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Neurodegenerative Disorders

Understanding how drug candidates target neurodegenerative disorders

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The development of drugs for neurodegenerative disorders represents both one of the biggest opportunities and one of the biggest challenges in the biopharma industry. Despite an estimated average of $5.7B being spent on the development of any single new Alzheimer’s drug, the past years have seen more than 99% of clinical trials fail, with outcomes for other neurodegenerative disorders such as Parkinson’s Disease scarcely better.

These failure rates are particularly striking given that a broad consensus on the pathology of these diseases has existed for more than 20 years. This discrepancy highlights a stark reality: we still lack a sufficient understanding of how – or if at all drug candidates interact with their intended targets.


 

Why we need a different approach to characterize the targets of new drug candidates to understand neurodegenerative disorders

In diseases such as Parkinson’s Disease and Alzheimer’s Disease neuronal loss is associated with an accumulation of misfolded and aggregated proteins, and drug candidates have largely been developed to either lower the concentration of these proteins, or lower the rate at which they form. But while these proteins are obvious drug targets, they are also highly heterogeneous, short-lived and low in abundance. These characteristics are the reason why conventional surface-based technologies have struggled to reliably validate complex targets and accurately characterize how drug candidates interact with them.

More than 99% of Alzheimer’s drug trials failed in the last decade

To address these challenges, Fluidic Analytics has developed a novel in-solution assay to help researchers and biopharma companies more accurately validate the mechanisms via which potential drug candidates interact with their targets – even complex targets such as those involved in neurodegenerative disorders.

 

Why accurately characterizing protein interactions is crucial for successful drug development

With billions of dollars being spent on unsuccessful drug development and failed clinical trials, it is vital to focus on the mechanisms via which  drug candidates interact with their intended targets. This includes understanding whether the candidate drug interacts with its intended protein target (on-target binding) or with other forms of the same protein (off-target binding), quantifying the strength of these interactions (binding affinity), understanding how many drug molecules interact with each target protein (stoichiometry) and determining whether or not these interactions ultimately reduce the levels of the most toxic forms of the target species. 

Providing tools to help researchers and drug developers answer these questions will enable more rapid development and validation of new drug candidates against these devastating diseases and ease the burden on our healthcare system in years to come.

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Why conventional technologies struggle to characterize interactions involving complex proteins

Conventional technologies such as SPR (Surface Plasmon Resonance) and BLI (Biolayer Interferometry) have made significant contributions to drug development in general. But they have failed to provide a detailed understanding of the interactions between drug candidates for neurodegenerative diseases and their challenging, highly heterogenous, misfolded and aggregated protein targets.

A major reason for this failure is that both technologies rely on attaching one of the binding partners to a surface. For traditional, well-folded targets, attachment to a surface presents no problem. But for more complex targets, attachment to a rigid surface can result in changes in the protein’s structure, such as eliminating structural disorder or masking or changing the accessibility of certain disease-relevant epitopes. When these structural characteristics are integral to the function of the target itself, such changes in structure can significantly change the behaviour of the protein.

In addition, surface-based technologies can struggle to distinguish on-target binding from non-specific binding to the detection surface, or distinguish whether a drug candidate binds to a monomeric protein, a misfolded protein, an aggregated protein, or a multi-protein complex. 

Understanding the mechanisms via which drug candidates bind their targets is key for successful drug development

Another problem with most surface-based technologies is that these methods rely on measuring binding kinetics to determine binding affinity. For heterogenous protein targets such as aggregates the binding kinetics can become increasingly complex which makes it challenging to extract any meaningful quantitative information about the binding reaction and its stoichiometry, specifically without any additional information on complex composition or size.

As a consequence, billions of dollars might be spent developing drugs that either do not bind efficiently or bind to the wrong target altogether.

 

How characterizing protein interactions in-solution can accelerate the validation of new drug candidates

Fluidic Analytics has developed a novel approach that characterizes protein interactions in-solution, not on a surface. This approach generates protein fingerprints that help researchers and drug developers distinguish on-target binding from off-target binding via protein sizing, and characterize the mechanisms of interaction between drug candidates and difficult-to-drug targets in their native environment to best reflect in-situ interactions. In addition, with the ability to measure protein sizes the composition and stoichiometry of protein complexes can easily and directly be determined – an approach that does not require interpretation of complex binding kinetics which regularly occur in multi-protein complexes.

 In summary, our in-solution technology allows the: 

  • Determination of binding affinity
  • Identification of binding epitopes and conformational epitopes that only occur in certain types of aggregates
  • Determination of binding stoichiometry
  • Assessment of target binding through sizing – on/off target binding
  • Elimination of artefacts as seen in surface-based technologies

These detailed insights into the mechanisms via which drug candidates bind to their intended target can help more accurately validate drug candidates with mechanisms of action similar to those of previous successful drugs, discard candidates with mechanisms of action known to be ineffective and identify candidates with entirely new mechanisms of action earlier in the development process, thereby saving millions of dollars due to failed clinical trials.

Resources

Glossary of neurodegenerative terms

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How our microfluidic in-solution approach works

Our in-solution approach is based on microfluidic diffusional sizing (MDS), a fundamentally novel technology that characterizes proteins and protein interactions in solution, under native conditions and on the basis of physical properties that determine function. As these parameters are assessed directly in solution, MDS eliminates complications typically associated with surface-based measurements such as changes in the protein structure or accessibility of disease-relevant binding sites, and enables researchers to obtain valuable information about binding targets, size and stoichiometry that cannot be obtained using other technologies.

MDS is the underlying technology of our Fluidity One-W instrument and exploits the properties of liquid laminar flow to measure the rate of protein diffusion under steady-state flow in a microfluidic chip. This approach allows the accurate assessment of on/off target binding and rapid characterization of the mechanisms of interaction between new drug candidates and difficult to drug targets to help accelerate drug development in the fight against neurodegenerative disorders.

Watch the video below to understand how the Fluidity One-W works:

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