Problem to be Solved by h.o.p.e.

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No neural repair drugs are being used in clinical practice today. One of the reasons is that neurological injuries are extremely complex and no academic or industry lab has applied the necessary skills and resources to solve the enormous challenge of how to regrow the missing tissue. Additionally, different incentives in industry and academic labs discourage tests on a drug for which they don’t own the patent or that doesn't present the possibility of a novel publication. This also means that the skill set to orchestrate thousands of therapeutic decision points into a safe, comprehensive, and translatable treatment plan does not currently exist. The field desperately needs a comprehensive approach to central nervous system tissue regrowth that overcomes these barriers.

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Technology to Orchestrate

Current Drug Libraries

Science has discovered over 125 million unique chemical and molecular compounds with tens of thousands of these compounds being drug candidates. These compounds are categorized in existing drug libraries and include information on FDA approval status, what cellular mechanisms are influenced, toxicology, drug–drug interactions, drug clearance and excretion, drug delivery options, etc. These drug libraries also can be examined per intellectual property, patents, cost, and supplier options. These massive resources will allow the selection of a comprehensive repair strategy, which has never before been possible. 

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Combination Drug Modeling

The fields of pharmacology, informatics, and dynamic modeling are sophisticated in their analysis of millions of decision points within databases. Combination drug design is also making great progress in fields such as infectious disease and cancer, but has not yet been applied to neurorepair. Combinatorial drug design is a drug functional network analysis partitioned into numerous drug network communities, integrative informatics, and dynamic modeling. Powerful computational tools can predict drug combinations, targeting multiple signaling modules of cellular molecular pathway networks through the analysis of proteomic pathways. As drugs within overlapping communities share common mechanisms of action, scientists can build specific signaling networks based on targets. The idea is to use as few drugs as possible to overlap with as many pro-growth pathways as necessary. A preference will be to use drugs with an established safety profile and have been used in prior clinical trials.

 

Safety

Despite all of the FDA requirements and preclinical trials, drugs frequently have off-target effects, which are only detected once they are used in routine clinical practice. However, over 30 surveillance research organizations exist to address this problem. Each one is working to develop better algorithms to detect drug effects - both alone and in combination therapies - by using big data regarding molecular mechanisms, coupled with the electronic health record. Predictive models are ever advancing and are critical tools to speeding up the discovery of safe, comprehensive therapies. The need to monitor for toxicity will always be vital. 

 

Goal of h.o.p.e.

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Drug combinations are a hallmark of therapies for complex diseases such as cancer, HIV, and hypertension, but no one has applied this technology to brain tissue engineering. All of the aforementioned technologies need to be repurposed into pro-growth strategies for neural tissue regrowth. Also, because drug effect is dose-dependent, the effect of multiple doses of an individual drug needs to be examined, the result of which may yield a rapidly rising number of combinations and a challenging high-dimensional statistical problem. The h.o.p.e. Orchestra will make informed decisions about each possible drug combination and test these predictions in the lab, which is explained further in the following section about the lab clinical trial. 

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The regrowth regimen section begins with the calculated amount of cell damage from the 3D missing tissue hologram section and the biological requirements for regrowth calculated by the regrowth simulation section. The comprehensive cell biologists, computational modelers, drug-combo rankers, and informatics will develop the total amount of therapeutics needed to achieve cellular repair. “Comprehensive” remains the key term. This complex number of therapeutic options must be orchestrated to include dose, duration, sequence, cost, purchasing option, delivery route, toxicology, drug–drug interactions, pharmaceutical grade, and excretion per each cell type.

 

The process begins with

Removal of scar tissue around patient’s injury cavity:

1. Which drugs for extracellular matrix removal, debris removal, and immune modulation?

2. What dose is required per number of each extracellular matrix protein, debris amount, and immune cells present?

3. What duration of drug delivery is needed?

4.  In what sequence should drugs be delivered?

5. What is the delivery method for each drug?

6. What drug–drugs interactions will exist?

7. What toxicity may arise?

8. What excretion pathway will be present for each drug?

Cell replacement survival (for each cell type):

1. Which drugs for growth factors, metabolism, blood supply, cell trafficking, cell communication, apoptosis, cell adhesion, cell–cell interactions, guidance cues, gap junctions?

2.  What dose and gradient are required for each cell?

3. What duration of drug delivery?

4. In what sequence should drugs be delivered?

5. What is the delivery method for each drug?

6. What drug–drug interactions will exist?

7. What toxicity may arise?

8. What excretion pathway will be present for each drug?

Cellular network guidance and survival (for each cell network type):

1. Which drugs for growth factors, metabolism, blood supply, cell communication, network integration – local, regional and distant, gap junctions, synapse formation?

2. What dose and gradient are required for each cellular network?

3. What duration of drug delivery?

4. In what sequence should drugs be delivered?

5. What is the delivery method for each drug?

6. What drug–drug interactions will exist?

7. What toxicity may arise?

8. What excretion pathway will be present for each drug?

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The output of this phase will be a treatment strategy that is a detailed algorithm of the thousands of decision points performed in the lab clinical trial phase. Reproducible experiments will always remain the gold standard in science to validate the predictions made by these models.

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Impact of h.o.p.e. 

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As the team learns and the model develops simultaneously, there will be a feed-forward acceleration in sophistication to regrow a patient’s injured CNS. The scientific, medical, technical, legal, and financial challenges will be illuminated from this regrowth regimen, and identify additional translational barriers to be surmounted.