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Reduced activity of the TDP-43 protein, a hallmark of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), leads to changes in the DNA of nerve cells, which alters the activity of important genes, a new study reports.
These findings may help explain how problems with this protein can contribute to the death of nerve cells in ALS and other disorders marked by TDP-43 abnormalities.
The study, &#8220;<a href="https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01673-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221112472301673X%3Fshowall%3Dtrue">TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk</a>,&#8221; was published in <a href="https://www.cell.com/cell-reports/home">Cell Reports</a>.
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<h3>In ALS, TDP-43 protein can form clumps outside the cell&#8217;s nucleus</h3>
Though the <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> aren&#8217;t fully understood, abnormalities in <a href="https://alsnewstoday.com/?s=tdp-43">TDP-43</a> are a molecular hallmark of most cases of the disease. TDP-43 normally is present in the nucleus (the cellular compartment that houses DNA), but in ALS and some other neurological diseases, the protein instead forms clumps outside the nucleus.
When TDP-43 forms these clumps, it cannot perform its normal functions. The protein is known to interact with RNA, a molecule made as a temporary intermediate when DNA is &#8220;read&#8221; to make proteins. However, this new study suggests TDP-43 also alters the shape of DNA, and interferes with molecular modifications to DNA molecules (known as epigenetics).
“Most studies of TDP-43’s function focus on it as an RNA-binding protein. But our analysis really captures how it is playing a genome-wide and epigenetic role, which is not fully appreciated,&#8221; Bing Yao, PhD, a co-author of the study and professor at Emory University in Atlanta, said in a <a href="https://news.emory.edu/stories/2024/01/er_genetic_zombies_23-01-2024/story.html">university news story</a>.
For these experiments, the scientists used a nerve cell line engineered to produce lower-than-normal amounts of TDP-43. This model &#8220;closely corresponds to the neuronal populations exhibiting TDP-43 partial loss of function due to age-dependent pathological sequestration in ALS,&#8221; the researchers said.
DNA has a double-helix shape, with two strands spiraling around each other. When a gene is &#8220;read,&#8221; the two strands of the DNA helix &#8220;unzip&#8221; to form an opening, and an RNA molecule starts to be put together in the opening. This structure of unzipped DNA and RNA is called an R-loop.
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<h3>TDP-43-deficient nerve cells can lead to changes in gene expression</h3>
Through a battery of molecular tests, the researchers determined TDP-43-deficient nerve cells show widespread dysregulation in where R-loops are located within the genome. The abnormalities in R-loops were closely associated with epigenetic changes, as well as alterations in gene expression (how much certain genes were &#8220;turned on or off&#8221;), affecting many genes known to be important for nerve cells to maintain their health.
The R-loop abnormalities were also associated with increased activation of transposable elements, which are sections of DNA that are able to jump around to different spots in the genome. Transposable elements aren&#8217;t normally active in healthy adult cells. When activated, they can lead to major genetic disruption.
Collectively, these data &#8220;provide a common mechanism underlying genome-wide DNA modification dysregulation in several neurodegenerative disorders&#8221; in which TDP-43 is not working properly, the researchers wrote. The team noted a need for more studies to work out the detailed molecular mechanisms of exactly how TDP-43 affects R-loops and related genetic elements.
The scientists also think other proteins that can bind to RNA might similarly affect R-loops, which may be a promising area for future studies to explore.
“Our findings suggest that besides TDP-43, other RNA-binding proteins could have this kind of genome-wide role,” Yao said.

