A singular focus: Tau

At Pinteon, we focus on a protein called tau, which plays a vital role in brain health.

Normal tau helps stabilize the microtubules that assist in transporting proteins, nucleotides and organelles along brain neurons.

However, like other proteins in the body, tau can fold into different structures, known as conformations. One of the conformations, cis-p-tau, is believed to be highly neurotoxic. Cis-p–tau can promote disease in two ways. First, when the brain is injured, for example in an accident leading to concussion, cis-p-tau may be released from neurons, causing toxicity acutely to neighboring neurons. Second, in the months following a brain injury or during the development of Alzheimer’s disease or progressive supranuclear palsy, cis-p-tau spreads through the brain and promotes abnormal aggregation of tau proteins in neurons. These clumps of tau, known as neurofibrillary tangles, block communication between neurons. In turn, this disruption impedes learning, memory and cognition.

Both acutely released cis-p-tau and the spread of cis-p-tau and neurofibrillary tangles are believed to be potent drivers of the neuronal degeneration observed in traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP).

Interrupting the effects
of a toxic protein

While cis-p-tau is highly toxic, it does have a vulnerability. In this conformation, the protein exposes an epitope, or binding site, labeled cis-pT231. At Pinteon, we have developed an antibody that precisely targets and firmly binds to cis-pT231. Our preclinical data suggest that when the antibody binds to this epitope, it interrupts both the acute and longer-term effects of toxic tau.

By inhibiting the acute neurotoxic and long-term spread of tau pathology, we believe our antibody will preserve cognitive function and significantly improve quality of life in patients with neurodegenerative diseases. Our goal is to halt or slow the rate of decline of tauopathy patients.

PNT001 is the only antibody in development that targets cis-pT231 tau, which has been identified in multiple preclinical studies as a potent driver of neurodegenerative disease.

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Fewer of the most densely packed tau tangles in the brain in animal models
Reduced neuronal death spread of tau pathology in animal models of TBI
- Significance: Suggests the progression of neurodegeneration has been slowed

Reductions in levels of serum neurofilament light chain, a marker of neuronal death, in animal models
- Significance: Suggests that neurons remain healthier longer after treatment
Reductions in preclinical inflammatory markers linked to the presence of tau
- Significance: By clearing cis-pT231 tau from the brain, PNT001 reduces neuroinflammation which also contributes to neuronal death in tauopathy

Improved performance on a spatial memory test in animal models
- Significance: Suggests positive effects on cognitive health

Preclinical improvements in long-term potentiation, a measure of synaptic strength
- Significance: Suggests improvement in neuronal communication, a foundation of learning and memory

Improvement in the acute and long-term consequences of brain injury
- Significance: Suggests positive effects on recovery from injury

These data give us confidence that PNT001 can reduce both the acute toxicity and and the spread of toxic tau in the brain and slow the neuronal death observed in diseases such as TBI, CTE, PSP and Alzheimer’s.

Supporting Literature

Albayram, O., et al. Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae. Nature Communications, 2017.

Albayram, O., et al. Traumatic Brain Injury-related voiding dysfunction in mice is caused by damage to rostral pathways, altering inputs to the reflex pathways. Scientific Reports, 2019.

Galas, M., et al. The Peptidylprolylcis/trans-Isomerase Pin1 Modulates Stress-induced Dephosphorylation of Tau in Neurons. Journal of Biological Chemistry, 2006.