Sherman Oaks, CA, United States
Sherman Oaks, CA, United States

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Patent
Librede Inc. | Date: 2015-07-09

Exemplary embodiments provided herein include genetically engineering microorganisms, such as yeast or bacteria, to produce cannabinoids by inserting genes that produce the appropriate enzymes for the metabolic production of a desired compound.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.92K | Year: 2016

Abstract As the population ages there is a growing concern about the impact of neurological diseases on the healthcare system Neurological diseases e g Alzheimer s Disease are the fastest growing cause of death in the United States and the development of new drugs has been very slow Natural products are powerful sources for the discovery of new medications recently cannabinoids have been identified as a general class of natural compounds with a wide range of proven therapeutic effects including treatment of neurodegenerative diseases In fact studies of cannabinoids led to the discovery of the endocannabinoid system ECS regarded as one of the most important modulators of nervous system processes and a targetable system for neurological diseases Since then cannabinoids have been found to have efficacy in treating pain neuroinflammation and bone loss among many other conditions Cannabinoids can be found in many plants the most well known is Cannabis sativa from which a variety of cannabinoids have been isolated and shown to be medically relevant However it is difficult to source cannabinoids in high purity inhibiting research and making large scale commercial production problematic A biosynthetic approach to producing these natural products not only addresses these problems but allows a detailed understanding of the natural product chemistry furthering medical research and pharmaceutical development into the ECS To enable the development of natural cannabinoids as therapeutic agents Librede has developed a biosynthetic cannabinoid production drug discovery platform by genetically engineering yeast with selected portions of the Cannabis sativa metabolic pathways The production of cannabinoids in yeast is an ideal platform because fermentation and genetic engineering are well established low cost and scalable Librede s biosynthetic cannabinoid production platform is modular by adding or removing expression of different enzymes different cannabinoids can be produced as desired even cannabinoids produced in low abundance naturally Using this approach in preliminary work we have produced Cannabidiolic acid CBDA in yeast the world s first biosynthetically produced cannabinoids outside of plants Although this proof of concept work showed that cannabinoids can be produced by yeast the yield of CBDA production was limited by the availability of a specific chemical intermediate geranyl pyrophosphate GPP In order to make our platform feasible for research and cannabinoid production we will improve GPP levels by reducing its diversion to alternative products by knocking out or down regulate diverting metabolic pathways as well as increasing GPP production Narrative Cannabinoids have been shown to be efficacious to treat multiple sclerosis and other neurodegenerative diseases but they are produced in plants in small amounts Librede has developed the world s first in vivo biosynthetic platform for cannabinoid production from genetically engineered yeast We propose to increase the yield of cannabinoid production in our platform by engineering yeast to increase the production of geranyl pyrophosphate GPP a biochemical intermediate in cannabinoid biosynthesis


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.77K | Year: 2010

This Small Business Innovation Research (SBIR) Phase I project will support the development of a novel ion channel measurement platform. Ion channels are important in a wide range of physiological processes including cardiac and neural activity. The technology is centered on inexpensively manufactured ion channel biochips which can be shipped to the end user and indefinitely stored until needed. This platform greatly simplifies the process of ion channel measurement, with the potential to significantly increase throughput, decrease cost, and eliminate the expertise necessary to perform these sophisticated measurements. The proposed research will maximize the biochip yield and minimize the formation time. The broader impacts of this research are that the increased throughput and data quality will significantly impact healthcare in terms of cost and quality of care by reducing drug development R&D costs. The multi-billion dollar market for ion channel drugs is actually underserved because of the lack of cost effective, high quality, high throughput screening solutions. The company's low cost high throughput solution will enable the cost of ion channel screening to significantly drop. The storability, shippability, and simplicity of the technology also opens ion channel measurement capability to a much wider, non-specialist scientific audience and a low cost system suitable for high school and college laboratory courses.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2012

This Small Business Innovation Research Phase I project is aimed at developing improved technology for drug discovery and safety screening of ion channels. Ion channels are present in every cell and play key roles in a wide range of physiological processes including the cardiac cycle and neural activity. Librede Inc. is developing an ion channel screening platform based on artificial cell membrane technology that has the potential for decreased instrumentation and running costs with higher throughput and minimal training. In the work proposed here, Librede will design and fabricate a consumable prototype ion channel array plate with 32 measurement sites and measure an ion channel across the whole plate simultaneously. At the completion of this Phase I work we will have an SBS standard consumable array plate ready for integration into an automated platform with solution perfusion to be developed in Phase II. The broader/commercial impacts of this research are to decrease the cost and increase the throughput of ion channel screening. These are well-recognized pain points felt by pharmaceutical and academic researchers. This problem is shared for screening of all drug candidates, since all drugs must be screened against cardiac ion channels for issues of safety. Librede?s fundamentally different approach to ion channel screening will streamline the screening process, reducing its cost and time, resulting in better/safer drugs reaching the market sooner. Our platform gives us a competitive advantage in cost, throughput, and ease of use when compared to the state of the art.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 150.00K | Year: 2012

