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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

More than a third of people diagnosed with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) also showed signs of frontotemporal dementia (FTD), according to a new study of brain tissue.
In more than 90% of tissues examined, patients had clumps of the TDP-43 protein, a hallmark of ALS that contributes to nerve damage, but ALS patients with FTD signs showed more extensive involvement. Moreover, when the tissue analysis was compared with clinical examination, ALS was more accurately diagnosed than ALS-FTD due to a wide variability in clinical presentation in FTD, the researchers noted.
&#8220;Neuropathological [tissue-examination] studies and correlation with clinical characteristics help us expand our knowledge of the basis of diseases such as ALS and frontotemporal dementia, opening doors to future studies on biomarkers and specific therapies,&#8221; Álvaro Carbayo, MD, co-lead author and a researcher at the Sant Pau Research Institute, in Spain, said in a <a href="https://www.recercasantpau.cat/en/now/desxifren-les-connexions-cerebrals-entre-lesclerosi-lateral-amiotrofica-ela-i-la-demencia-frontotemporal/">press release</a>.
The tissue examination study, &#8220;<a href="https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae011/7560436">Clinicopathological correlates in frontotemporal lobar degeneration: motor neuron disease spectrum</a>,&#8221; was published in <a href="https://academic.oup.com/brain">Brain</a>.
ALS, also called motor neuron disease, is marked by progressive muscle weakness and wasting (atrophy). It&#8217;s <a href="https://alsnewstoday.com/causes-of-als/">caused</a> by the degeneration of motor neurons, the specialized nerve cells that control voluntary muscle movements, in the brain, brainstem, and spinal cord. FTD is a group of dementias marked by changes in behavior and language. Like ALS, it&#8217;s also caused by motor neuron degeneration, but it mainly affects neurons in two different brain regions, the frontal and temporal lobes.
In most ALS patients, and up to half of those with FTD, motor neuron function is disrupted by the toxic accumulation of a misfolded version of the TDP-43 protein. The two diseases are also associated with mutations in the C9orf72, TBK1, and TARDBP genes. Moreover, about half of ALS patients will develop behavior and cognition changes, with an estimated 10-15% meeting the criteria for an FTD diagnosis.
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<h3 class="p1"> Frequency of FTD in ALS explored</h3>
Because brain tissue analysis remains the reference for a definite diagnosis of FTD, and not many studies have performed those analyses in ALS, the exact frequency of FTD in ALS patients is difficult to estimate.
To find out, a team of researchers led by Carbayo and Ricard Rojas, MD, PhD, examined clinical data and brain tissue from ALS patients with and without FTD to analyze the frequency of FTD and also to define specific subgroups based on their clinical, genetic, and tissue-related characteristics.
&#8220;It is crucial that we work together to better understand this spectrum of neurodegenerative diseases and to better care for our patients,&#8221; Carbayo said.
The researchers examined brain samples from 124 patients, whose mean age at death and brain donation was 66.4. Among them, 44 (35.5%) showed features associated with FTD (ALS-FTD), which exceeded previous clinical estimates, the researchers noted.
Nearly all brain samples (93.6%), with or without FTD, had TDP-43 protein aggregates. Among those with signs of FTD, 90.9% had TDP-43 aggregates, which were more widely distributed across brain tissue than in people with ALS alone.
Cognitive or behavioral changes during clinical follow-up were seen in 38.7% of patients, but significantly more patients in the FTD group had these changes than those with ALS alone (88.6% vs. 13.3%).
A clinical diagnosis of FTD was more common in ALS patients with FTD signs than in those with ALS alone (67.4% vs. 6.3%). Five patients received an FTD diagnosis without tissue signs of FTD, but they had other disease-related changes in brain tissue that could explain cognitive-behavioral impairment.
When the team compared diagnosis between clinical data and tissue analysis, ALS disease was more accurately diagnosed than ALS-FTD (93.8% vs. 61.4%).
No statistically significant differences were found in the survival rate between ALS and ALS-FTD, with both groups showing a similar disease duration. Similar survival rates were also found regardless of area of onset, the presence of symptoms affecting the face and throat, or disease-causing mutations.
Genetic mutations related to ALS occurred more frequently in ALS-FTD than in ALS (31.8% vs. 5%) and C9orf72 mutations were independently associated with signs of FTD in brain tissue.
&#8220;We have observed astonishing heterogeneity [variability] in the clinical presentation and pathological and genetic characteristics of patients, with a higher frequency of frontotemporal dementia than described in other series,&#8221; Carbayo said.
Said the researchers: &#8220;We describe a frequency of [FTD] of 35.5% in our series of neuropathologically confirmed cases of MND. The [ALS-FTD] spectrum is highly heterogeneous in all aspects, especially in patients with [FTD], in whom it is particularly difficult to define specific subgroups.&#8221;