TDP-43 deficiency leads to changes in physical structures of cell DNA

<a href="http://dewpointx.com">Dewpoint Therapeutics</a> has received a grant from the <a href="https://www.targetals.org/">Target ALS Foundation</a> to advance the development of small molecules called c-mods, which will target the TDP-43 condensates thought to drive most cases of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Condensates are borderless compartments in cells that can cause cellular processes to go awry, leading to a so-called condensatopathy. In ALS, TDP-43 condensates are linked to multiple markers of disease.
“Receiving the Target ALS grant is a tremendous honor and a significant validation for Dewpoint’s novel, therapeutic approach to target condensatopathies,” Ameet Nathwani, MD, Dewpoint’s CEO, said in a <a href="https://www.globenewswire.com/news-release/2024/01/16/2809938/0/en/Dewpoint-Therapeutics-Awarded-Target-ALS-Grant-for-Development-of-C-mods-for-ALS.html">company press release</a>.
“This grant will propel our research efforts and accelerate the development of our ALS-targeted c-mods towards becoming the first molecules to address the underlying pathology [disease mechanism] in most ALS patients,” Nathwani said.
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<h3>Grant to support proof-of-concept study using mouse model of ALS</h3>
The in-kind grant, awarded in collaboration with the <a href="https://www.als.org">ALS Association</a> and <a href="https://www.jax.org/">The Jackson Laboratory</a>, will support an in vivo proof-of-concept study of the company’s c-mods in a mouse model of ALS.
The TDP-43 protein normally resides in the nucleus, the cells’ control center that harbors most of the genetic material. In ALS, however, TDP-43 moves outside the nucleus and clumps into toxic condensates that prevent nerve cells from working properly, causing <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a>.
“Cellular mislocalization [incorrect or faulty localization] and aggregation of TDP-43 is the pathological hallmark of 97% of ALS cases, however, no marketed drugs target TDP-43 directly,” said Amy Easton, PhD, Target ALS Foundation’s senior director of scientific programs.
Dewpoint identified small molecules that can move mislocalized TDP-43 back into the nucleus. These small molecules, which the company <a href="https://www.frontiersin.org/articles/10.3389/fmolb.2022.1007744/full">dubbed c-mods</a> (from condensate-modifying drugs), are expected to rescue damage to nerve cells and ease symptoms.
In cell models of ALS, the company has demonstrated <a href="https://dewpointx.com/modulation-of-tdp-43-condensates-rescues-als-ftd-disease-phenotypes-in-multi-stressor-paradigms-presented-at-icgeb-conference-on-tdp-43-function-and-dysfunction-in-disease/">c-mods can reverse some of the cellular changes</a> induced by the aberrant TDP-43 protein clumps, including alterations in gene activity and stress-induced damage.
With support from the grant, Dewpoint will now test whether c-mods can similarly ease disease processes in a mouse model of ALS. This model carries a repeat expansion of a short DNA sequence in the C9orf72 gene, the most common genetic mutation in <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial</a> and <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a>.
“Dewpoint’s research proposal, reviewed by the Target ALS Independent Review Committee, included a high-quality preliminary data package, sufficient to trigger in vivo studies in a disease model,” Easton said.
“Dewpoint’s study is one of the first to test whether reducing TDP-43 condensates is beneficial in the context of a C9orf72 repeat expansion, the most common <a href="https://alsnewstoday.com/causes-of-als/#Genetics_of_ALS">genetic cause of ALS</a>,” Easton added.
The company also recently filed multiple patent applications to cover c-mods and their use in ALS and other TDP-43-mediated conditions. Over the next few years, it is expected to produce multiple additional c-mods to target a number of other conditions, according to another company <a href="https://www.globenewswire.com/news-release/2024/01/07/2805015/0/en/Dewpoint-Therapeutics-Filed-Multiple-Patent-Applications-with-the-US-Patent-Office-on-Novel-Composition-of-Matter-for-the-Treatment-of-ALS.html">press release</a>.

