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Minutes of the 142nd Meeting of the NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
142nd Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
June 9, 2016
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 142nd meeting at 10:17 a.m. on Thursday, June 9, 2016, at NIAAA headquarters in Rockville, Maryland. The Council met in closed session at 9:00 a.m. to review grant applications; the review session recessed at 10:03 a.m. Dr. Abraham Bautista, Director, Office of Extramural Activities, presided over the Council’s review session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds.
Council Members Present:
NIAAA Director and Chair: George F. Koob, Ph.D.
Acting NIAAA Deputy Director: Patricia Powell, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Senior Staff: Vicki Buckley, M.B.A.; Mark Egli, Ph.D.; Vivian Faden, Ph.D.; Ralph Hingson, Sc.D., M.P.H.; Robert Huebner, Ph.D.; George Kunos, M.D., Ph.D.; Raye Litten, Ph.D.; Gary Murray, Ph.D.; Kenneth Warren, Ph.D.
Other Attendees at the Open Session:
Approximately 40 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order and Introductions
NIAAA Director George Koob, Ph.D., called the open session of the Council meeting to order at 10:17 a.m. on Thursday, June 9, 2016. He introduced new Council member Tatiana Foroud, Ph.D. Council members and senior NIAAA staff introduced themselves.
Hughes Award Presentation
Dr. Koob presented General Arthur T. Dean, Chairman and Chief Executive Officer (CEO) of Community Anti-Drug Coalitions of America (CADCA), with the Senator Harold Hughes Memorial Award. General Dean accepted the Hughes Award on behalf of his colleagues at CADCA and coalition leaders across America. He praised NIAAA for its commitment to translating research so that communities can use it and expressed his appreciation to NIAAA staff for their support of CADCA.
Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report which was distributed to Council members.
Budget: Both NIH and NIAAA received increasing funding for Fiscal Year (FY) 2016 in the Consolidated Appropriations Act, 2016, which was signed into law by President Obama on December 18, 2015. NIH received $32 billion, $2 billion above the FY 2015 enacted level. NIAAA received $467.7 million, which represents a $20.5 million (4.9 percent) increase from FY 2015. NIAAA anticipates funding 684 research project grants and 111 individual fellowships in FY 2016, compared to 668 and 104 respectively, in FY 2015. Training positions in FY 2016 are focused on National Research Service Awards (NRSAs). Whether NIAAA can sustain such increases is unclear. The NIAAA budget request for $467.5 million in the President’s FY 2017 budget is flat, compared to the FY 2016 enacted budget. Dr. Koob reported that the proportion of funding that is allocated to each NIAAA Division remains stable. Training and post-doctoral fellowships were a priority for FY 2016; other priorities will be addressed as funds allow.
NIH Strategic Plan: NIAAA contributed to the NIH-wide strategic plan, Turning Discovery into Health, that outlines a vision for biomedical research to capitalize on new opportunities for scientific exploration and address new challenges; it is designed to complement the individual strategic plans of the NIH Institutes, Centers, and Offices. Each Institute was asked to provide 10 bullet points for what NIH could achieve in the next 10 years. One of NIAAA’s bullet points, addressing sensors, was included in the NIH-wide plan.
NIAAA Strategic Plan: NIAAA’s five-year strategic plan is in the final stages of development. The plan reviews NIAAA’s progress to date and identifies goals for the future, based on the following priorities: Identifying the basic mechanisms of alcohol action and alcohol-related pathology; tracking, preventing, and diagnosing alcohol misuse, alcohol use disorder, and alcohol-related consequences across the lifespan; developing and improving treatments for alcohol misuse, alcohol use disorder (AUD), co-occurring conditions, and alcohol-related consequences; and enhancing the public health impact of NIAAA-supported research. Cross-cutting themes that inform the strategic plan include addressing alcohol misuse across the lifespan; addressing co-occurring conditions; reducing health disparities; advancing precision medicine; strengthening research and clinical training: and building a diverse workforce. The draft strategic plan will be released for public comment in the coming weeks and is expected to be completed in the summer of 2016.
