Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 233.24K | Year: 2015
DESCRIPTION provided by applicant Preclinical evaluation of treatment strategies for retinal neurodegenerative diseases is highly dependent on mouse models Classical methods to assess the visual function of animals such as electroretinogram ERG which measures electrical responses in the retina do not address connections between the eye and brain or visual perception by the visual system This often raises concerns regarding the functional relevance of the therapeutic benefit Difficulty in assessing visual perception and related behavior in mice and rats largely due to their subtle visual behavior cues and the lack of adequate measuring devices presents a critical barrier to the application of mouse models for evaluating treatment efficacy of new drugs and for scaling up for behavior phenotyping to screen genetic vision defects Pupillary light reflex PLR and optokinetic reflex OKR tests are useful methods in clinics for assessing human visual responses and perception However such tests have been difficult to conduct in rodents because current rodent visual testing methods or devices either do not allow accurate quantitative assessment for PLR or OKR or use subjective measures to score visual responses To address these challenges we propose to advance the technology by designing an easy to use automated platform that employs an eye pupil tracking device equipped with a computer vision system chiefly the interactive tracking system for unambiguous objective scoring of visual responses Our proposed new device will allow real time quantitative and accurate assessment of rodent visual function including light responses visual acuity and contrast sensitivity The novelty of our system also lies in that it does not require complicated calibration procedures needed in commonly used human eye tracking Rather than precisely measuring the extent of eye turning or orientation we propose to detect the signature eye movement in accordance with the speed and direction of visual stimuli The system will be validated using normal wildtype mice and mouse models of retinal neurodegeneration known to develop visual behavior changes in the parameters mentioned above Although rodent eye tracking has been investigated before this proposed visual assessment system would be the first commercially viable product that uses an eye pupil tracking device to automatically assess visual perception in rodents The combined PLR and OKR tests and vastly simplified and automated quantification methods will also provide the first scalable behavior platform for phenotyping and drug discovery in the vision research area In the future this technology has the potential of being expanded to measure responses from various visual stimuli This may translate into broader applications for evaluating brain diseases that afflict the visual pathways This platform for mouse visual behavior assessment will therefore greatly facilitate drug discovery and development aimed at preventing and slowing vision loss or restoring sight helping to combat devastating blinding conditions such as age related macular degeneration AMD and glaucoma PUBLIC HEALTH RELEVANCE The objective of the current proposal is to design and develop an automated system for the measure of rodent mice and rats light response visual acuity and contrast sensitivity The system will apply human eye pupil tracking techniques for objective and unambiguous evaluation of light response and visual perception This platform will provide a powerful tool for phenotypic studies as well as for discovery of new drugs that can prevent or restore sight caused by blinding conditions such as age related macular degeneration and glaucoma
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 223.63K | Year: 2016
DESCRIPTION provided by applicant The abuse of illicit drugs such as cocaine marijuana and heroin remains a critical public health concern throughout the country and is associated with staggering economic and social consequences Cocaine remains the most frequently recorded illicit drug in emergency hospital visits and the leading cause of drug related deaths in the United States Since as high as of fatally injured drivers were found positive results in drug tests the Office of National Drug Control Policy emphasizes the major concern of drugged driving in the United States Urinalysis is the most common type of cocaine test though urine collection has challenged its practicality There are other biological specimen based cocaine tests that have been explored such as blood and saliva tests but are not practical since blood samples need high level medical administrators and specialized analytic equipment Another alternative is the minimally invasive diagnosis through skin using surface modified microneedles MNs However since concentrations of most blood biomarkers in the skin are too low to be captured by the MN array the test suffers from low sensitivity and high variation Here we propose a novel probe MN based assay in conjunction of using brief laser illumination on a tiny skin area to accumulate blood biomarker such as cocaine into the upper dermis This sample accumulation method enables the biomarker to be readily detected and quantified in situ using the probe MNs inserted into the laser treated skin The objective for the STTR Phase I is to characterize and validate sensitivity and specificity of the probe MN array in vitro and in vivo and compare detection reliability with conventional analysis of cocaine in plasma and in urine samples The specific aims are as follows Aim Determine optimal design of cocaine