Dewpoint wins grant to develop its condensate-modifying therapies

<a href="https://www.vectorytx.com/" rel="nofollow">VectorY Therapeutics</a> has raised about $138 million in funding aiming to bring into clinical testing VTx-002, its lead treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS). The therapy equips nerve cells to produce antibodies against the damaging <a href="https://alsnewstoday.com/news/scientists-find-how-tdp-43-affects-important-nerve-protein-als/">TDP-43 protein clumps that are an ALS hallmark</a>.
“The investment will enable us to advance our lead program VTx-002, a potentially disease-modifying therapy for ALS, into clinical development. Our program is uniquely positioned to address TDP-43 pathology, which underlies the disease in the vast majority of ALS patients,” Sander van Deventer, CEO of VectorY, said in a <a href="https://www.vectorytx.com/news/vectory-raises-129-million-138-million-series-a-financing-to-advance-vectorized-antibody-programs-in-neurodegenerative-diseases">company press release</a>.
The accumulation of TDP-43 protein clumps in nerve cells is seen in about 97% of all ALS cases, and clearing these toxic molecules is regarded as a potential approach to delaying or preventing disease progression in nearly all patients.
[recommended-reading id=86261]
<h3>A faulty TDP-43 protein clumps in nerve cells of ALS patients</h3>
Antibodies are natural proteins made by the immune system that are able to bind a specific target. A few <a href="https://alsnewstoday.com/news/italian-researcher-granted-20k-tdp-43-antibody-research-als-treatment/">antibodies aimed at clearing misfolded TDP-43</a> proteins from nerve cells are in development.
However, traditional antibody-based therapies are usually too large and limited in their ability to reach the brain and spinal cord. They also require regular administrations, as infused antibodies eventually degrade and lose their effectiveness.
VectorY is developing <a href="https://www.vectorytx.com/vectorized-antibody-platform" rel="nofollow">vectorized antibodies</a>, a class of antibodies that essentially deliver the genetic sequence of an antibody to target cells, enabling them to produce their own therapeutic antibodies.
The platform uses harmless adeno-associated viruses (AAV) that were modified to be highly specific to cells in the brain and spinal cord. In VTx-002, that AAV carries a gene designed to enter cells, where it can be used to produce an antibody against the faulty TDP-43 protein, while leaving functional TDP-43 proteins unharmed.
Notably, because the virus stays inside cells until they die, a single administration of the therapy is expected to result in long-term antibody production and durable responses.
Proceeds from the Series A financing also will be used to boost the development of existing and new vectorized antibodies for other conditions marked by the buildup of toxic protein aggregates, diseases called proteinopathies that include <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington’s</a> and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson’s</a>.
“The series A will also support advancement of additional pipeline programs targeting proteinopathies in neurodegenerative diseases demonstrating the broad potential of our platform,” van Deventer said.
The financing round was co-led by EQT Life Sciences and the Forbion Growth Opportunities Fund, with the support of multiple new and past investors.
“We are very impressed with VectorY’s unique capabilities to combine gene and antibody therapy drug development with deep neuroscience expertise. The company’s technology allows for targeted protein degradation while restoring or preserving normal protein function, with applications across multiple neurodegenerative diseases,” said Arno de Wilde, director at EQT Life Sciences.
Previous and new finance round investors included MRL Ventures Fund, a corporate venture arm of Merck in the U.S., Insight Partners, ALS Investment Fund, Forbion Ventures, and BioGeneration Ventures.
“The Series A financing, supported by such a strong syndicate of European and US investors, is an endorsement of our pioneering approach &#8230; to bring much-needed therapies to patients with neurodegenerative diseases,” van Deventer said.
As part of the financing, de Wilde, Wouter Joustra, a partner at Forbion Growth Opportunities Fund, and Karin Kleinhans, a partner at MRL Ventures Fund, will join VectorY’s board of directors.

VectorY raises millions to support antibody gene therapy for ALS

<a href="https://www.takeda.com/" rel="nofollow">Takeda</a> has obtained an exclusive, worldwide license to <a href="https://acurastem.com/" rel="nofollow">AcuraStem</a>’s investigational therapies targeting the PIKfyve enzyme, including AS-202, a potential treatment for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) that ultimately aims to lower toxic TDP-43 protein buildup in nerve cells.
While Takeda will be responsible for clinical development, regulatory affairs, and global commercialization, AcuraStem will contribute to work in AS-202’s preclinical development, including running clinical trial-enabling studies and characterizing potential alternative PIKfyve-targeted therapies.
&#8220;Our mission at AcuraStem is to get our promising therapeutics to the patients who need them as quickly as possible,&#8221; Sam Alworth, CEO of AcuraStem, said in a <a href="https://www.prnewswire.com/news-releases/acurastem-enters-into-a-license-agreement-with-takeda-to-advance-pikfyve-therapeutics-301937595.html">company press release</a>. &#8220;We are delighted to have secured a partner in Takeda who has the world class clinical development and commercial capabilities to deliver on our mission.&#8221;
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<h3>TDP-43 in ALS accumulates in nerve cells, ultimately killing them</h3>
AcuraStem will receive upfront and milestone payments totaling about $580 million during the agreement&#8217;s term if all future clinical, regulatory, and commercial milestones are met. It also will earn royalties on commercial sales should any products reach the market.
In about 97% of ALS patients, including both <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a> and <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic disease</a> cases, a misfolded version of the TDP-43 protein accumulates in nerve cells.
While TDP-43 normally is found in the cell&#8217;s nucleus, the abnormal protein toxically clumps outside the nucleus, disrupting the function and health of the motor nerve cells needed to control voluntary movement, causing <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a>.
AS-202 is designed to <a href="https://acurastem.com/therapeutics" rel="nofollow">activate multivesicular body (MVB) exocytosis</a>, a process essentially involved in engulfing cellular waste and unwanted proteins and facilitating their removal.
The therapy belongs to a class of small molecules called antisense oligonucleotides, or ASOs, which bind to DNA or RNA and block their ability to produce a protein. In this case, AS-202 boosts MVB exocytosis by blocking production of the PIKfyve enzyme, which regulates that process.
AcuraStem expects that AS-202 will promote the clearance of misfolded TDP-43, thereby preventing the neurodegeneration that characterizes ALS and frontotemporal dementia (FTD), a related condition also marked by toxic TDP-43 buildup.
The therapy is designed to be delivered directly into the central nervous system, or the brain and spinal cord, via an injection into the spinal canal. Called an intrathecal injection, this approach aims to protect nerve cells, while avoiding the toxicity associated with a lack of PIKfyve activity elsewhere in the body.
<h3>AS-202 seen in animal studies to help clear misfolded clumps of TDP-43 in cells</h3>
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Preclinical studies in animal models of ALS and FTD demonstrated that AS-202 effectively reduced TDP-43 protein clumps, in addition to <a href="https://alsnewstoday.com/news/acurastems-as-202-als-shows-promise-preclinical-studies/">easing neurodegeneration</a>, restoring motor function, and improving the animals&#8217; survival.
Justin Ichida, PhD, AcuraStem&#8217;s co-founder, initially identified <a href="https://www.cell.com/cell/pdf/S0092-8674(23)00005-3.pdf">PIKfyve as a promising target</a> for treating ALS across disease subtypes in his laboratory at the University of Southern California.
&#8220;We originally identified PIKFYVE &#8230; using nerve cells derived from [ALS] patient stem cells, and this illustrates the power of using this modern approach,&#8221; Ichida said.
After licensing this therapeutic approach from the university, AcuraStem developed AS-202 using its iNeuroRx platform, which couples patient-derived disease models with human genetic data to identify clinical treatment candidates.
&#8220;We look forward to building on AcuraStem&#8217;s work to progress this exciting science into development and to patients,&#8221; said Sarah Sheikh, head of the neuroscience therapeutic area unit at Takeda.
AcuraStem is continuing work on other therapeutic approaches to ease TDP-43 pathology in ALS and FTD, including ASOs targeting the UNC13A and SYF2 proteins. These programs are not covered by the licensing agreement with Takeda.