Surgeon General’s Report: NIAAA and the National Institute on Drug Abuse (NIDA) have played major roles in the development of the first Surgeon General’s Report on Alcohol, Drugs, and Health. The report will present the state-of-the-science on alcohol and other substance misuse, including addiction, with a focus on neurobiology, prevention, treatment, recovery, and delivery of care. NIAAA has contributed significantly to the report. The hope is that the report will be released later in the year and will energize the public on alcohol and drug issues.
ABCD Study: The Adolescent Brain Cognitive Development study is a longitudinal study of 10,000 9-10 year olds, co-sponsored by NIAAA, the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS), among other Institutes and Centers (ICs). Protocols for imaging and neuropsychological portions of study are being pilot tested and finalized this summer; recruitment will begin in the fall.
Wearable Alcohol Biosensor Challenge: NIAAA sponsored a contest for companies to develop a wearable alcohol biosensor. The winning prototype, the BACtrack Skyn, is a wrist-worn device that detects alcohol using a fuel cell technology similar to that used in roadside testing devices. It offers continuous, non-invasive blood alcohol concentration (BAC) monitoring, transferring and storing data to a smartphone via Bluetooth.
Staff Transitions: New staff at NIAAA include Kim Bochniak, Inventory Management Specialist, Administrative Services Branch; Christie Halcomb, Program Specialist, Office of the Director; and Celia Burke Herlihy, Grants Management Specialist, Grants Management Branch/Office of Extramural Activities (OEA). Desiree Marshall-Brown, Staff Assistant to the Executive Officer in the Office of Resource Management, and Katrina Foster, Scientific Review Officer in the Extramural Project Review Branch/OEA, transferred to other federal agencies.
New Funding Opportunity Announcements (FOAs): NIAAA has released FOAs on Targets of Low-Dose Alcohol in the Brain (R01, R21); Program for Extramural/Intramural Alcohol Research Collaborations (U01); Specialized Alcohol Research Centers (P50); Comprehensive Alcohol Research Centers (P60); and Limited Competition for the Continuation of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA; U24).
Collaborative Research on Addiction at NIH (CRAN) FOAs: Two new FOAs were released: Integrative Research on Polysubstance Abuse and Addiction (R21/R33), and Target Assessment, Engagement, and Data Replicability to Improve Substance Use Disorder Treatment Outcomes (R21/R33).
Alcohol, Stress, and the Brain Briefing: Friends of NIAAA, in cooperation with the Congressional Addiction, Treatment and the Recovery Caucus and the Military Mental Health Caucus, hosted a Congressional briefing: Alcohol Stress and the Brain: Implications for Treatment and Recovery. One hundred people attended the successful briefing. NIAAA plans to do more such briefings, both on its own and in collaboration with NIDA.
NIAAA Research Highlights: Dr. Koob presented highlights of NIAAA-funded studies, both extramural and intramural.
Concept Council Clearance: Continuums of Care for Women Living with HIV/Aids and Alcohol
Deidra Roach, M.D., presented an overview of a proposed research initiative to advance the development of Model Continuums of Care for Women, Girls, and Families At-risk and Living with HIV/AIDS and Problem Alcohol and Other Drug (AOD) Use. HIV/AIDS is the leading cause of death among women of reproductive age. Women and girls who use substances at harmful levels are especially vulnerable. With the goal of increasing women’s access to women-focused, integrated HIV/AOD interventions, this concept is a proposal for research to advance the development of model continuums of care for women and families at-risk and living with HIV/AIDS in NIAAA’s 2017 Plan for HIV/AIDS Research. Specifically proposed is a community-based participatory health systems and services research initiative to accelerate the translation of effective women and family-focused HIV, alcohol and other drug-related prevention and treatment interventions to community practice. If approved, the Model Continuums of Care Initiative (MCCI) will support implementation research to identify best approaches to implementing promising women and girl-focused interventions in real world settings. Research on interventions beyond individual-level therapies, i.e., on multilevel interventions, will be strongly encouraged, including research on organizational strategies to increase integration of services and the use of clinical data to inform service planning.
