NRG Therapeutics gets grant to test mitochondria-targeting ALS therapy
Target ALS, Biospective grants support promising proof-of-concept studies
NRG Therapeutics has received a grant from the nonprofit Target ALS to advance preclinical studies of its new class of oral small molecules targeting mitochondria, the energy producers of cells, as a potential treatment for amyotrophic lateral sclerosis (ALS).
The 2024 In Vivo Target Validation grant program, an initiative from the nonprofit Target ALS in collaboration with Biospective, seeks to support proof-of-concept studies to foster the development of promising new therapies.
“This initiative, in collaboration with Biospective, is designed to accelerate the evaluation of potential therapeutics, bridging the gap from preclinical research to clinical trials,” Target ALS said in a press release announcing this year’s recipients.
Damage to motor neurons, the nerve cells that control voluntary movements, is the hallmark feature of ALS. While the mechanisms that cause ALS remain to be fully explained, mitochondria impairments are thought to be one of earliest disease-related events.
About 97% of ALS patients have toxic clumps of TDP-43 protein
A large majority of ALS patients (about 97%) have toxic clumps of the TDP-43 protein, which contribute to nerve cell damage in ALS and other disorders. Recent evidence suggests these clumps disrupt mitochondrial function, causing the release of mitochondrial DNA that abnormally activates the immune system.
The release of DNA from mitochondria happens through a channel called the mitochondrial permeability transition pore (mPTP). The sustained activation, or opening, of that channel can cause mitochondria to swell and rupture, ultimately leading to the cell’s death.
NRG Therapeutics believes inhibiting that channel and preventing it from carrying molecules can be a potential approach for treating ALS. The company is developing first-in-class small molecules that inhibit the mPTP, and are designed to enter the brain effectively when taken orally.
By targeting the mPTP, the inhibitors are expected to protect mitochondria and prevent nerve cell death. In preclinical experiments with an ALS mouse model engineered to carry the TARDBP human gene, which contains the instructions for TDP-43, the company’s candidate inhibitor lessened nerve cell death.
“Preliminary experiments using a mouse model of ALS which contains the human gene for TDP-43 showed that our mPTP inihibitor candidate therapeutic reduced brain cell death,” Neil Miller, PhD, NRG Therapeutics’ cofounder and CEO, said in a company press release. “However, due to the rapid disease progression in that mouse model, a full assessment of the therapeutic potential was not possible.”
NRG Therapeutics to test its candidate in mouse model of slow-progressing ALS
The new grant will allow NRG Therapeutics to test its candidate in a mouse model of slow-progressing ALS. Developed by Biospective, the model exhibits symptoms and biological alterations similar to those seen in ALS patients, including TDP-43 mislocalization, neurodegeneration, and motor deficits.
Validating its candidate inhibitor in this model will complement NRG Therapeutics’ preclinical studies, helping to determine its ability to protect mitochondria, reduce nerve cell death, and lessen inflammation. Researchers will also measure changes in muscle function and strength.
“This project aims to evaluate NRG’s small molecule inhibitor, in a modified ALS TDP-43 mouse model that progresses more slowly,” Miller said. “If successful, [it] will provide crucial support for advancing our mPTP inhibitor into clinical trials for ALS.”
Other recipients of this year’s grants include Neumora Therapeutics, Dewpoint Therapeutics, Mabylon, and Genentech, all of which will have a preclinical candidate molecule tested in Biospective’s TDP-43 mouse model.
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