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P4*

Anti-KLK8 against Alzheimer’s disease - Kallikrein-8 as an early biomarker and therapeutic target for AD

Prof. Kathy Keyvani, University of Duisburg-Essen; Dr Arne Herring, University of Duisburg-Essen

PROvendis GmbH


Challenge

With currently ~ 35 Mio. patients worldwide Alzheimer’s disease (AD) is the most common neurodegenerative disease and the primary cause for dementia. Due to the demographic change, this number will presumably triple until 2050. All costs associated with AD are immense, estimated by the World Health Organization at over US-$ 600 billion worldwide.

There is clear evidence that AD starts to damage the brain decades before the first symptoms appear. This has led to the current consensus that any disease-modifying treatment can be efficacious only when initiated at the earliest stages of the disease. For decades, amyloid beta (Aβ) and tau were considered as the key molecules in AD pathogenesis, therapy and diagnosis. To date, extensive evaluation of Aβ and tau as potential therapy targets resulted in conflicting and disillusioning results in clinical trials. Accordingly, there is still an urgent need for supportive minimally invasive and cost-effective biomarkers for early diagnosis of AD as well as for causal, multimodal acting medicaments.


Technology

Memory loss and increased anxiety are clinical hallmarks of AD. Kallikrein-8 is a protease implicated in memory acquisition and anxiety. It is considerably upregulated in human and murine brain at incipient stages of AD, long before the “clinical” signs of disease appear (1,2). Furthermore, KLK8 elevation is not only detectable in the brain but also in the blood and cerebrospinal fluid (CSF) of patients with early AD and even stronger with mild cognitive impairment (MCI) (3).

In a pilot trans-sectional study the diagnostic performance of KLK8 in CSF and blood was more or less comparable and in case of MCI even superior to that of the established CSF core biomarkers Aβ42, phospho-tau and total tau (3).

Moreover, short-term inhibition of pathologically elevated KLK8 in transgenic mice was capable of attenuating various pathologic features of AD (i.e. Aβ pathology, tau hyper-phosphorylation, neurovascular dysfunction, disturbances in autophagy and microglial Aβ phagocytosis, deficits in structural neuroplasticity, anxiety and cognitive decline) (1,4). Intriguingly, these effects could be recapitulated also by genetic knockdown of KLK8 (5).

These data identify KLK8 as potential early biomarker for AD in blood and CSF and as promising first-in-class therapeutic target for AD via antibody-mediated inhibition.


Commercial Opportunity

PROvendis is offering licenses for the invention to interested companies on behalf of the University of Duisburg-Essen. Collaboration with the inventors are welcomed.


Development Status

The therapeutic value of KLK8 has been confirmed in mice. Mechanisms of action have been largely untangled in vitro and in vivo.


Patent Situation

A European patent application is pending.


Further Reading

1. Kallikrein-8 inhibition attenuates Alzheimer's disease pathology in mice. Alzheimer's & dementia 2016;12:1273-87. doi.org/10.1016/j.jalz.2016.05.006

2. Higher levels of kallikrein-8 in female brain may increase the risk for Alzheimer's disease. Brain Pathol. 2018;28:947-64. doi.org/10.1111/bpa.12599

3. CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer's disease. J neurol, neurosurg, psychiatry. 2020;91:40-8. doi.org/10.1136/jnnp-2019-321073

4. Inhibition of excessive kallikrein-8 improves neuroplasticity in Alzheimer's disease mouse model. Exp neurol. 2020;324:113115. doi.org/10.1016/j.expneurol.2019.113115

5. Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer’s pathology in mice. Neuropathol Appl Neurobiol. doi.org/10.1111/nan.12687


 

Anti-KLK8 against Alzheimer’s disease - Kallikrein-8 as an early biomarker and therapeutic target for AD