The vision for the Model Continuums of Care (MCCI) initiative is for a partnership among NIH agencies, other federal health agencies, well-established community-based research and service organizations such as the Centers for AIDS Research (CFARS), and local health departments to build a collaborative research and services framework.
The Office of AIDS Research (OAR) at the NIH Office of the Director (OD) approved the MCCI concept in January 2016. Since then the concept has been further developed within NIAAA. If an FOA is issued, the Institute is considering the U34 Cooperative Agreement planning grant mechanism to support an incremental planning approach to the launch of the initiative. The U34 planning grant will allow significant involvement by NIAAA scientific and program staff, and will prepare the grantees for a full-scale launch of the initiative using the U01 or R01 mechanism in the future.
NIAAA anticipates that it can reasonably expect to emerge from Phase I of the Model Continuums of Care Initiative with several high impact products: 1) a detailed profile of existing service systems in each of the participating communities; 2) a viable blueprint for continuous community surveillance where these don’t already exist; 3) substantial progress towards the integration of key health and other human service data systems in participating communities; and 4) results from one or more pilot projects at each site that will inform plans for future implementation research.
Discussion: Dr. Koob asked Kendall Bryant, Ph.D., Director of Alcohol and AIDS Research, to briefly explain the shift in AIDS funding and where the money would come from for this initiative. Dr. Bryant replied that there was an OAR notice of award that identified low, medium, and high priorities for AIDS research. ICs write plans and submit them to the Office as funding requests 2 years in advance; thus, this initiative is slated for FY 2017 funding. Next, the IC drafts an FOA that it submits to OAR for approval. OAR reviews the draft in order to place it in the order of its priorities. Dr. Koob explained that funding for the initiative does not come from any given NIAAA Division budget, but from the AIDS budget. NIAAA has not expanded its HIV budget, but has been able to maintain it during the priority reorganization
Carlo DiClemente, Ph.D., asked who is envisioned as a recipient of funding, noting that collaboration across research centers is a challenging undertaking. Dr. Roach responded that the initial vision is that these grants will go to universities where researchers are currently doing HIV and alcohol research, and have experience developing interventions. These awardees would be responsible for building networks in their communities. Dr. Bryant interjected that OAR explicitly asks for collaboration. NIAAA currently has a consortia platform for HIV outreach in place. Those consortia that have community-based activities are the ones that would be involved. Dr. DiClemente asked how the initiative would incorporate both academics and the many HIV-related coalitions already in place. Dr. Bryant responded that the White House is looking at team science as part of its collaborative approach. Carmen E. Albizu-Garcia, M.D., asked if NIAAA will work with the 12 cities that CDC has identified as those with the highest rate of AIDS infections. Dr. Roach replied that NIAAA wants to put the programs where there is the highest impact, but hasn’t yet incorporated this as a requirement. Dr. Bryant noted the Institute would be looking at locations in the South, such as Florida and Louisiana, where HIV rates are high; the effort would also be part of rural health. Constance Weisner, D.R.P.H., observed that the Interagency Coordinating Council on Fetal Alcohol System Disorders (ICCFASD) has one of the strongest AIDS collaborations, and includes NIH, CDC, advocacy groups, health systems, and community organizations. Dr. Roach noted that the foundational idea for this initiative emerged from this group.
Kathy Jung, Ph.D., reminded Council members that the development of a biosensor has been a priority of NIAAA that has also generated interested within NIH. At present, the most widely-used biosensor is a large and ungainly ankle device, required by courts that measures alcohol levels in an individual’s sweat at 30-minute intervals. NIAAA adopted a new approach last year to promoting development of a less stigmatizing biosensor by issuing a prize challenge to develop a discreet wearable device capable of measuring blood alcohol concentrations in near real time. The winner would earn a cash prize with no strings attached.
In March 2015, NIAAA issued the challenge on Challenge.gov and the Federal Register. Applicants were required to submit a testable working prototype; written evidence of the functionality, technical approach, and capacity to meet all required criteria; an image of the proposed wearable, including overall dimensions; and a video demonstrating the wearable's capabilities. Eight submissions were received by the December 1, 2015 deadline; these were subjected to a technical evaluation from December 2015 to May 2016.