Takeda acquires license to ALS therapy aimed at toxic TDP-43

When the TDP-43 protein is less able to form two-protein complexes called dimers, it appears to be more likely to form the toxic clumps seen in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a study reports.
As these clumps are found in about 97% of all ALS cases, a better understanding of the mechanisms leading to TDP-43 protein aggregates may help in developing therapies for most patients.
&#8220;Maintaining the &#8230; equilibrium of these pathogenic proteins may represent a common therapeutic target for neurodegenerative diseases,&#8221; its researchers wrote.
The study, &#8220;<a href="https://www.science.org/doi/10.1126/sciadv.adf6895">Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis</a>,&#8221; published in <a href="https://www.science.org/journal/sciadv">Science Advances</a>.
[recommended-reading id=86183]
<h3>Research into how TDP-43 aggregates in nerve cells of ALS patients</h3>
One of the key molecular features of ALS is the abnormal aggregates — clumps — of the protein TDP-43 in nerve cells. This protein normally is found in the nucleus — the cellular compartment that houses DNA — but in virtually all ALS cases, the protein instead forms <a href="https://alsnewstoday.com/news/als-study-links-abnormal-rna-modifications-tdp-43-function/">aggregates outside the nucleus</a>.
It&#8217;s thought that TDP-43 clumps disrupt normal nerve function and contribute to driving the disease. Exactly how these clumps form, however, remains incompletely understood.
Under normal circumstances, TDP-43 is found in two states in nerve cells. Either the protein exists as a monomer containing just one TDP-43 protein, or the protein exists in a dimer where two of the proteins are attached to each other.
Scientists set out to investigate whether changes in the monomer/dimer status of TDP-43 is disrupted in ALS, and whether such changes may play a role in the protein&#8217;s abnormal clumping.
They first conducted tests on nerve tissue collected from people with <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic ALS</a>. Results showed that these tissues had more TDP-43 monomers, and correspondingly fewer dimers, than what&#8217;s normally seen in people without the disease.
More TDP-43 in its monomer state might help to trigger ALS-related molecular changes, findings implied. To test this idea, the researchers engineered nerve cells harboring a modified version of the TDP-43 protein — one not able to form dimers, so it only exists as a monomer unless it&#8217;s forming clumps.
Experiments in these cells showed that, when TDP-43 is only present as a monomer, it&#8217;s more likely to move outside of the nucleus into the cytoplasm and clump.
<h3>Lack of TDP-43 &#8216;monomer-dimer equilibrium&#8217; may occur early in ALS</h3>
Further experiments revealed clues as to the biochemical processes underlying these changes. Dysregulations in transcription — the initial process where a cell &#8220;reads&#8221; a gene — can lead to more TDP-43 in monomer form, the researchers found. The movement of TDP-43 from the cell nucleus to the cytoplasm also was seen to be regulated by another protein called Nxf1.
&#8220;TDP-43 monomerization induced its cytoplasmic mislocalization in an Nxf1-dependent manner, along with &#8230; aggregation of TDP-43, which is a pathological hallmark of ALS,&#8221; the scientists wrote.
These findings &#8220;may be important in future research on early pathogenic [disease-causing] events related to TDP-43 and in the search for early diagnostic markers,&#8221; they added.
&#8220;Our study showed that the disruption of TDP-43 monomer-dimer &#8230; equilibrium may be a relatively early change, followed by cytoplasmic mislocalization of monomeric TDP-43, leading to &#8230; sequestering of normal TDP-43 into aggregates,&#8221; the scientists concluded. &#8220;We speculate that this vicious cycle may exacerbate TDP-43 pathology.&#8221;