specific binding MN probe and characterize cocaine assay in vitro We will develop a protocol of surface modification of MNs with Cy labeled cocaine specific aptamer and Cy labeled neutralizer Length of the MNs ranging from um will be optimized based on iterative feedback from in vivo test Sensitivity specificity and response time of the MNs array will be evaluated by in vitro tests Aim Demonstrate the feasibility and consistence of upper dermal cocaine detection in mice and rats The cocaine specific MN probe will be evaluated in mice and rats to demonstrate feasibility of the proposed minimally invasive MN based cocaine detection in conjunction of using a brief illumination of a clinically safe dose of laser on the skin Sensitiviy specificity and reliability will be determined with respect to conventional assays of plasma and urinalysis of cocaine The ultimate goal of the entire STTR project is to develop and commercialize the minimally invasive sample free in situ cocaine detection toolkit consisting of device and cocaine specific probe MN arrays for prompt onsite cocaine detection in humans in community work places or emergency rooms and clinics PUBLIC HEALTH RELEVANCE Cocaine remains the most severe illicit drug in emergency room visits and cocaine urinalysis is the most common test Although the test has been used for more than years urine collection has challenged its practical use The proposed MN based upper dermal detection will provide the new test to obtain blood cocaine information using a painless minimally invasive dermal test The onsite cocaine test will enable cocaine screening in the hospital emergency and community to reduce widespread drug abuse and ultimately help to prevent cocaine related disorders and crimes
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 852.60K | Year: 2013
DESCRIPTION (provided by applicant): Sleep deprivation (SD) occurs universally in modern societies and causes significant social and financial harm. Numerous human and animal studies indicate that various forms of SD are deleterious to mental and physicalhealth. Therefore, SD has been recognized as an unmet challenge to public health. There is increased need to study the effects of different forms of SD on physiological functions in animal models. However, better methods are sorely needed. Existing SD systems have low throughput and capacity and are difficult to use and expensive. In our Phase I project, we have developed an automatic sleep monitoring/sleep deprivation system for rodents. Our system is based on floor sensors, the data from which yield automatic sleep scoring. We demonstrated that hands-off automatic SD using our method is technically feasible. We have also verified the advantages of our system over other competing systems, namely, that our method is less invasive, more selective, less time-consuming, and easier to use. Based on the success of our Phase I project, our Phase II project will be focused on the commercialization of our research product. The objective of the present project is to develop a unified, non-invasive, high throughput and low cost SD system for mice and rats. Our specific aims are the follows. Aim 1. Development of a full-featured SD system with multiple lines of hardware and software products Aim 1a. Development of Hardware. We will refine, ruggedize, and make more reliable our mouse SD system while simultaneously lowering the costs for mass production. Because rats are used frequently in sleep research we will develop a rat SD system based on the mouse SD system. Aim 1b. Development of software. We will develop softwareproducts with the following innovative features: 1) Establish bi-directional information exchange through USB cable to perform three common types of SD: acute SD, sleep fragmentation and chronic sleep restriction; 2) Create a user-friendly interface for flexible experimental design on the host PC; 3) Expand system capability to perform simultaneous studies in as many as 64 rats or mice. 4) Extend the software functionality to perform group statistical analysis including group means, standard errors and data lists in animals from multiple groups of animals, and 5) Extend the software products to both 32-bit and 64-bit Windows XP, Vista and Windows 7 platforms. Aim 2. Evaluation and validation of the SD system, and development of standardized SD protocols The validation of the system includes: 1) verification of sleep loss and rebound following SD using EEG evaluation and verification of the robustness and ease of use of the system, 2) investigation of the consequences of SD on animals, especially social recognition/preference tasks, and 3) development of an experimental cook book through performing different types of SD to standardize SD protocols in order to facilitate comparison results generated by different laboratories. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The aim of the present project is to develop an automated, noninvasive, high throughput and low lost sleep deprivation system for rodents. This system can help to study sleep loss impact on health and drug discovery for the treatment of sleep disorders.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 221.87K | Year: 2016