The prizes were announced on May 19, 2016. First prize of $200,000 went to BACtrack, a company that already has breathalyzers on the market, for the BACtrack Skyn. Their prototype was for a wrist-worn wearable that samples the ethanol molecules escaping through the skin once a second and stores the data on the user’s cellphone. The second prize of $100,000 for the Milo Alpha went to a start-up company called Milo Sensor, Inc. that was founded by recent graduates who developed their prototype with their own investment of $15,000. Milo printed the device’s band on a 3-D printer. Honorable mentions went to bioINK for a tattoo that changes color, and to a team at Florida International University for a device with promising advanced electronics, but which failed to detect alcohol during the testing.
During the technical evaluation, submissions were evaluated for accuracy and frequency of blood alcohol measurement; data collection, data transmission, and data storage; safeguards for privacy protection and data integrity; plans for process of manufacture; marketability and likelihood of bringing the product to market; appeal and acceptability to wearers; and feasibility. A two-tier evaluation process was used. Tier 1 involved human laboratory testing at NIAAA to determine the device’s ability to measure alcohol in a human being. The testing relied on a well-established method in which the blood alcohol levels of volunteers are measured before and after an intravenous injection of alcohol. Tier 2 consisted of evaluation of the written documentation by three teams, one with engineering, electrochemical expertise (representatives of the National Institute of Biomedical Imaging and Bioengineering [NIBIB] and the National Institutes of Standards and Technology [NIST]); one concerned with data security (representatives from NIAAA);and one addressing marketability, feasibility, design appeal (representatives of NIAAA). Marketability was an important criterion because NIAAA wants the device to exist and to be available. Submissions were ranked and the ranking was sent to Dr. Koob, who made the final decision.
The technical advances that resulted from the challenge include a vastly shortened interval between sampling events, approaching real time; reduction in the delayed alcohol detection inherent in transdermal monitoring; and data handling ease and flexibility in transferring data to a cellphone. In addition, these new devices are similar to fitness watches, bypassing the stigma of the ankle bracelets. Less tangible results include stimulating the interest of inventors and entrepreneurs, thereby re-awakening the development of improved alcohol biosensors; stimulation of competitive market forces; and introduction of other form factors.
Discussion: Rajita Sinha, Ph.D., said the results were impressive and wondered if the first and second prize winners would be supportive of researchers contacting them and/or providing subsidized devices to researchers who wanted to test them. Dr. Jung replied that the BACtrack is supposed to be marketable at $99. Subsidies may not be needed at that price point. Milo’s product requires replaceable cartridges, so that would be an ongoing cost. Dr. Sinha asked when the devices will be on the market. Dr. Jung said BACtrack reports they will be available this year. Arun Sanyal, M.D., inquired about how one could be assured that the person in need is wearing the device and not giving it to someone else. Dr. Jung responded that NIAAA said a biometric would be desirable, but it’s still too early in the development process to require one. The device is meant to be removable, which the ankle bracelet is not. Patricia Molina, Ph.D., inquired about the safety of the mechanism to keep data intact. Dr. Jung responded that the technical reviewers thought that the winning device was up to current data security standards.
Consideration of Minutes of the February 2016 Council Meeting and Future Meeting Dates
Council members unanimously approved the minutes of the fourth Joint Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA), National Advisory Council on Drug Abuse (NIDA), and the National Cancer Advisory Board of the National Cancer Institute on February 11, 2016, and the minutes of the NIAAA Advisory Council meeting held February 12, 2016.
In 2016, the NIAAA Council will meet September 15. In 2017, the NIAAA Council will meet on February 9, on May 2, and September 14. The Collaborative Research on Addiction at NIH (CRAN) Council meeting will take place on May 3, 2017. In 2018, the Council will meet on February 8, May 15, and September 13; the CRAN Council will meet on May 16, 2018.
