We are a company focused on detecting and developing projects that impact neurodegenerative diseases at what we believe is the root cause, inflammation. Our goal is to catalyze the transfer of these ideas to the pharmaceutical industry and basic research laboratories. We believe that our work will generate shortcuts to achieve early diagnosis and novel therapeutic strategies for neurodegenerative diseases.
As detailed below, we are currently focused on repurposing drugs capable of inhibiting aggregation and neuroinflammation, while also possessing good antioxidant activity in order to prevent mitochondrial damage. Other vital and synergistic projects include finding more reliable ways to detect and diagnose neurodegenerative diseases at a much early stage.
One of the main objectives of SkyBio is to design and test novel molecules based on our expertise in structure-function relationships and structural predictions of existing commercial drugs and their interaction with neurotoxic protein aggregates. We have defined the structural determinants for antiaggregant properties, and we are working in collaboration with chemical synthesis experts in order to obtain different families of compounds that would inhibit revert this toxic aggregation.
The increased longevity of the human population situates neurodegenerative diseases as a critical challenge to health care systems throughout developed countries. In fact, according to a systematic study on PD, approximately 4.6 million Western European patients were diagnosed in 2005, and that number is expected to increase to approximately 9 million in 2030. These data highlight the urgent need for identification of effective neuroprotective therapies in order to avoid the collapse of the healthcare systems. In this scenario, treatments must directly target underlying disease pathogenesis. Since abnormal aggregation of specific proteins like a-synuclein, tau, prionic protein or TDP-43, among others, would seem to be the common cause for almost all neurodegenerative diseases, inhibiting these anomalous aggregations or promoting their degradation are nowadays the main goals of drug design. Unfortunately, despite significant investment in research and drug development, to date, all attempts have failed.
Oxidative stress, mitochondrial dysfunction, and neuro-inflammation have also been recognized as triggers of neuronal cell death in neurodegenerative disorders. Compelling evidence shows that α-synuclein aggregation can trigger all these events, and sometimes vice versa, suggesting that these processes are intertwined and would foster a vicious cycle with fatal consequences for neurons.
Despite that a significant number of molecules are recognized as efficient in vitro inhibitors of α-synuclein amyloid self-assembly, they have failed to provide an effective neuro-protection in vivo. In addition, drugs developed to block these processes individually proved ineffective in clinical trials. Therefore, the big challenge today must be centered in finding molecules that target these multiple processes simultaneously in order to reach an efficient neuroprotective effect. That is, we must envision a multitask drug, capable of inhibiting aggregation and neuroinflammation, while also possessing good antioxidant activity in order to prevent mitochondrial damage.
In this context, our studies on existing commercial drugs as a potential neuroprotectors acquire relevance.
Aggregates species of proteins like a-synuclein, tau, prionic protein and TDP-43, among others, are nowadays considered responsible for neuronal death in neurodegenerative diseases like Parkinson’s and Alzheimer’s. Unfortunately, to date, there is no reliable biomarker to detect, nor follow, the evolution of these pathologies.
Quantification of aggregated species of these proteins in biological fluids would represent the most promising strategy for early detection of these disorders. In these cases, classical techniques such as ELISA do not possess the sensitivity, reliability nor reproducibility necessary to be a wide spread diagnostic and prognostic method. This is due to the great difficulty of obtaining specific antibodies to recognize the great diversity of aggregated species.
Currently, there is no biochemical blood or cerebrospinal fluid (CSF) analysis or diagnostic test for PD, and clinical manifestations in early stages are difficult to detect. The lack of a widespread analysis or diagnostic test for PD and AD is relevant if we consider that novel therapies against neurodegenerative disorders will require the ability to detect their earliest possible presymptomatic manifestations, since lost neurons generally cannot be replaced.
In this context, the main goal of this project is to develop and validate novel tools for early detection of a-synuclein and tau aggregates in biological fluids and novel PET radiotracers based on our knowledge of the molecular determinants that strongly bind toxic species of a-synuclein and tau. This development would revolutionize the field of neurodegenerative pathologies.
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