DESCRIPTION provided by applicant Management of pain and inflammation is the most critical aspect of dental practice Inadequate pain control affects patients in many ways beyond the treatment and its outcome Inflammation of tissues inside the tooth pulpitis and surrounding the tooth apical periodontitis induced by injury and or infection is a major cause of tooth pain due to thermal hyperalgesia and mechanical allodynia Hyperalgesia manifests clinically as increased and prolonged painful response to thermal stimuli while mechanical pain from allodynia appears as painful responses to biting percussion palpation and other non noxious non painful stimuli In response to the inflammation sensory neurons secrete neuropeptides especially Calcitonin Gene Related Peptide CGRP from their peripheral nerve endings causing vasodilatation and plasma extravasation in tissues inside and surrounding the tooth These neuropeptides exacerbate inflammatory reactions and lead to an increased receptive field of peripheral nerve endings altering nerve resting potentials increasing neural excitability and up regulating expression of tetrotoxin resistant TTX R sodium Na channels Nav and Nav in the dental pulp Conversely we observed that incubation of the CGRP receptor antagonist CGRP decreased Na current density in DRG neurons see Preliminary Studies These findings suggest that excessive CGRP augments Na channels which may underlie the failure of local anesthetic agents to attain effective pulpal anesthesia in the inflamed tooth prior to surgical intervention and the extensive use of nonsteriodal anti inflammatory drugs NSAIDs or even opiates post surgery Currently there are no effective and safe analgesics with anti neuroinflammation properties available for these conditions The mainstay treatment is to surgically remove infected and inflamed neural tissues inside the tooth by root canal treatment This method is effective in managing pain by removing the altered neural tissues inside the tooth However a new therapeutic is of great need to block the pain completely before performing the root canal treatment procedure and to prevent the transition from acute pain to prolonged or even chronic pain after the surgery Further changes in neural tissues outside the tooth due to peripheral and central neural sensitization can remain even after the root canal operation and contribute to the development of persistent pain Postoperative pain was estimated to affect of patients receiving root canal treatment due to painful pulpitis and apical periodontitis Here we propose to use our novel AFA P a amino acid antagonist selectively against the CGRP receptor for local treatment of dental inflammatory pain Our preliminary data showed that P displayed higher binding affinity than the conventional amino acid antagonist CGRP inhibiting CGRP receptors and downstream signaling more effectively Further P mitigated thermal hyperalgesia in teeth with pulpitis and restored local anesthetic efficacy of lidocaine to attain effective pulpal anesthesia of the inflamed teeth We propose this SBIR Phase I study with the following Specific Aims Aim To determine P efficacy in alleviating neuroinflammatory pain following pulpitis and apical periodontitis induction in mice Aim To investigate how P modulates neuroinflammation and TTX R Na channel expression and activity Success in this Phase I project will lead to a Phase II to further develop a novel therapeutic to produce dental analgesia via anti neuroinflammation and to increase effectiveness of dental local anesthetics for the management of painful pulpitis and or apical periodontitis PUBLIC HEALTH RELEVANCE Pain from teeth and surrounding tissues due to injury or infection is the most common type of dental pain Local anesthetic agents fail to completely block pain in severely inflamed teeth We recently discovered that our novel peptide P mitigated the pain and enhanced local anesthetic efficacy in these inflamed teeth We now propose to develop P as a new analgesic agent with anti inflammation and or as an adjunct therapeutic agent to achieve complete tooth pulpal anesthesia in this SBIR project
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 338.88K | Year: 2013
Under this Small Business Innovation Research (SBIR) Phase I project, Research Topic 149, the Contractor shall develop predictive in vivo screening systems for phenotypic drug discovery for smoking cessation. The Contractor shall accomplish this throughthe following objectives: Objective 1- Evaluate a battery of tests aimed at examining various components of nicotine addiction to be used for phenotypic drug discovery and development of smoking cessation medications. Objective 2- Phenotypically profilefour FDA approved smoking cessation drugs (varenicline, bupropion, clonidine and nortriptyline, each tested at three doses) and two controls (positive drug at an appropriate dose and negative with vehicle) using the behavioral tests/assays validated inObjective 1. PUBLIC HEALTH RELEVANCE
Afasci, Inc. | Date: 2015-06-01
The present invention provides compositions, and methods for local administration of certain peptides or combination with certain small molecules that produce analgesia and anti-inflammation in a mammal. Exemplary polypeptides provide peripheral analgesia and anti-inflammation when administered via local topical, subcutaneous, intradermal, or intranasal administration, to provide analgesia and anti-inflammation. Through antagonism of peripheral CGRP receptors alone, or in combination with inhibition of sensory sodium channels or anti-inflammation, the compositions of the invention provide local therapeutic pain relief with minimal undesired systemic side effects in a subject. Also provided are improved peptide delivery techniques including microneedle unit dose administering apparatus and methods. Also provided are hydrogel formulations for sustained local delivery to a subject of one or more of the compositions according to the invention in a therapeutically effective amount, thereby providing local pain relief and/or reducing associated inflammation.
