Investigational molecule protects against ALS-linked cellular toxicity

FP802 reduced neurological disability, prolonged survival in mouse model

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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FundaMental Pharma’s investigational molecule FP802 reduced neurological disability, protected nerve cells, and prolonged survival in a mouse model of amyotrophic lateral sclerosis (ALS), according to recent research.

The molecule also protected tissue from glutamate toxicity, a type of cellular toxicity that’s implicated in ALS, in lab-grown “mini-organs,” called organoids, that were derived from ALS patient cells.

Belonging to the company’s new portfolio of molecules called TwinF interface inhibitors, FP802 is designed to safely prevent cell death while preserving normal neurological functions.

“This latest publication … provides tremendous validation of our work and guides us towards ALS as [the] prime indication for our new medicines,” Thomas Schulze, PhD, CEO and co-founder of FundaMental, said in a company press release.

FundaMental was spun off from the lab of Hilmar Bading, MD, a professor at the University of Heidelberg, Germany, where the recent research was conducted. The study, “TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS,” was published in Cell Reports Medicine.

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 The role of glutamate

Glutamate is a chemical messenger that aids in the normal function of nerve cells. Excessive amounts of this neurotransmitter can result in nerve cells being overstimulated, a process called excitotoxicity, that may contribute to their death in ALS.

One way glutamate exerts its effects is by binding to N-methyl-D-aspartate receptor (NMDAR) proteins. But where in the cell these receptors are located determines whether glutamate will exert a toxic or beneficial effect.

FWhen glutamate binds to NMDARs receptors in synapses (sNMDARs) — regions where neurons communicate with each other through chemical signals — it plays a critical role in proper nerve cell signaling and cognitive function. But if the receptors are in the extrasynaptic space, called eNMDARs, they are believed to mediate excitotoxic effects.

NMDARs could be a possible neuroprotective strategy in ALS, but existing molecules indiscriminately block both NMDAR types, which may result in unwanted side effects.

Bading and his colleagues recently discovered that eNMDARs may drive cell death through their interactions with a protein called TRPM4.

FundaMental’s TwinF interface inhibitors, including FP802, are made to disrupt that interaction, thus preventing the ensuing cell death signaling cascades. This works to “selectively eliminate toxic signaling of eNMDARs while sparing the physiological functions of sNMDARs,” the researchers wrote.

Neuroprotective effects of FP802

In the new study, the researchers evaluated the possible neuroprotective effects of FP802 in a mouse model of ALS.

The medication was administered via a mini-pump inserted under the skin that allowed FP802 to be continuously released. The investigational molecule was found to disrupt the interaction between NMDARs and TRPM4 in the spinal cord, as intended.

When treatment was started at the onset of neurological symptoms — to better resemble a clinical situation — mice treated about one month with FP802  exhibited significantly better neurological scores, and had less weight loss and better motor performance than untreated mice.

The treatment also significantly prolonged survival. Untreated mice lived a median of 151 days; mice treated with FP802 lived 164 days.

The improved clinical outcomes were associated with a preservation of specialized motor nerve cells in the spinal cord involved in movement that are progressively lost in ALS. Reductions in neurofilament light chain (NfL), a biomarker of nerve cell damage sometimes used in ALS clinical trials, were also observed relative to untreated mice. No treatment side effects were observed in the liver, kidneys, or heart.

Research on lab organoids

The researchers then explored the effects of FP802 in brain organoids, a type of three-dimensional tissue structure grown in the lab that’s intended to mimic the structure and function of the human organ, to further evaluate the possible translatability of their findings to ALS patients. The organoids were grown from the cells of people with sporadic or familial forms of ALS.

Administering FP802 effectively blocked NMDAR-induced nerve cell death in the organoids.

“The success of FP802 in protecting brain organoids derived from human ALS patients underscores the translatability of our preclinical findings, offering a glimpse into the potential impact of TwinF interface inhibitors on patients,” Bading said.

The researchers believe the study positions FP802 as “a promising treatment option for both familial and sporadic forms of ALS that share glutamate neurotoxicity as a [disease mechanism].” The company is working to develop versions of FP802 that could be taken orally, Schulze said.