This Small Business Innovation Research Phase I project is aimed at developing improved technology for drug discovery and safety screening of ion channels. Ion channels are present in every cell and play key roles in a wide range of physiological processes including the cardiac cycle and neural activity. Librede Inc. is developing an ion channel screening platform based on artificial cell membrane technology that has the potential for decreased instrumentation and running costs with higher throughput and minimal training. In the work proposed here, Librede will design and fabricate a consumable prototype ion channel array plate with 32 measurement sites and measure an ion channel across the whole plate simultaneously. At the completion of this Phase I work we will have an SBS standard consumable array plate ready for integration into an automated platform with solution perfusion to be developed in Phase II.

The broader/commercial impacts of this research are to decrease the cost and increase the throughput of ion channel screening. These are well-recognized pain points felt by pharmaceutical and academic researchers. This problem is shared for screening of all drug candidates, since all drugs must be screened against cardiac ion channels for issues of safety. Librede?s fundamentally different approach to ion channel screening will streamline the screening process, reducing its cost and time, resulting in better/safer drugs reaching the market sooner. Our platform gives us a competitive advantage in cost, throughput, and ease of use when compared to the state of the art.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.64K | Year: 2015

DESCRIPTION provided by applicant It is well known that cancer diagnosis in early stages can greatly increase survival rates and decrease treatment cost Diagnostics such as colonoscopies and mammograms are among the best tools in the fight against colon and breast cancers since they allow for routine screening and therefore early detection Early detection of lung cancer is particularly problematic there are no routine screens As a result lung cancer is the most common of all cancer deaths annually causing deaths in the United States and million worldwide Routine screening of biomarkers is possible with simple low cost non invasive assays making them a promising approach for early cancer detection they have already been used to great effect for prostate cancer and breast cancer leading to their almost survival rates when detected early MicroRNAs are a powerful class of biomarkers for a wide range of diseases including heart disease sepsis and all types of cancer including indication of metastasis and progression stage A miRNA diagnostic platform could be used to test for several cancers simultaneously essentially allowing for routine early detection and identification of all cancers from a small blood sample drawn at an annual physical exam Unfortunately current methods of miRNA detection suffer from a variety of shortcomings including speed amplification errors and cost limiting their role in routine cancer diagnosis Nanopore detection of miRNA has the potential to address these shortcomings combining the low cost features of microarray assays with qRT PCRandapos s ability to quantify the amount of miRNA present but with low cost instrumentation and no amplification Nanopore miRNA detection works by detecting the binding of target miRNAs to probes which are then measured electrically using a nanopore The general idea of this method is similar to optical bar coding technologies but utilizes low cost electronics and simplified probes This method has already successfully shown detection of circulating miRNAs in cancer patients Librede is developing a nanopore based microRNA instrumentation and assays that will enable routine low cost cancer screening We aim to develop an automated instrument based on our established artificial membrane platform combined with nanopore technology for the cancer diagnostic market In the work proposed here we will automate our nanopore platform to detect lung cancer related miRNA quantitatively determine miRNA concentrations and measure miRNA from blood samples This will lead to a laboratory prototype that will be used in Phase II to measure miRNA in clinical samples Successful completion of this work will lead to a new tool for early and routine detection and diagnosis of cancer PUBLIC HEALTH RELEVANCE Cancer survivability is greatly improved by early detection which is most easily achieved if it is convenient routine low cost and non invasive Librede has successfully used nanopores to detect miRNA cancer biomarkers which can indicate the presence and progression of many different cancer types We propose here to establish the feasibility for an automated parallel instrument for nanopore based microRNA detection