Discussion: James Eberwine, Ph.D., asked if NIAAA anticipated sponsoring more competitions similar to the one for a wearable biosensor. Dr. Koob responded that the Institute is considering another challenge for a biosensor that uses infrared spectroscopy. He asked Vicki Buckley, Acting Executive Officer, to explain how funding for the challenges is obtained. Ms. Buckley stated that NIAAA plans to fund the proposed competition from its gift fund, made up of private donations. There is enough money in the fund to go forward with one more challenge. NIAAA is also exploring if it can partner with the Foundation for NIH, whereby the Foundation could do some fundraising on behalf of the Institute. There is no plan to reduce grant funding to fund the challenges. Dr. Eberwine commented that this approach is a great way to bring non-academics into the field, but questioned whether academic researchers could compete because they would not be able to use NIH funding for further development. Dr. Jung responded that researchers could not use NIH funding to participate in a challenge, but could use NIH funds once the challenge was completed. Dr. Koob observed that challenge winners could still apply for a Small Business Innovation Research award. Thomas Gentry, Ph.D., commented that a small company can use winning the competition as an argument to convince venture capitalists to invest money in the firm. Frank Sloan, Ph.D., asked how the prize amounts were determined. Dr. Jung replied that NIAAA copied what other ICs did, speculating about what size prize would incentivize companies to participate. Dr. Sloan stated that adopting such an approach for drug development would require larger dollar amounts. In a similar initiative, pharmaceutical companies pushed back because they were worried that it would interfere with their pricing structure. Dr. DiClemente suggested that the prize amount should be based on its incentive value to get companies to participate. Dr. Koob invited Council to submit additional suggestions.
Council took a break for lunch at 12:08 p.m.
Overview of the NIAAA Intramural Program
The Council reconvened at 1:35 p.m. for the afternoon session. Dr. Koob introduced George Kunos, M.D., Ph.D., Director of the Division of Intramural Clinical and Biological Research. Dr. Kunos identified the following presentations as examples of recent advances in the intramural research program.
A Novel Synaptic Mechanism in the Nucleus Accumbens that Mediates Stimulant Effects. Dr. Veronica Alvarez began by explaining that her laboratory conducts animal studies to understand how ethanol and drugs affect synapsis and connectivity within neurons in the brain. The goal is understand how these effects lead to changes in behavior. Enhanced sensitivity to the stimulant effects of ethanol is associated with higher levels of alcohol use in some human populations. The study she presented to address this issue focused on increases in locomotion in mice due to cocaine intake; locomotion is a stimulant effect that is easily measured. This study identified a synaptic mechanism in the nucleus accumbens by which drugs and dopamine Cause an increase in locomotion.
In the nucleus accumbens, there are two main classes of projection neurons direct pathway and indirect pathway cells. Activation of the direct pathway neurons leads to increases in locomotion, while activation of indirect pathway neurons leads to a decrease in locomotion. These neurons also form local connectivity, forming synapses onto each other. The synapses have asymmetrical strength, with indirect (I) synapses stronger than direct (D) ones.
In the study, the NIAAA scientists asked: What is the effect of synchronized activation of these indirect pathway neurons onto the D1 neurons? They recorded from a direct pathway neuron and expressed channelrhodopsin on the indirect pathway neurons, using light to synchronously activate these neurons and the inhibition was blocked by and the inhibition was blocked by applying a GABA_A receptor blocker. They were able to measure the synaptic responses from the indirect pathway neurons to the direct pathway neurons and found they were inhibited by dopamine, which could be reproduced by a D2 receptor agonist. Specifically, the application of a D2 receptor agonist inhibited more than 55 percent of the synaptic inputs onto the other neurons. The researchers also showed that the D2 receptors had to be present on the indirect striatal medium spiny neurons (iMSNs). Targeted deletion of D2 receptors to I-neurons impaired locomotor response to cocaine and the inhibition by the D2-like agonist was also lost, while the effect of another GABA_B agonist used as a control was preserved. Thus, the scientists speculated that when dopamine is increased in the striatum, it leads to an inhibition of lateral connectivity and lateral transmission, resulting in enhanced output of the direct pathway neurons, and hence to an increase in locomotion. Further experiments demonstrated that animals with targeted deletion of D2 receptors to iMSN had a very impaired locomotive response, compared to control animals who ran a great deal when they received cocaine. In summary, suppression of the lateral inhibition between striatal MSNs in the nucleus accumbens (NAc) contributes to the stimulant actions of cocaine. NIAAA is currently testing to see if alcohol has the same stimulant effects as cocaine, studying the effects of repetitive exposures to the drugs, and looking at models for investigating the effects of drugs in inducing compulsive behaviors.
