VectorY Therapeutics presented new preclinical data for its innovative amyotrophic lateral sclerosis (ALS) therapy at the Target ALS Annual Meeting in Boston this week, revealing promising results for its vectorized antibody treatment VTx-001.
The Amsterdam and Boston-based biotech showcased data demonstrating VTx-001's potential to neutralize key upstream pathological drivers in ALS, specifically oxidized phosphatidylcholines (PC-OxPL), which have been linked to the development of TDP-43 proteinopathy and motor neuron degeneration—hallmark features of ALS.
"These findings support our hypothesis that PC-OxPL molecules are a key mediator of ALS pathology, acting upstream of TDP-43 proteinopathy and motor neuron toxicity," said Sander van Deventer, M.D., Ph.D., president of research and development at VectorY Therapeutics.
Novel Mechanism Targeting Oxidative Stress in ALS
VectorY's research team identified a distinct PC-OxPL profile in the brains of sporadic ALS (sALS) patients, with apolipoprotein E (APOE) particles emerging as the primary carriers of these oxidized phospholipids in the central nervous system.
The company's investigations revealed that exposure of induced pluripotent stem cell (iPSC)-derived motor neurons to PC-OxPL induced an ALS-like transcriptome, significant TDP-43 pathology, and ultimately led to motor neuron death—establishing a potential causal link between oxidized phospholipids and ALS pathogenesis.
VTx-001, an adeno-associated virus (AAV)-delivered single-chain antibody fragment, demonstrated multiple beneficial effects in preclinical models:
- Neutralization of PC-OxPL-induced TDP-43 pathology
- Normalization of disease-associated transcriptomic profiles
- Prevention of motor neuron death and functional decline in vivo
- Robust biodistribution and expression at therapeutic levels in a minipig model following intrathecal administration
These results suggest that targeting oxidative phospholipid toxicity could represent a novel therapeutic approach for ALS and potentially other neurodegenerative conditions.
Complementary Approach to ALS Treatment
VTx-001 represents one component of VectorY's two-pronged strategy to combat ALS. The company is also developing VTx-002, which directly targets TDP-43, a protein that forms toxic aggregates in approximately 97% of ALS cases.
"VTx-001 offers a novel and complementary mechanism of action to our lead candidate, VTx-002," explained Dr. van Deventer. "We anticipate filing an IND for VTx-002 before the end of this year."
The dual approach—targeting both upstream drivers with VTx-001 and downstream pathology with VTx-002—could potentially provide more comprehensive treatment options for ALS patients.
Vectorized Antibody Platform
VectorY's technology platform combines therapeutic antibodies with one-time AAV-based delivery to the central nervous system. This approach aims to overcome the blood-brain barrier limitations that have historically challenged traditional antibody therapies for neurological conditions.
The company's vectorized antibody approach allows for sustained expression of therapeutic antibodies directly in the central nervous system following a single administration, potentially improving efficacy while reducing the need for repeated treatments.
ALS: A Devastating Neurodegenerative Disease
ALS, also known as Lou Gehrig's disease, is a rare neurodegenerative disorder characterized by progressive loss of motor neurons, leading to paralysis and eventually death, typically due to respiratory failure. Most patients survive only 3-5 years after diagnosis.
The vast majority of ALS cases (90-95%) are sporadic, occurring without a known cause, while 5-10% are familial, linked to genetic mutations. Despite decades of research, treatment options remain limited, highlighting the urgent need for novel therapeutic approaches like those being developed by VectorY.
The data presented at the Target ALS Annual Meeting were recently published in the online publication bioRxiv in a manuscript titled "AAV-Delivered Anti-PC-OxPL Antibody Fragments: A Novel Therapeutic Approach to Target ALS."
Future Directions
While these preclinical results are promising, the path to clinical validation remains ahead. The company has not yet announced a timeline for advancing VTx-001 into human clinical trials, though the progress with VTx-002 suggests the platform is moving forward.
If successful in clinical development, VectorY's approach could represent a significant advancement in the treatment landscape for ALS, potentially addressing both upstream triggers and downstream effects of the disease process.