Signs of frontotemporal dementia seen in about 35% of ALS patients

<a href="https://www.athira.com">Athira Pharma</a>’s experimental therapy ATH-1105 shows anti-inflammatory and neuroprotective effects, promoting neuron growth and reducing damage associated with mechanisms of <a href="https://alsnewstoday.com">amyotrophic lateral sclerosis</a> (ALS) and frontotemporal dementia (FTD), a related condition.
The small molecule reduced inflammation and the buildup of a faulty version of TDP-43, a protein that’s thought to drive neuronal damage in both ALS and FTD.
That’s according to new data from preclinical studies in lab-grown cells and a mouse model of the two diseases that were shared in a poster at this year’s Alzheimer’s Association International Conference (AAIC), July 16-20, virtually and in person in Amsterdam, the Netherlands.
The poster was titled “<a href="https://www.athira.com/wp-content/uploads/2023/07/AAIC2023_FTD_L5_6July2023.pdf">ATH-1105, a small-molecule positive modulator of the HGF/MET system, is neuroprotective and attenuates TDP-43 protein pathology in ALS and frontotemporal dementia-relevant preclinical models</a>.”
The findings add to previous evidence that ATH-115 <a href="https://alsnewstoday.com/news/als-mouse-model-sees-prolonged-survival-with-ath-1105/">extended lifespan</a> and <a href="https://alsnewstoday.com/news/ath-1105-aid-nerve-health-motor-skills-als-mouse-model/">improved motor function</a> in ALS mouse models.
“We are encouraged by the growing body of preclinical research supporting ATH-1105, which shows the molecule is protective against several [disease-causing mechanisms] common to ALS and FTD,” Kevin Church, PhD, Athira’s chief scientific officer, said in a <a href="https://www.globenewswire.com/news-release/2023/07/17/2705476/0/en/Athira-Pharma-Presents-Phase-2-Clinical-Data-Correlating-Improvements-in-Biomarkers-of-Neurodegeneration-and-Neuroinflammation-with-Improvements-in-Measures-of-Cognition-and-Functi.html">company press release</a>.
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<h3>Effects of ATH-1105 on ALS, FTD</h3>
Mutations in the TARDBP gene, which codes for TDP-43, have been linked to the risk of <a href="https://alsnewstoday.com/causes-of-als/">developing ALS</a>. The mutations cause the protein to fold into the wrong shape and form toxic clumps.
Nearly everybody (97%) with ALS grow these TDP-43 aggregates in motor neurons, the nerve cells that control voluntary movement and are progressively lost with the disease. The damage results in <a href="https://alsnewstoday.com/symptoms-of-als/#Muscular_symptoms">muscle weakness</a> and an inability to control movement. The aggregates also form in roughly half of people with FTD.
ATH-115 works as a <a href="https://www.athira.com/science/">positive modulator</a> of the HGF/MET system, meaning it activates it. The HGF/MET system is a signaling pathway that helps safeguard neurons from damage by promoting their growth, repair, and survival.
“Positive modulation of the HGF/MET system has been shown to protect against several drivers of neurodegeneration in preclinical models, and this approach may represent a potential therapeutic strategy for ALS and FTD,” wrote the researchers, who tested ATH-115 in lab-grown neurons from the hippocampus of healthy rats. The hippocampus is a brain region linked to memory and learning, and TDP-43 clumps <a href="https://alsnewstoday.com/news/study-links-cognitive-impairment-with-toxic-protein-clumps-in-als/">also build up there</a>.
Neurons treated with ATH-115 grew about twice as many neurites, or projections that form connections with other neurons, and about three times more synapses, which are the points of contact between them.
The effect had about the same magnitude as treatment with HGF, the growth factor in the HGF/MET system.
<h3>ATH-1105 offers protection</h3>
The scientists then used four chemicals in amounts that were toxic to lab-grown rat cortical neurons, or neurons from the brain’s outermost layer. The chemicals were the neurotransmitter glutamate, bacteria-derived lipopolysaccharide (LPS), hydrogen peroxide, and 1-methyl-4-phenylpyridinium, a neurotoxin.
Each of them reduced the number of neurons that remained alive. However, when treated with ATH-1105 beforehand, the neurons were protected against their associated damage and didn&#8217;t die as much. In fact, almost all remained alive.
The researchers then analyzed the effects of ATH-1105 when added to LPS-exposed lab-grown human macrophages, a type of immune cell. LPS exposure increased the cells’ production of IL-6 and TNF-alpha, two pro-inflammatory signaling molecules, while ATH-1105 significantly reduced their levels.
Inflammation induced by LPS can cause cognitive impairment. In mice, this can be studied using a test called a T-maze. Compared with a placebo, ATH-1105 (given by mouth once daily for 14 days) eased cognitive impairment in LPS-exposed mice.
Finally, the researchers used a mouse model of ALS and FTD that produces a faulty version of human TDP-43. Some mice were given ATH-1105 by mouth once daily from 1-3 months of age. Others were given a placebo.
Similar to data from previous preclinical studies, ATH-1105 reduced blood IL-6 and TNF-alpha levels. It also reduced the levels of neurofilament light chain, a marker of neuronal damage.
Moreover, ATH-1105 reduced TPD-43 levels in the mice’s sciatic nerve by about three times, nearly reaching those seen in healthy mice. The sciatic nerve is a long nerve that runs from the lower back down the lower limbs.
“The consistency and breadth of these effects in reducing markers of inflammation, neurodegeneration, and TPD-43 protein pathology continue to support the broad therapeutic potential and continued advancement of ATH-1105,” Church said.