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.55M | Year: 2012

DESCRIPTION (provided by applicant): Ion channels are important drug targets-present in every cell, they play key roles in a wide range of physiological processes including the cardiac cycle and neural activity. As a result, unintended drug interactions with ion channels are also of critical importance, requiring the screening of all drug candidates against specific ion channels. Unfortunately, assaying ion channels for pharmaceutical discovery and safety screening is problematic to perform in high throughput because the ion channels must be incorporated into a cell membrane to allow measurement of their ionic transport to determine their functionality. As a result, there are currently no high quality, high throughput assays for ion channel screening. Recentdevelopments of automated patch clamp instrumentation are still over an order of magnitude lower throughput than conventional drug screening for soluble proteins and also require expensive instrumentation, specialized cell lines, and consumables. For existing methods of ion channel screening, there is a large gap in information quality, throughput, and cost. Librede's goal is to develop new technologies that increase the efficiency of early stage pharmaceutical research and development. To this end, Librede is developing an alternative cell-free technology for ion channel screening using artificial cell membranes. Librede's patent pending formulation of cell-free artificial membranes can enable higher throughput and lower consumable costs while requiring less expensive equipment and trained personnel. Librede was founded by UCLA researchers and the inventors of this technology. In Phase I, we measured a 48 membrane array plate simultaneously with a multichannel amplifier and verified that the measurement performance was equal to or exceeded competitive automated patch clamp instruments. In the Phase II work proposed here, we will build on this work by integrating our Phase I instrumentation with fluid handling and motion control hardware to construct an automated workstation for cell-free ion channel screening using Librede's artificial membrane technology. We will consult with a pharmaceutical screening industry automation expert in the design, construction, and operation of our workstation and confirm that it can process and measure Librede's artificial membrane plates similarly to our previous work. To demonstrate its capabilities, we will perform a limited screen of CLIC1, an ion channel implicated in Alzheimer's disease. CLIC1 is particularly difficult toscreen with conventional patch clamp, which makes this an ideal proof-of-concept application of our platform. We will work with the Schmidt group at UCLA, who have previously demonstrated the measurement of CLIC1 in artificial membranes. We will run the workstation in full automation mode, measuring ion channel activity as a function of drug concentration for a 72 compound ion channel-targeted drug library. This demonstration is essentially identical to an industry screen and is a major milestone for Librede's development of our artificial membrane technology, which promises an order of magnitude improvement in cost and throughput for ion channel screening. PUBLIC HEALTH RELEVANCE: Librede is developing a novel cell-free ion channel screening platform that has the potential to significantly reduce costs and increase throughput of drug discovery and safety screening for ion channels. We will develop an ion channel measurement workstation that is capable of completely automated processing and measurement of Librede's ion channel plates after the addition of drug compounds modulating the channel activity. We are validating this workstation by screening compounds for activity against the CLIC1 human ion channel which is thought to play an important role in Alzheimer's disease.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 163.75K | Year: 2011

DESCRIPTION (provided by applicant): Ion channels pharmaceutical discovery and safety screening is slow and expensive and as a result, there are currently no high quality, high throughput assays for ion channel screening. Librede Inc. is developing alternative cell-free technologies for ion channel measurement which have the potential for higher throughput and lower cost. In preliminary work, we have demonstrated a platform for formation and measurement of artificial cell membranes that is compatible withautomated motion control hardware. Measurements of these membranes show that they are able to house ion channels with properties matching the scientific literature. The initial work with this platform utilized manual positioning and assembly of the components under constant monitoring and feedback. Although this was sufficient to demonstrate the technology, it is not sufficient to demonstrate its suitability for high throughput and automation processes. Here we propose to construct a mechanical jig which will allow assembly of the membrane components blind , simulating automated processes. With this jig, we will cycle the membrane formation apparatus, measuring the properties of the resultant artificial membranes to determine the degree of reproducibility and therefore the suitability of this process for automation and high throughput. We have designed a plate which is compatible with industry standard 384 well fluid handling systems and contains a modification of our initial membrane formation apparatus which tolerates minor mechanical positioning errors. In the proposed work, we will use the plate and ascertain whether these modifications are sufficient or require further improvement. We will cycle the apparatus over 500 times, measuring the yield of the resulting membranes and their ability to reconstitute ion channels. The processes developed will be scalable an entire 384 well plate and the mechanical jig easily adapted for use with motion control robotics, positioning our platform for Phase II adapting it for high throughput automation. PUBLIC HEALTH RELEVANCE: Measurement of ion channel interactions with drugs is a key process in drug screening, but current technologies are slow and expensive. Our team has recently developed a method for formation of an artificial cell membrane that is compatible with robotic automation. We propose here to develop tools and processes that enable the scaling and cycling of this technology resulting in high throughput ion channel measurement.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 221.37K | Year: 2016

