Scenic Biotech and Stanford University researchers have made a significant scientific breakthrough by identifying PLA2G15, a lysosomal phospholipase, as a promising new therapeutic target for treating neurometabolic disorders. The groundbreaking study, published in Nature, demonstrates that inhibiting PLA2G15 can significantly improve disease outcomes in models of Niemann-Pick type C (NPC) and potentially other neurodegenerative conditions.
The collaborative research reveals that PLA2G15 plays a crucial role in modulating bis(monoacylglycerol)phosphate (BMP), a lipid essential for proper lysosomal function that is implicated in various neurodegenerative and metabolic disorders.
Promising Results in Niemann-Pick Type C Models
In animal models of Niemann-Pick type C, often referred to as "juvenile Alzheimer's," inhibiting PLA2G15 led to remarkable improvements. The intervention restored BMP levels, enhanced lysosomal function, and significantly reduced neurological symptoms while minimizing liver and spleen damage.
"We demonstrate that targeting PLA2G15 improves neurodegeneration, spleen and liver damage, as well as neurological symptoms and survival in NPC mice," explained Dr. Vincent Blomen, Senior Director of Discovery Sciences at Scenic Biotech.
The findings are particularly significant as NPC currently lacks effective disease-modifying treatments. This rare lysosomal storage disorder causes progressive neurological deterioration, but the PLA2G15 inhibition approach could potentially slow or halt disease progression.
Challenging Previous Scientific Understanding
The research challenges long-held assumptions about BMP metabolism. Dr. Monther Abu-Remaileh, Assistant Professor of Chemical Engineering and Genetics at Stanford University and co-author of the paper, explained: "BMP plays an integral role in promoting lysosomal function including lipid degradation and cholesterol trafficking; however, little is known about BMP degradation."
"BMP is deregulated in a multitude of diseases and has long been thought to be resistant to degradation by lysosomal enzymes. We now show that PLA2G15 can hydrolyse BMP, and importantly, that inhibition of the enzyme presents a promising therapeutic approach," Dr. Abu-Remaileh added.
This new understanding of BMP regulation opens potential therapeutic avenues for multiple conditions where lysosomal dysfunction plays a role.
Validation of Scenic Biotech's Platform Technology
The publication represents a significant validation of Scenic Biotech's modifier therapy platform, which utilizes human haploid cells to identify novel drug targets.
"The publication in Nature is both a validation and a demonstration of the power of our platform that uses human haploid cells to discover disease-relevant targets in various therapeutic areas including our focus areas of neuro- and metabolic diseases," said Dr. Blomen.
Broader Therapeutic Potential
While the initial focus has been on Niemann-Pick type C, the researchers believe PLA2G15 inhibition could benefit patients with other neurometabolic disorders, including Batten disease and Frontotemporal Lobar Degeneration (FTLD).
These conditions share underlying mechanisms related to lysosomal dysfunction and currently have limited treatment options. The ability to modulate BMP levels through PLA2G15 inhibition could potentially address fundamental disease processes across multiple conditions.
Moving Toward Clinical Development
Scenic Biotech is advancing its lead small-molecule PLA2G15 inhibitor through preclinical development. The company plans to initiate IND-enabling studies shortly, with the goal of progressing to first-in-human trials in the near future.
This development pipeline could eventually deliver much-needed therapeutic options for patients with neurometabolic disorders who currently have few or no effective treatments available.
The discovery of PLA2G15 as a key regulator of lysosomal function represents a significant step forward in understanding and potentially treating a range of devastating neurological conditions, offering hope to patients and families affected by these disorders.
