Why Neurome Now? Diseases Publications

Why Neurome Now?
Neuroscience is perhaps the most promising field for future application of bio-medical discoveries for the treatment and prevention of the major unsolved human diseases. This is because: 1) the brain is thought to express more genes than any other organ in the body, and 2) the brain must monitor and control all other aspects of bodily function, from heart rate and blood pressure, to temperature, to salt and water balance, to blood sugar and feeding, as well as all reproductive actions, and in humans complex mental activities such as language, mathematics, abstractions and long term strategies.

Until recently, the process of identifying genes expressed in the brain has been slow, let alone determining what these genes encode and where in the brain’s complex circuitry are the neurons that express these genes.

However, as widely trumpeted in the press, two massive efforts have now resulted in the nearly complete initial inventories of the human genome, and that of the mouse is said to be well along towards completion. The mouse genome is a critical next step in harvesting the value of the information of the genome pertinent to disease vulnerability and resistance, since the mouse is the only mammal in which we can manipulate human disease-related genes to be expressed in whole animal models of human disease to determine what are the critical environmental factors that interact to render an individual vulnerable or resistant to a disease.

By understanding the genetic vulnerabilities that underlie neurodegenerative illnesses, major opportunities for the development of new treatments begin to present themselves. Neurome has developed a suite of proprietary technologies that enable insight into these genetic vulnerability factors, and the company is positioned to employ these technologies in pursuit of novel therapeutics to treat Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis.

Neurons Exhibit Selective Vulnerabilities
Before the era of modern medical genetics, neurodegenerative diseases were understood mainly in terms of the neurological problems that arise during the final stages of the patients' lives, and the pathological findings revealed at autopsy by microscopic examination of their brains and spinal cords. The result of nearly a century of such studies has revealed that neurodegenerative disorders do not destroy all neurons. Rather, neurons show patterns of disease-specific selective vulnerability: certain neuronal cell classes and associated circuits fail during the progress of the disease whereas others remain viable. The symptoms of the disease reflect the losses of the vulnerable neurons and their circuits. As genetic clues to the biochemical basis of these diseases have emerged from human studies, powerful mouse models of these diseases have been developed through manipulation of key disease-related genes. Importantly, the brains of these genetically manipulated animals reproduce critical elements of the disease in humans: certain neuronal cell classes and their associated circuits fail whereas others remain viable, and do so in highly analogous circuit locations.

Figure 1. Images showing dendritic spine morphology in a mouse model of human Alzheimer’s disease. The image on the left shows spines from a normal animal, while the image on the right shows significant degenerative loss of spines in an age-matched diseased animal, as indicated by the arrows.

The key to each disease lies in these patterns of disease-specific selective vulnerability. If we understand the unique attributes that make a particular neuron vulnerable and how that neuron differs from a resistant one, we should be able to protect the vulnerable neuron from the disease process. Using tools with the speed and precision of the Neurome Technologies, these early reflections of pathology can be identified quantitatively in the animal models, thereby defining the earliest neurons vulnerable to the pathological process, as well as those shown to be fully resistant to the disease process. This time line of vulnerability and resistance creates a pathway for achieving opportunities for novel therapeutic and preventive solutions.

ALS is a particularly compelling example of selective vulnerability, particularly as manifested in the mouse models of familial ALS that result from mutations in the enzyme superoxide dismutase 1 (SOD1). However, while several clear molecular mechanisms of neurodegeneration have been proposed for ALS, they have not been carefully considered in the context of selective vulnerability, and in fact, the molecular and cellular determinants of selective vulnerability in ALS remain elusive.

How do we develop the cell and circuit-specific interventions that are required to effectively treat disorders such as ALS? A disease mechanism-based treatment development plan must ultimately identify the cellular and molecular changes that are the earliest maladaptations of the disease process. Such an approach should be designed to reveal mechanistic targets within vulnerable circuit-specific locations. Neurome’s technologies as applied to mouse models of ALS are ideal for both the discovery and evaluation of targets that can be associated with the cell classes and circuits at the core of this devastating disorder. Neurome is aggressively targeting ALS with such an approach.

