Targeting nitrated alpha-synuclein may delay toxic clumping, spread

Modified protein being explored as biomarker, therapeutic target

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A trio of mice are pictured crawling around a beaker and test tubes in a lab.

An antibody that targets a naturally occurring modified form of alpha-synuclein, a protein that forms into toxic clumps in the brain of people with Parkinson’s, delays its buildup and spread in vivo in a mouse model of the disease.

This modified form of nitrated alpha-synuclein is being explored by Nitrase Therapeutics, the antibody’s developer, as a biomarker to help predict and diagnose Parkinson’s and as a potential therapeutic target.

“We are not aware of any other program targeting the nitrated form of [alpha]-synuclein, and we look forward to advancing our promising therapeutic antibody towards the clinic,” Irene Griswold-Prenner, PhD, CEO of Nitrase, said in a press release.

The data were shared in an oral presentation “Unveiling of a Novel Therapeutic Antibody Targeting Nitrated Alpha Synuclein for the Treatment of Parkinson’s Disease” at the 2024 Alzheimer’s Disease and Parkinson’s Disease conference, March 5-9 in Lisbon.

In Parkinson’s, misfolded alpha-synuclein clumps into aggregates called Lewy bodies, which are toxic to nerve cells. Lewy bodies can spread from one area of the brain to another, causing more nerve cells to die. This is thought to contribute to the progression of symptoms.

They are rich in nitrated alpha-synuclein, which may be less soluble than other forms of the protein. The chemical modification occurs with the help of an enzyme called synuclein nitrase, but blocking its activity reduces toxic clumping of alpha-synuclein, according to Nitrase.

Earlier work in Parkinson’s patients found elevated nitrated alpha-synuclein in the cerebrospinal fluid, which surrounds the brain and spinal cord, suggesting it may be “driving spread between brain regions,” Griswold-Prenner said.

Researchers at Nitrase tested how well several newly developed antibodies interact with nitrated alpha-synuclein and whether they recognize the modified protein, but not its nonmodified form, in preclinical studies in vitro, or outside of a living organism.

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About the antibody NDC-0524

The antibody NDC-0524 was found to interact with nitrated alpha-synuclein with high affinity, meaning the binding between the antibody and its target molecule was strong and stable. NDC-0524 didn’t interact with other nitrated proteins or nonmodified alpha-synuclein.

In mice, the antibody reached the brain tissue at a concentration that far surpassed the half-maximal inhibitory concentration, which indicates how much antibody would be needed to inhibit a biological process driven by nitrated alpha-synuclein by half.

In a mouse model of Parkinson’s where the disease is induced by injecting preformed fibrils, small structures that can grow into Lewy bodies, the antibody delayed the buildup and spread of alpha-synuclein aggregates.

“The in vivo data we presented with our antibody demonstrates its ability to significantly delay the aggregation of [alpha]-synuclein,” Griswold-Prenner said, noting it may also stop Lewy bodies from spreading “from one area of the brain to another.”

NDC-0524 also was better than the parental antibody of prasinezumab at reducing the spread of alpha-synuclein aggregates. Prasinezumab, an antibody that targets nonnitrated alpha-synuclein, is under Phase 2 clinical testing for Parkinson’s.

“Currently, there is no effective intervention to slow, halt, or reverse the progression of Parkinson’s disease,” said Kalpana Merchant, PhD, an advisor at the Michael J. Fox Foundation for Parkinson’s Research. “Promising preclinical data indicate that Nitrase’s  neutralizing antibody targeting nitrated [alpha]-synuclein has the potential to slow the progression of this devastating disease.”

Nitrase has received grants from the foundation to advance work on synuclein nitrase.

“We have identified an antibody candidate worthy of [entering] into clinical trials to test this mechanism, which in turn, may prove to be an effective therapeutic approach to address the currently unmet need in Parkinson’s,” the researchers said.