Discussion: Dr. Koob inquired about the role of the D3 receptor. Dr. Alvarez responded that her lab is currently studying them. Dr. Eberwine asked about astrocytes. Dr. Alvarez noted a recent study published in Science (2015 Aug 14;349(6249):730-4) by Martín R, Bajo-Grañeras R, Moratalla R, Perea G, and Araque A, showing that subpopulations of astrocytes that responded to activity of direct MSNs appeared not to be connected to subpopulations of astrocytes that responded to activity from iMSN. Robert Messing, M.D., expressed concern about synchronization causing seizures. He asked if the striatum during movement is highly synchronized or very asynchronous, like the cortex. Dr. Alvarez concurred with the importance of his concern, stating that her lab has never done experiments with activation of channelrhodoposin and using locomotion. Dr. Messing followed up with another question about the use of tools, such as step function opsins, where the membrane potential is slightly changed or using low doses of the DREADD activator, which allows normal encoding to go on. Dr. Alvarez agreed such tools would be helpful, as would also having some of these receptors channelrhodopsin and DREADDs targeted specifically at axons.
Hybrid Inhibitor of Peripheral CB1 Receptors and iNOS for the Treatment of Liver Fibrosis.
Dr. Kunos’ presentation focused on the development of a compound that could lead to drug treatment of fibrosis of the liver. There is currently no medication approved by the Food and Drug Administration (FDA) to treat liver fibrosis. Liver fibrosis usually develops due to obesity, diabetes, chronic alcoholic liver disease or viral hepatitis. It can then progress to cirrhosis to hepatocellular carcinoma. The usual concept of a single target hit by a single drug limits therapeutic efficacy in the case of multi-factorial diseases like fibrosis, and combining treatments can lead to multiple side effects, drug interactions, and complex pharmacogenetics which could be improved by a single drug hitting more than one target.
NIAAA scientists reasoned that the optimal targets would be those that are involved not only in the fibrotic process and in cellular mechanisms, but also in the pathology of the underlying diseases. One target is the endocannabinoid CB1 receptor system. Previous studies demonstrated that liver fibrosis is associated with increased CB1 receptor activity and that the CB1 receptor antagonist rimonabant is moderately effective in limiting fibrosis. The same system is involved in obesity-related metabolic syndrome diabetes, as well as alcoholic liver disease and viral hepatitis. However, troublesome neuropsychiatric side effects halted further development of this CB1 antagonist. Another promising target is inducible nitric oxide synthase (iNOS), the enzyme responsible for the generation of fully inflammatory nitrogen species and nitrosative stress. There is evidence from animal studies that the predominant fibrogenic cell type in the liver is hepatic macrophages expressing high levels of iNOS. However, increased iNOS activity has been linked to hepatic insulin resistance, alcoholic liver disease and hepatitis.
With these two targets in mind, NIAAA experimented with a non-brain penetrant CB1 antagonist that it sought to modify to 1) limit its brain penetrance to limit or eliminate the potential for neuropsychiatric side effects; and 2) result in a chemical side group that would inhibit iNOS by replacing the amine group with acetamidine, which is known to inhibit this enzyme; inhibition was verified in the lab. This modification also did not affect the very high CB1 receptor potency of the hybrid compound, nor did it affect the high selectivity for CB1 versus CB2 receptors. At the same time, the chemical substitution significantly increased the total polar surface area which is a critical factor in limiting brain penetrance.