Afasci, Inc., Kansas State University and The Regents Of The University Of California | Date: 2014-09-30
Tricyclic pyrone compounds having high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity are presented. Administration of the compounds to Alzheimers Disease transgenic models resulted in substantially reduced soluble and insoluble A species in the brain without affecting general behavior and motor coordination. Furthermore, in addition to blocking the toxicity and formation of both intraneuronal and extracellular A aggregates, the compounds also increase cellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic plasticity.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.43M | Year: 2015
DESCRIPTION provided by applicant Millions of Americans suffer from chronic neuropathic pain which is often refractory to current treatment In search of a solution to this problem of chronic untreatable pain we intend to develop a new analgesic therapy based on modulation of the T type Ca channel T type Ca channels play key roles in pain signaling The Cav family of channels is involved in at least two key stages of pain pathways first at the dorsal root ganglion DRG and again at the thalamic pain relay Both chronic nerve constriction injury and diabetic neuropathy cause upregulation of one of these channels Cav in the DRG neurons of rats Conversely gene knockout antisense knockdown or silencing of the Cav isoform produces good apparent pain relief in both neuropathic and inflammatory pain in rats or mice In short the T type Ca channels appear to be excellent drug targets for treating neuropathic pain In our completed T channel biologic probe discovery project NS Xie through collaboration with the Vanderbilt Screening Chemistry Center we discovered four hit compounds from two different novel chemical scaffolds The best hit ML mitigates chronic pain induced by spared nerve injury streptozotocin induced diabetic neuropathy and reserpine induced chronic pain in rats We have therefore selected ML as the starting compound for chemical optimization in our proposed SBIR Fast Track project for our pain relief drug discovery program We will start with structure activity relationship SAR studies on a focus set of ML derivatives The milestone for advancement from Phase I to Phase II is identification of the top modified leads that meet our selection criteria higher potency and selectivity than ML The milestone for the end of Phase II is the production of a therapeutic candidate generation of sufficient data of in vivo efficacy pilot safety pharmacology and nonGLP toxicology which will help us to make a go no go informed decision for IND enabling studies in a Competing Renewal of SBIR Phase II Once we are ready to conduct IND enabling studies and file an IND application it will be enormously valuable in attracting non government support and industrial partners for clinical development Our ultimate goal is to develop a novel therapeutic with selective and state dependent inhibition of the Cav channel to treat chronic neuropathic pain PUBLIC HEALTH RELEVANCE Millions of Americans suffer from chronic pain especially neuropathic pain which is often not well treated and dramatically reduces their quality of life We propose to develop a novel therapeutic that selectively reduces abnormal chronic pain without interfering with normal pain sensation through normalizing sensory neuronal activity
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 1.66M | Year: 2014
DESCRIPTION (provided by applicant): Millions of Americans suffer from chronic neuropathic pain, which is often refractory to current treatment. In search of a solution to this problem of chronic, untreatable pain, we intend to develop a new analgesic therapy based on modulation of the T-type Ca2+ channel. T-type Ca2+ channels play key roles in pain signaling. The Cav3 family of channels is involved in at least two key stages of pain pathways: first, at the dorsal root ganglion (DRG) and again at the thalamic pain relay. Both chronic nerve constriction injury and diabetic neuropathy cause upregulation of one of these channels (Cav3.2) in the DRG neurons of rats. Conversely, gene knockout, antisense knockdown, or silencing of the Cav3.2 isoform produces good apparent pain relief in both neuropathic and inflammatory pain in rats or mice. In short, the T-type Ca2 channels appear to be excellent drug targets for treating neuropathic pain. In our completed T-channel biologic probe discovery project (NS05077