TDP-43 more likely to clump if it can’t form two-protein complexes

<a href="https://www.acimmune.com/">AC Immune</a> has been awarded more than $500,000 in nonprofit grants by the <a href="https://www.michaeljfox.org">Michael J. Fox Foundation</a> (MJFF) and the <a href="https://www.targetals.org/">Target ALS Foundation</a> to support its programs to detect abnormal forms of the TDP-43 protein via imaging scans and fluid samples.
&#8220;It is an honor to have the support of MJFF and Target ALS, two leading international organizations that recognize the pressing need for diagnostics to detect pathological TDP-43,&#8221; said Andrea Pfeifer, PhD, AC Immune CEO, in a <a href="https://ir.acimmune.com/news-releases/news-release-details/ac-immune-awarded-new-grants-mjff-and-target-als-supporting">company press release</a>.
TDP-43 accumulates and forms toxic protein clumps in nerve cells in about 97% of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients, which is associated with nerve cell dysfunction. This buildup also occurs in <a href="https://link.springer.com/article/10.1007/s13311-022-01260-5">about half</a> of the patients with the neurodegenerative disease frontotemporal degeneration (FTD).
While this makes it a promising disease biomarker for ALS and FTD, there are no technologies that accurately detect abnormal forms of this protein in tissues of the central nervous system (the brain and spinal cord) or in biofluids such as the blood or spinal fluid.
The two grants are meant to help AC Immune advance its efforts to develop these technologies.
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MJFF is supporting AC Immune&#8217;s TDP-43 positron emission tomography (PET) tracer program to produce the first imaging agent capable of detecting and monitoring the progression of neurodegenerative diseases associated with TDP-43 defects.
The Target ALS grant, meanwhile, will support AC Immune&#8217;s collaboration with world-class institutions to develop innovative biofluid tests to detect TDP-43-associated disease.
&#8220;We firmly believe that a sensitive and accurate diagnostic will represent a breakthrough for the field and will accelerate clinical development of therapeutic candidates against this novel target,&#8221; Pfeifer said. &#8220;Given the heterogeneity and irreversible nature of neurodegeneration, our precision medicine approach represents the most promising strategy to identify the right patients and treat them earlier.&#8221;
The company&#8217;s TDP-43-PET tracers have been able to target TDP-43 as intended and with high selectivity in brain tissue. AC Immune expects to announce a clinical trial candidate this year.
&#8220;Brain imaging agents uncovering aggregated pathological protein hold great promise to enable earlier and more accurate diagnosis of [neurodegenerative diseases], and we are pleased to be expanding our relationship with AC Immune to supports its TDP-43 tracer program,&#8221; said Jamie Eberling, PhD, MJFF senior vice president of research resources. &#8220;AC Immune and its collaborators recently demonstrated their expertise in developing cutting-edge PET imaging agents by providing the first images of alpha synuclein. With this new grant, we hope to make similar progress in the development of a TDP-43-PET tracer.&#8221;
The Target ALS grant will accelerate the efforts of a consortium comprised of AC Immune, Kansas City University, the Barrow Neurological Institute, and the International Center for Engineering and Biotechnology to develop an antibody-based assay to detect disease-related species of TDP-43 in fluid samples.
&#8220;We are delighted to support the collaborative consortium in which AC Immune is participating,&#8221; said Manish Raisinghani, PhD, Target ALS CEO. &#8220;The development of a TDP-43 specific biofluid-based diagnostic test has the potential to more rapidly enable confirmed early diagnosis.&#8221;

Tag: TDP-43

TDP-43 deficiency leads to changes in physical structures of cell DNA

Dewpoint wins grant to develop its condensate-modifying therapies

VectorY raises millions to support antibody gene therapy for ALS

Takeda acquires license to ALS therapy aimed at toxic TDP-43

TDP-43 more likely to clump if it can’t form two-protein complexes

AC Immune wins $500K to advance TDP-43 diagnostic programs