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A first healthy volunteer has been dosed in a Phase 1 clinical study evaluating how safe and well tolerated is CVN293, a treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer’s disease</a>, the therapy&#8217;s developer, <a href="https://www.cerevance.com" rel="nofollow">Cerevance</a>, announced.
The treatment, given orally, is designed to block a protein called KCNK13 on microglia, a type of immune cell that resides in the brain and is thought to play a role in ALS and other diseases.
Single ascending doses (SAD) and multiple ascending doses (MAD) are being tested in the study, with ascending doses of CVN293 administered once or repeatedly and compared with a placebo.
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<h3>Problems in microglia function may promote brain inflammation in ALS</h3>
A total of 64 healthy men and women, ages 18 to 55, will be randomly assigned in a 6:2 ratio to either CVN293 or a placebo. Five groups of eight people will be in the study&#8217;s SAD part; three groups of eight will enter its MAD portion.
In addition to therapy safety and tolerability, the study will evaluate CVN293&#8217;s pharmacokinetics, or how the drug moves into, through, and out of the body.
“We are very pleased to advance CVN293, a selective small-molecule inhibitor of the novel target KCNK13 into Phase 1 clinical development,” Craig Thompson, Cerevance’s CEO, said in a <a href="https://www.globenewswire.com/news-release/2023/09/19/2745619/0/en/Cerevance-Doses-First-Subject-in-Phase-1-Clinical-Study-of-CVN293-a-Selective-Inhibitor-of-KCNK13-Designed-to-Selectively-Modulate-Neuroinflammation-for-the-Treatment-of-ALS-and-Al.html">company press release</a>.
ALS occurs when motor neurons — the nerve cells that control muscle movement — become damaged and die over time. This results in <a href="https://alsnewstoday.com/symptoms-of-als/">muscle weakness</a>, leading to problems that include breathing, speaking, and eating.
What exactly <a href="https://alsnewstoday.com/causes-of-als/">causes ALS</a> is not known, but immune cells like microglia are believed to be involved. Like macrophages, the pathogen-engulfing immune cells that reside in tissues outside the brain, microglia eat bacteria, viruses, and debris.
It is thought that microglia, which normally protect the brain from harmful invaders, may go awry in ALS and allow a long-lasting cycle of inflammation that further damages motor neurons.
CVN293 was developed using the company’s proprietary <a href="https://www.cerevance.com/netsseq" rel="nofollow">Nuclear Enriched Transcript Sort sequencing (NETSseq) platform</a>, which lets researchers scan the molecular signature of specific types of cells within the brain and identify potential targets for neurological conditions.
It is designed to block KCNK13, also known as THIK-1, a channel protein that allows potassium ions to flow out of microglia. Earlier <a href="https://www.pnas.org/doi/10.1073/pnas.2106294118">work in mice</a> found that ion efflux (outflow) regulates the release of inflammatory signals from microglia, limiting communication between nerve cells.
By targeting the ion channel and preventing potassium release by microglia, CVN293 aims to lower inflammation in the brain without dampening immune cells working outside the central nervous system (brain and spinal cord).
Unlike other proteins, KCNK13 is almost exclusive to microglia and present only at very low levels in macrophages. As such, CVN293 may target microglia while leaving macrophages — needed for a healthy immune response — unharmed.
“KCNK13, an important modulator of neuroinflammation, was selectively identified using NETSseq and represents the power of the Cerevance platform in discovering precision neuroscience targets,” Thompson said.
“This [trial] is an important milestone as we continue to translate scientific discoveries into potential therapeutic options to address neuroinflammatory conditions,” he added.

Dosing of healthy adults begins in Phase 1 study of oral CVN293

<a href="https://www.modulo.bio/" rel="nofollow">Modulo Bio</a> has launched with $8 million in funding and a goal to map the neuroimmune system and develop treatments for neurodegenerative diseases, including <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The neuroimmune system involves interactions between the nervous system and the immune system, which normally protects the nervous system and helps it to recover from harm. But this interaction can be complicated in people with neurodegenerative conditions, where immune cells often play a key role in driving disease.
The company aims to map the entire neuroimmune system to understand how neurodegenerative diseases are related, and to discover more effective treatments that modulate this system.
“By embracing the complexity of the neuroimmune system, we can discover drugs that make an impact across neurodegenerative diseases,” Scott Patterson, chief technology officer at Modulo, said in a <a href="https://www.businesswire.com/news/home/20230601005502/en/Modulo-Bio-launches-to-map-the-neuroimmune-system-and-develop-treatments-for-neurodegenerative-diseases-starting-with-ALS-and-FTD">company press release</a>.
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<h3>Work starts with studies of microglia, immune cells of the brain</h3>
While the larger goal is to understand how the entire immune system influences nerve function, Modulo initially is focused on microglia, the brain&#8217;s resident immune cells.
These cells are key regulators of the nervous system, helping to protect, maintain, and repair or eliminate nerve cells to keep the brain working properly. But microglial sometimes shift gears, with toxic effects on the nervous system.
To find therapeutic targets supporting the neuroprotective role of microglia, researchers at Modulo developed the Modulo Neuroimmune Platform, which tests patient-derived microglia in a variety of models and uses artificial intelligence (AI) to better understand their behavior.
&#8220;We ask questions like: What biological targets influence microglia and shift them into different states? How do microglia in specific states influence disease? How can microglia protect the brain? What neurotoxic outcomes occur when microglia behavior is changed?,&#8221; the company states on its <a href="https://www.modulo.bio/platform">website</a>.
In addressing these questions, researchers might discover ways to effectively reprogram microglia to slow or stop disease progression, and possibly reverse damage done.
“We use AI to create multi-layered maps of cellular systems, and accurately predict the effects of genetic mutations, drugs, and their combinations on cells like microglia,” Patterson said.
The company reports having identified new microglia targets and potential treatment candidates for neurodegenerative diseases, such as ALS and frontotemporal dementia (FTD), a related condition.
“We believe reprogramming microglia is one of the best strategies in the fight against neurodegenerative disease,” said Justin Ichida, PhD, a University of Southern California professor and scientific founder of Modulo, which is based in California.
“By identifying targets on the microglia that reprogram them into protective states, we leverage the natural, evolutionary function of the neuroimmune system to protect and repair neurons,” added Ichida, who has expertise in modeling ALS and FTD using patient-derived cells.
Modulo&#8217;s team includes cell biologists, neuroscientists, immunologists, and experts in computational and drug development. The $8 million in funding that helped launch the company came from Initialized Capital, Cantos, Bioverge, Spacecadet, Builders VC, Refactor Capital, and Hawktail.
“We invest in founding teams obsessed with disrupting stagnant, large and meaningful industries,” said Alda Leu Dennis, general partner at Initialized Capital. “In Modulo, we found a team relentlessly focused on modeling and reprogramming the neuroimmune system — and we believe their tenacity and experience will revolutionize the approach to drug development in neuroscience.”

Tag: microglia

Dosing of healthy adults begins in Phase 1 study of oral CVN293

Modulo Bio’s goal: Better understand and treat ALS, like diseases