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 596.06K | Year: 2013
DESCRIPTION (provided by applicant): Development of Novel Tricyclic Pyrone Drugs for Treatment of Alzheimer's Disease Alzheimer's disease (AD) afflicts approximately 35 million people worldwide and is the most common cause of dementia in the elderly. Thereis an unmet medical need for new AD therapeutic development. Amyloid-b (Ab) deposited in AD brains has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death observed in AD brains. Therefore, designing therapies targeting Ab and downstream events have become a major effort in AD drug development. We have taken the rational design approach and synthesized a class of tricyclic pyrone compounds (TPs). The lead compounds CP2 and TP70 werefound to have high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity. Administering compounds either orally or intraperitoneally to young AD transgenic models in 'preventive studies' resulted in substantially reduced soluble and insoluble Ab species in the brain and preserved memory and motor function. Furthermore, we have found that in addition to being able to block the toxicity and formation of both intraneuronal and extracellular A aggregates, the lead TPs also increasecellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic placidity - these synergistic cellular actions could be potential mechanisms underlying in vivo effects. The discovery of these lead TP compounds comes from the collaboration among Dr. Hua, a medicinal chemist, Dr. Jin, an AD neuropathology expert, and recently the PI Dr. Xie, who has substantial experience in pharmaceuticals and contributed to drug development in the CNS therapeutic area. Dr. Xie at AfaSci started with developing the SmartCageTM system and then has taken advantage of the technology in translational research. In the proposed project with the support of this phase I SBIR, we will thoroughly study pharmacokinetics (PK) and in vivo pharmacodynamics (PD)of the lead TPs, through accomplishment of the following Specific Aims: 1. Focus on two novel lead compounds CP2 and TP70 in the therapeutic studies: We will generate PK/PD and ADME (absorption, distribution, metabolism, and excretion) profiles of lead compounds. We will focus on investigating the in vivo efficacy (neurobehavioral and neuropathological outcomes) of lead compounds by oral administration to the AD model APP/PS1 mice. These studies will provide evidence-based selection of a therapeutic candidate using the criteria of druggable PK profile, in vivo efficacy especially in cognition, and improved pathologic outcomes. 2. Utilization of novel lead compounds LRL22 and LRL50 as backup compounds, if needed, and preparation for good manufacturing practice (GMP) production of the selected therapeutic candidate. Although we have identified five top backup TP compounds, we will use our previously discovered novel leads LRL22 and LRL50 which possess different chemical structures from TP, but alsoshown inhibition of Ab-induced toxicity and neuroprotection as backup compounds. The backup compounds will be re-synthesized and ready to be tested in vivo as described in Aim 1, should both CP2 and TP70 not fulfill the criteria of therapeutic candidates. We will also optimize the chemical synthesis process in preparation for GMP production of the identified therapeutic candidate for a Phase II study. Success in the Phase I study will prepare for investigational new drug (IND)-enabling studies in a PhaseII project. Our ultimate goal is to translate our preclinical discovery of the novel TP compounds into clinical therapeutic candidates that possess AD disease-modifying properties. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the major cause of dementia and one of the most disabling health conditions worldwide. Current drugs only have modest effects and there is an unmet need to develop more effective and safer medicines for the treatment of AD. We here propose tostudy two novel tricyclic pyrone compounds that show potent cell protective action against Ab toxicity for their potential to treat cognitive impairment and slow disease progression in an animalmodel of AD.