NIAAA scientists, however, also wanted develop real-time evidence that there was no significant CB1 receptor occupancy in the brain. The researchers were able to show very strong labeling of CB1 receptors in the brain of mice with the CB1 PET ligand. If the mouse was pretreated acutely with rimonabant, there was significant suppression of labeling indicating that rimonabant occupies brain CB1 receptors but no significant displacement with low or high doses of the non-brain penetrant compound. In examining bile duct ligation-induced biliary fibrosis, the researchers found the rimonabant treatment significantly reduced the degree of fibrosis but didn’t eliminate bridging, i.e., collagen fiber formation. In contrast, the dual target compound at comparable CB1 blocking
duals doses caused a much more robust reduction and minimized the bridging formation. The new compound also provided reduced fibrosis in CB1 knock out mice for whom rimonabant was no longer effective since its target had been removed. It was similarly successful when they repeated the experiment with iNOS knockout mice. When fibrosis had already been induced in the mice, rimonabant moderated the further progression of the fibrosis but didn’t reduce it. In contrast, the dual target compound completely arrested and even slightly, but significantly, reduced the fibrosis compared to what it was at the start of the study. Similar results were observed for iNOS, with the dual compound having greater effect than either one alone.
In conclusion, combined targeting of hepatic CB1R and iNOS for inhibition by a peripherally restricted, orally bioavailable hybrid inhibitor is highly efficacious and also safe as a novel type of treatment of liver fibrosis of different etiologies. In addition to this lead compound, NIAAA scientists generated several dozen related compounds and a second class of dual target compounds where CB1 inhibition is coupled with adenosine monophosphate-activated protein (AMP) kinase activation. Three patents for the outcomes of this research have been filed by NIH, and this has generated significant licensing interest from two start-up companies that want to continue collaborating with NIAA to move these compounds from bench to bed side.
Discussion: Paul Kenny, Ph.D., stated that the modified compound created by NIAAA provided good increased polar surface area, but it's very greasy. He asked if the group had looked to see if there was accumulation over time. Dr. Kunos responded that this particular compound didn’t accumulate, especially comparing a single dose with a 28-day daily oral dose. They were able to verify that almost all of these compounds are substrate for the PGP transporter, which contributes to their limited brain penetrance. Working with the licensees, NIAAA will definitely plan to use the compound in chronic alcohol induced liver disease to see if it could mitigate fibrosis. It may take about two years to get to the Investigational New Drug (IND) phase. Dr. DiClemente inquired if the presence of alcohol would affect the action of the compound; Dr. Kunos replied that there was no reason to think so, but it would have to be tested. NIAAA is currently looking for a model of alcohol-induced fibrosis. It has developed one model using binge drinking, but it’s highly variable and therefore requires a large number of animals for testing. Dr. Sanyal asked if CB2 has some effects on hepcidin and iron status, and thus potentially cause anemia. Dr. Kunos responded that CB1 plays a significantly greater role than CB2. Dr. Sanyal also noted differences in the types of fibrosis; Dr. Kunos said that NIAAA planned to test the compound on the model used in Dr. Sanyal’s newly-published paper. Dr. Molina asked for clarification about when the animals in the study were treated. Dr. Kunos explained that his laboratory used two paradigms. In one, treatment was started on the same day when the bile duct was ligated. In the other, treatment began on day six after determining there was already significant fibrosis.
Council Member Presentation: Developing PKC Epsilon Inhibitors to Treat Alcohol Use Disorder
Dr. Koob introduced Council member Robert O. Messing, M.D. Dr. Messing summarized 15 years of research into the development of new therapeutics to treat AUD in which Protein Kinase C epsilon (PKCƐ) has emerged as a potential drug discovery target. PKCƐ is an enzyme that transmits intracellular signals from lipid second messengers and is activated by diacylglycerols formed as a result of receptor activated phosphoinositide hydrolysis. It’s heavily expressed in the brain, including the amygdala and the striatum. Several cytoskeletal and synaptic proteins are phosphorylated by PKCƐ. Thus, this enzyme is key for changing the shape of cells and the location of signaling complexes in cells.