ATH-1105 protects against common ALS, FTD disease mechanisms

The <a href="https://www.als.org/">ALS Association</a> and the <a href="https://www.theaftd.org/">Association for Frontotemporal Degeneration</a> (AFTD) have opened a global grant program to accelerate the development of digital assessment tools for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and frontotemporal dementia (FTD), a related condition.
The <a href="https://www.theaftd.org/for-researchers/funding-opportunities/digital-assessment-tools-for-ftd-and-als-awards/">Digital Assessment Tools for FTD and ALS Awards</a>, backed by a $500,000 ALS Association Partnership Grant, will provide researchers with $750,000 to help develop assessment tools for the neurodegenerative disorders. From two to four grants will be funded over two years.
The tools must utilize wearable trackers, smartphones, or other devices to remotely collect data on a patient&#8217;s symptoms or ability to function. Such assessment tools could remove some of the barriers that prevent ALS and FTD patients from participating in research, which could improve care for both diseases.
&#8220;Carefully developed digital tools can help people living with a diagnosis of ALS, FTD, or ALS-FTD to participate in research more easily and more frequently, and from the comfort of their own homes,&#8221; Penny Dacks, PhD, AFTD&#8217;s senior director of scientific initiatives, said in a <a href="https://www.prnewswire.com/news-releases/aftd-and-als-association-launch-funding-opportunity-for-digital-tool-development-in-als-and-frontotemporal-dementia-301822641.html">press release</a>. &#8220;Because digital tools allow for remote participation from those who may not have the means to travel to sites due to cost or distance, the data is more likely to represent the people living with these diseases.&#8221;
The awards are open to scientists at academic or nonprofit research institutions, as well as for-profit organizations such as digital technology developers and biotechnology companies, although other types of organizations may qualify. Academia and industry partnerships are encouraged to apply. Applications must include proof of research expertise in both ALS and FTD.
Depending on a project&#8217;s scope and development stage, budget requests can be between $150,000 and $400,000. Grant applications at nonprofit or academic institutions may request up to 10% of their budget to cover indirect costs. The <a href="https://www.theaftd.org/wp-content/uploads/2023/05/AFTD-ALSAssn-Digital-Assessment-Tools-RFP.pdf">application</a> deadline is July 14. The funding period will start Jan. 1, 2024, and end Dec. 31, 2026.
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<h3>The case for shared ALS, FTD research</h3>
ALS is marked by the loss of motor neurons — the nerve cells that control voluntary movement — leading muscles to shrink and weaken. FTD is a group of neurological disorders that impact the brain&#8217;s frontal and temporal lobes, areas typically associated with behavior, personality, and language.
Both diseases share common underlying processes that promote disease development, namely the abnormal accumulation of the protein TDP-43. In healthy cells, this protein enters the nucleus and binds DNA and RNA to mediate protein production. In ALS and FTD, though, the protein is abnormally shaped and tends to accumulate in the cytoplasm, where it forms protein clumps that are toxic to cells.
ALS and FTD symptoms can overlap. For example, ALS patients can have language and behavioral issues that are common in FTD, while people with FTD can have movement problems such as those exhibited in ALS.
&#8220;Despite being intertwined biologically, research into ALS and FTD has traditionally been conducted in silos. This partnership and collaborative funding will help bridge the divide, bringing together researchers with interests spanning the continuum of these two diseases,&#8221; said Kuldip Dave, PhD, senior vice president for research at the ALS Association. &#8220;Together, we can achieve much more than we could on our own.&#8221;
Research into both diseases is hamstrung by the severely limited pool of prospective participants with the time and means to travel to a study site. Also, clinical centers that provide ALS care and conduct disease research are typically separate from those for FTD patients. Digital assessment tools could surmount such barriers.
Dacks said it&#8217;s time to focus on the disorders&#8217; commonalities to help both patient communities.
&#8220;AFTD is proud to partner with The ALS Association to foster collaboration across the FTD and ALS research communities. This program will advance digital tool development at the intersection of these two worlds, helping to create tools that can meet the families that are often living in the middle,&#8221; she said.

Tag: frontotemporal dementia (FTD)

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

Signs of frontotemporal dementia seen in about 35% of ALS patients

ATH-1105 protects against common ALS, FTD disease mechanisms

Improving ALS, FTD research is aim of digital tool grant program