DESCRIPTION provided by applicant Cannabinoids are a general class of natural compounds that have a wide range of proven therapeutic effects Studies of cannabinoids led to the discovery of the endocannabinoid system ECS regarded as one of the most important modulators of nervous system processes Cannabinoids have been found to have efficacy in treating pain neuroinflammation and bone loss among many other conditions Cannabinoids can be found in many plants the most well known is Cannabis sativa but like many other natural products that have been developed into pharmaceuticals the production of most of these compounds by the plant are at low levels The difficulties in sourcing these cannabinoids inhibits research and makes their eventual development and production into pharmaceuticals problematic To increase the accessibility as well as our basic knowledge of cannabinoids and enable the pursuit of natural cannabinoids as therapeutic agents Librede has developed a biosynthetic cannabinoid production drug discovery platform based on genetically engineered yeast with selected portions of Cannabis sativa metabolic pathways The production of cannabinoids in yeast is an ideal platform because fermentation and genetic engineering are well established low cost and scalable Since we can choose to engineer yeast strains to produce only a single cannabinoid the effort and cost of separation purification are minimized Furthermore it is a modular platform technology by adding or removing expression of different enzymes different cannabinoids can be produced as desired even cannabinoids produced in low abundance naturally Using this approach in preliminary work we have produced Cannabidiolic acid CBDA in yeast the worldandapos s first biosynthetically produced cannabinoids outside of plants This preliminary work converted hexanoic acid added to the growth media to CBDA demonstrating that the production of cannabinoids was possible In order to increase the yield to provide compounds for early testing and to prepare for large scale production Librede has developed a method to produce cannabinoids from glucose In the work proposed here we will add the published glucose hexanoic acid pathways to our yeast allowing for the production of CBDA from glucose The platform is modular and can be used to create a wide range of natural cannabinoids By swapping out the last enzyme in the biosynthetic pathway e g change CBDA synthase to CBCA synthase different cannabinoids can be produced As a result we will have a modular high yield platform for synthesis of specific natural cannabinoids from glucose which is scalable for production of compounds at levels suitable for basic research clinical trials and for therapeutic use PUBLIC HEALTH RELEVANCE Cannabinoids are natural products with the potential to treat a wide range of diseases but most are expressed in plants in very low levels making their production and extraction highly uneconomical Librede has developed the worldandapos s first in vivo biosynthetic platform for cannabinoid production from genetically engineered yeast We propose to enable practical production with our platform by engineering the yeast to use glucose as a feedstock


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 777.83K | Year: 2011

DESCRIPTION (provided by applicant): Assaying ion channels for pharmaceutical discovery and safety screening is problematic to perform in high throughput because the ion channels must be incorporated into a cell membrane to allow measurement of their ionictransport to determine their functionality. As a result, there are currently no high quality, high throughput assays for ion channel screening. Recent developments of automated patch clamp instrumentation are still over an order of magnitude lower throughput than conventional drug screening for soluble proteins and also require expensive instrumentation, specialized cell lines, and consumables. For existing methods of ion channel screening, there is a large gap in information quality, throughput, and cost.Librede Inc. is developing an alternative cell-free technology for ion channel screening using artificial cell membranes. Librede's patent pending formulation of cell-free artificial membranes can enable higher throughput and lower consumable costs whilerequiring less expensive equipment and trained personnel. Librede was founded by UCLA researchers and the inventors of this technology. In the work proposed here, we aim to develop materials and methods for measurement and packaging of the hERG channel inour artificial membrane platform. hERG is an important ion channel to screen, since off-target activity of pharmaceuticals on the hERG channel can lead to cardiac arrhythmia and death; thus all drug candidates, irrespective of target, must be screened against interaction with hERG. For this work, we will collaborate with the Schmidt group at UCLA, who has demonstrated the measurement of hERG in artificial membranes in preliminary work, a first. We aim to determine the compatibility of hERG with Librede's artificial membrane platform and determine the conditions with optimize the long term storage of hERG packaged with our membrane array plates. Finally, we will perform a demonstration of our technology by screening hERG against known channel blockers over a48 membrane array plate simultaneously. This work is a key step toward our goal of reducing the cost and expertise required for ion channel screening. PUBLIC HEALTH RELEVANCE: We have recently developed a novel ion channel measurement platform thatmay be indefinitely stored, commercially shipped, and requires very little input from the end user to operate. We aim to validate this platform with the human cardiac ion channel hERG to demonstrate the utility of this technology for ion channel screening.

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