases/transposon-announces-final-results-from-a-phase-2-study-of-its-line-1-reverse-transcriptase-inhibitor-tpn-101-for-the-treatment-of-progressive-supranuclear-palsy-and-interim-results-from-a-phase-2-study-of-tpn-101-for-the-treatmen-302060254.html">company press release</a>.
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<h3>How does TPN-101 work in ALS. FTD?</h3>
In ALS and FTD, the toxic accumulation of certain proteins outside the nucleus <a href="https://alsnewstoday.com/news/tdp-43-deficiency-changes-physical-structures-dna/">is believed to cause the activation</a> of certain transposable elements — pieces of viral DNA incorporated in human DNA thousands of years ago that are able to jump around to different regions in the genome.
These transposable elements aren’t normally active in healthy adult cells. When activated, they can lead to major genetic disruption, which triggers an antiviral immune response in cells that can ultimately result in nerve cell death.
TPN-101, known as censavudine, is designed to inhibit the LINE-1 reverse transcriptase, an enzyme involved in activating transposable elements, which should ease inflammation and neurodegeneration in ALS/FTD. As this enzyme is more active in people carrying C9orf72 mutations, the <a href="https://www.frontiersin.org/articles/10.3389/fncel.2021.770937/full">most common genetic cause</a> of both ALS and FTD, TPN-101 is believed to be helpful to them.
The ongoing Phase 2a trial was initiated in 2021 to evaluate TPN-101’s safety and efficacy in 42 adults with C9orf72-associated ALS/FTD.
The participants were first randomly assigned to receive 400 mg TPN-101 or a placebo, once daily for 24 weeks, or about six months. They were then able to transition to the trial&#8217;s open-label part, where all are receiving TPN-101 for another 24 weeks.
The trial&#8217;s main goal is to see if the therapy is safe and well tolerated. Secondary goals include measures of TPN-101’s pharmacological properties, along with changes in biomarker levels and in disease progression.
Results from the predefined interim analysis demonstrated TPN-101 exerted an impact on key biomarkers of neurodegeneration, neuroinflammation, and microglial activation over the first 24 weeks. Microglia are the brain’s resident immune cells and are thought to participate in the inflammation that drives ALS.
The therapy also had an effect on vital capacity, a measure of respiratory function that correlates with mortality in ALS patients, according to the company.
&#8220;Transposon&#8217;s founding mission was to establish human proof-of-concept that dysregulation of retrotransposable elements in neurodegenerative diseases such as PSP, ALS and Alzheimer&#8217;s disease can be addressed with a new class of LINE-1 reverse transcriptase inhibitors,&#8221; said Eckard Weber, MD, Transposon’s founder and chief innovation officer. &#8220;The results obtained with TPN-101 &#8230; show for the first time that neurodegenerative diseases that involve LINE-1 dysregulation are treatable with a specific inhibitor of this important novel target.&#8221;

TPN-101 improves ALS/FTD caused by C9orf72 gene mutations

Mutations in the C9ORF72 gene may lead to <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and the related disorder frontotemporal dementia (FTD) in part by boosting the production of a powerful inflammatory protein called interleukin 17A (IL-17A), recent preclinical research suggests.
Inhibiting IL-17A via genetic manipulations or medications was associated with lowered inflammation and motor performance gains in mice who lacked C9orf72, offering a possible therapeutic approach for both conditions that could be achieved by repurposing IL-17A inhibitors already approved for certain inflammatory conditions.
“Our research indicates that IL-17A blockade may be quickly repurposed to treat ALS patients to slow down the progression of their disease or possibly stop ALS from ever occurring,” Aaron Burberry, PhD, assistant professor at Case Western Reserve University in Ohio and the study&#8217;s senior author, said in a <a href="https://thedaily.case.edu/new-study-identifies-gene-believed-to-be-responsible-for-als-and-dementia/">university press release</a>. “For people living with a neurodegenerative disease &#8230; our work offers hope for a future where quality-of-life and cognition can be maintained long after their diagnosis.&#8221;
The study, “<a href="https://www.science.org/doi/10.1126/scitranslmed.adg7895">Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice</a>,” was published in <a href="https://www.science.org/journal/stm">Science Translational Medicine</a>.
Mutations in C9ORF72 are the most <a href="https://alsnewstoday.com/causes-of-als/#Genetics_of_ALS">common genetic cause</a> of ALS and FTD, neurodegenerative diseases marked by the progressive loss of key nerve cells in the brain and spinal cord. Such mutations are implicated in up to 50% of <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> cases, up to 10% of <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> cases, and up to <a href="https://www.frontiersin.org/articles/10.3389/fnagi.2022.907122/full">around 30%</a> of cases of FTD.
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<h3 class="p1"> Exploring C9ORF72 gene&#8217;s role in ALS, FTD</h3>
While the exact role of C9ORF72 in ALS isn&#8217;t well established, its protein product, C9ORF72, is prevalent in the brain and is believed to be important for nerve cell function and communication. It&#8217;s also found in the immune system.
Brain inflammation and evidence of autoimmunity — where the immune system attacks healthy tissue — is a feature of these neurodegenerative diseases and is often evident even before the onset of neurological symptoms.
Still, the mechanisms by which this autoimmune-like profile arises haven&#8217;t been fully established. <a href="https://alsnewstoday.com/news/researchers-find-autoimmune-role-gene-central-als-development-need-bone-marrow-transplant-trials/">Previous research</a> has implicated a possible role for C9ORF72 in ALS-associated autoimmunity.
Here, the scientists explored the gene&#8217;s possible role in modulating these immune processes by genetically engineering mice to lack C9orf72 in various hematopoietic cell types, which encompasses all the cell types found in the blood, including immune cells.
A loss of the gene in myeloid cells, those from the innate immune system that are produced in the bone marrow, led to signs of severe autoimmunity. In turn, its deficiency in lymphoid cells, immune cells that defend the body from specific threats, led to increased IL-17A production and an excess of immune neutrophil cells.
In mice lacking C9orf72, certain myeloid immune cell subsets, including macrophages and monocytes, which are found in circulation, and in microglia, their brain-resident relatives, had increased levels of the CD80 protein on their surface. CD80 elevations were also observed in microglia from the spinal cord of people with C9ORF72-mediated ALS relative to people without ALS. The protein modulates immune function and has been implicated in some inflammatory diseases of the gastrointestinal system.
The research indicates C9ORF72 normally works to suppress IL-17A production in lymphocyte cells and to prevent CD80 trafficking to the myeloid cell surface in response to the signaling of IL-17A and other inflammatory molecules. When the gene is lacking or dysfunctional, these inflammatory activities may become amplified.
Consistent with these observations, deleting the gene encoding IL-17A in C9orf72-deficient mice prevented CD80 elevations in the spinal cord, reduced neutrophil counts, and lowered the number of a certain type of immune cells in the gut. And treatment with an anti-IL-17A antibody improved motor function and suppressed inflammation in the C9orf72-deficient mice.
The findings “provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD,” the researchers wrote.
Medications to block IL-17A, the brand names of which include Cosentyx and Taltz, are already approved in the U.S. for certain autoimmune diseases.
Burberry’s research team plans to examine the mechanisms by which C9ORF72 normally works to inhibit IL-17A in lymphoid cells and to identify the specific microorganisms and molecules in the gut that contribute to inflammation in the brain.

Tag: C9orf72 gene mutations

TPN-101 improves ALS/FTD caused by C9orf72 gene mutations

C9ORF72 gene mutations drive inflammatory molecule’s production