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<a href="https://acurastem.com/">AcuraStem</a> has secured nearly $7 million in grant funding from the National Institutes of Health (NIH) and the Department of Defense (DOD) to accelerate the development of therapies for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and related diseases.
Coming on the heels of a <a href="https://alsnewstoday.com/news/takeda-acquires-license-als-therapy-aimed-toxic-tdp-43/">$580 million deal with Takeda</a>, which obtained an exclusive, worldwide license to AcuraStem&#8217;s investigational therapies that target the PIKfyve enzyme, the new funding, awarded via a peer-review process, will help the company advance several other programs toward clinical trials.
&#8220;We are thrilled to receive continued support from NIH and the DOD,&#8221; Sam Alworth, MS, AcuraStem&#8217;s co-founder and CEO, said in a <a href="https://www.prnewswire.com/news-releases/acurastem-secures-7-million-in-funding-support-from-nih-and-dod-to-accelerate-therapies-for-als-and-ftd-302048227.html">company press release</a>. &#8220;Leaders from the scientific community selected AcuraStem for these awards through a rigorous peer-review process, which demonstrates the excellence of our research.&#8221;
Nearly all ALS patients, including those with <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic</a> or <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a>, accumulate a misfolded version of the TDP-43 protein in nerve cells. Normally found inside the nucleus, abnormal TDP-43 forms clumps outside it, which disrupts the function of motor neurons, the nerve cells that control voluntary movement.
The Takeda deal covers therapies, including AS-202, which is designed to target and block PIKfyve. Blocking this enzyme activates <a href="https://acurastem.com/therapeutics">multivesicular body (MVB) exocytosis</a>, a process that removes waste and unwanted proteins from cells.
By activating this process, AS-202 should promote the clearance of abnormal TDP-43 and prevent the neurodegeneration that marks ALS and frontotemporal dementia (FTD), a related condition also caused by TDP-43 clumping.
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<h3 class="p1"> Funding covers other therapeutic programs</h3>
The NIH and DOD funding will also advance the development of therapies that target UNC13A and SYF2, programs not covered by the Takeda licensing agreement.
Inside the nucleus, TDP-43 normally acts as an RNA-binding protein involved in processing messenger RNA (mRNA), an intermediary molecule produced as part of protein production.
When abnormal TDP-43 moves outside the nucleus, it disrupts the processing of UNC13A mRNA, leading to a loss of the UNC13A protein. This loss, which is worsened by mutations in the UNC13A gene, is associated with reduced survival in ALS and FTD patients.
The company&#8217;s iNeuroRx platform, which couples patient-derived disease models with human genetic data, was able to replicate UNC13A-related disease in patient neurons, according to AcuraStem.
Building on these findings, the company has developed antisense oligonucleotides (ASOs), a class of DNA/RNA-binding small molecules that prevent the disruption of UNC13A mRNA processing by TDP-43, thereby restoring UNC13A function.
These advances offer &#8220;a promising therapeutic approach for TDP-43 proteinopathies [protein-clumping diseases] and a deeper understanding of UNC13A&#8217;s role in disease progression,&#8221; AcuraStem wrote in its release.
The company says it&#8217;s also discovered that SYF2, another protein in the nucleus that&#8217;s involved in mRNA processing, is a potential ALS target. SYF2 regulates mRNA processing, which is affected by the movement of TDP-43 out of the nucleus. Modulating SYF2 may address both the toxic buildup of TDP-43 and counter the widespread dysregulation of genes, including UNC13A.
&#8220;Targeting SYF2 could offer a more direct and potentially effective therapeutic strategy compared to addressing each dysregulated gene individually,&#8221; AcuraStem noted.

AcuraStem awarded NIH, DOD grants to boost ALS therapies

<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>
<h3></h3>
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.

Tag: AcuraStem

AcuraStem awarded NIH, DOD grants to boost ALS therapies

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