The Neurome Technologies are capable of generating data ranging from the level of whole brains down to the level of DNA and protein sequence. All levels of resolution for a given gene product may be probed, in a seamless, integrated 3-D display that is quantitatively accurate. For example, if a particular neurotransmitter receptor were the object of inquiry, the data will reflect relative mRNA levels across brain regions, distribution and number of neurons containing the related protein within the brain areas of interest, high-resolution data on intraneuronal distribution of the protein, and quantitative ultrastructural data on the synaptic representation of the receptor. The high-resolution data, in particular, will be obtained and displayed within the context of identified cells and circuits, not just brain regions.

Figure 2. Distribution of plaque accumulation in a mouse model of human Alzheimer’s disease. The region outlined in red shows plaque accumulation restricted to a selective area (outer molecular layer) within the dentate gyrus of the hippocampus. This plaque accumulation is associated with damage to vulnerable neurons in this region.

Neurome's scientists have already demonstrated, using this research approach, their ability to define at a cellular and neuronal circuitry level those neurons that are vulnerable and those neurons that are resistant (in AD), and to establish when these neurons begin to show their divergence in vitality. Neurome’s technology platform is uniquely suited for both the discovery and evaluation of targets and drug candidates that may be useful in addressing defects associated with the cell classes and circuits that are at the core of those human neurologic disorders.

The Neurome Technologies
While the tools for neurochemistry, neuroimaging, and neuronal gene discovery are advancing rapidly, the same cannot be said for current methods of gene expression mapping in the brain – a critical next step in determining the molecular basis for the diseases that can confer vulnerability or resistance to brain related diseases. Neurome’s technology platform is comprised of a suite of proprietary, patent-protected software, hardware, instrumentation, reagents and methods that in combination allow high-throughput, rigorous and standardized quantitative measurement of brain morphology and quantify gene expression patterns and the resultant morphological details of brain structures with an unprecedented level of sensitivity, specificity, and resolution. The technologies include:

TOGA® (TOtal Gene expression Analysis) is a patented method of identifying and determining the concentration of nearly all of the genes active in a sample cell or tissue. TOGA® will reveal new molecular targets for intervention strategies, and Neurome’s microscopy-based technologies can be used to identify and characterize the cells that express these molecular targets to account for the pathologies in animal models of neurodegenerative diseases.

MiceSlice™ provides ultra-high resolution digital brain sections from the standardized preparation of brain section tissues. Microscope image tiles are seamlessly reassembled into one brain section and rotated to perfect alignment. MiceSlice™ provides the foundation material for the development of standardized experimental protocols.

NeuroZoom™ is a computerized microscopy system that supports the precise extraction, analysis, and display of quantitative data from the MiceSlice™ microscope images of the brain, including morphometrics, stereology and image processing. NeuroZoom™ automation supports high throughput analysis of ultra-high resolution images and promotes standardization of data analysis using the brain database models in BrainArchive™.

BrainArchive™ is a comprehensive database of neuroinformation and serves as an electronic brain "atlas", for archiving, integrating and comparing brain structure and circuitry data from NeuroZoom™. Reference brains from several transgenic mouse models have been imaged and aligned with high precision and ultra-high resolution using NeuroZoom™. BrainArchive™ presents virtual sections from its electronic brain atlas, digitally displaying both qualitative and quantitative gene expression data required from the mouse brain.

BrainPrint™ supports digital profiles for comparison of quantitative, spatial and volumetric data from different transgenic mouse models. BrainPrint™ analyzes all of the experimental data originating from NeuroZoom™ stored in BrainArchive™ and identifies those characteristics useful for developing profile information corresponding to certain traits under various phenotypes. Once a brain dataset has been properly described, different genetic conditions may be quickly compared and displayed.

Neurome’s strategy hinges on the ability to obtain a new generation of brain information: standardized, quantitative datasets that for the first time adequately and accurately depict the molecular, cellular and circuitry patterns of brain activity that determine both normal and variant functions of the brain, region by region and circuit by circuit – a new generation of data offering answers to new questions. These are the types of datasets the Neurome Technologies were designed to collect, organize and analyze, and it places Neurome on the leading edge of CNS drug discovery and development.

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