Dr. Messing began this work by studying a model cell system using a pheochromocytoma cell line called PC12 which are cells from an adrenomedullary tumor. He found that exposure of these cells to ethanol for several days increased the abundance of the enzyme, which was required for increasing the production of a certain type of voltage-gated calcium channel that allowed greater neurotransmitter release from the cells and also made them more responsive to nerve growth factor and fibroblast growth factor induced differentiation. When a post doc, Bhupinder Hundle, Ph.D., wondered if this effect also changed behavior, they generated a mouse model in which they knocked out the enzyme. Experiments by a collaborator, Clyde Hodge, Ph.D., established that PKCƐ-deficient mice consumed substantially less alcohol and were much more sensitive to alcohol intoxication than wild type littermates. Messing’s group validated this finding by inducibly restoring PKCƐ in key limbic brain regions in the knockout mice, and found it rescued ethanol consumption and sensitivity to intoxication. When they turned the inducible system off and the enzyme levels fell, the animals again hardly drank any ethanol at all and were very sensitive to the intoxicating effects. This result suggested that the enzyme changes responses to alcohol.
Subsequently, another post-doc, Anna Lee, Ph.D., wanted to study PKCƐ as a potential regulator of nicotine consumption, based on the high co-occurrence of alcohol and nicotine abuse. She allowed the PKCƐ knockout mice to drink a nicotine solution. Over a four-week period, wild-type animals escalated their consumption of the nicotine solution, while the knockout mice did not. Results from conditioned place preference tests showed that the knockout mice found nicotine much less rewarding than wild-type mice. She discovered that PKCƐ phosphorylates the alpha 4 subunit of nicotinic receptors in the brain which mediate the addictive properties of nicotine. In knockout mice, this phosphorylation is reduced resulting in impaired recovery of nicotinic receptor function from desensitization by nicotine. These mice also showed a decrease in the abundance of the alpha 6 subunit of nicotinic receptors, which is highly expressed in ventral tegmental area (VTA) dopamine neurons that mediate the rewarding effects of nicotine. As a result, the knockout animals showed impaired cholinergic enhancement of dopaminergic transmission in the nucleus accumbens. These findings suggested that, if PKCƐ could be inhibited, there could be a drug to treat two addictive disorders that are highly comorbid. Working with post-doc Kevan Shokat, Ph.D., this conclusion led to a chemical genetics study in which PKCƐ was mutated to sensitize it to a drug that would selectively inhibit the mutant enzyme. The Messing lab then generated a mutant mouse that expresses this mutant enzyme. Rajani Maiya, Ph.D., found that selective inhibition of the PKCƐ mutant enzyme reduced alcohol consumption and prolonged intoxication.
These findings led to the conclusion that it's worthwhile to further develop PKCƐ inhibitors. A search of the patent literature and of commercially available compounds revealed Y-27632 to be a weak PKCƐ inhibitor, and led to the synthesis of several novel compounds, four of which inhibited PKCƐ with high potency (< 20nM). Two of were found to have reasonably long half-lives both in the plasma and in the brain. Currently, post-doc Angelo Blasio, Ph.D., is testing alcohol consumption using an intermittent access procedure where the animals drink alcohol every other day. This procedure results in consumption of 18 to 20 grams per kilogram per day, and produces blood alcohol levels greater than 80 milligram percent in most animals. When the animals are given either of the two compounds described above, they have a dose-dependent reduction in alcohol consumption and preference. And when given a hypnotic dose of alcohol, they sleep longer like the epsilon knockout mice do. Thus, these compounds look promising for treating alcohol addiction. In summary, inhibitors derived from Y-27632 potently inhibit PKCƐ with partial selectivity within the PKC family, particularly for the novel PKCs. They reduce ethanol consumption. Despite their brain penetrance and target availability, the safety profile and the target availability probably need optimization.
Discussion: Dr. Kunos inquired if there is a canonical substrate sequence for PKCƐ and, if there is, can one develop an assay where there is a synthetic peptide and the enzyme is used to show direct inhibition. Dr. Messing replied that he used a substrate peptide to assay the enzyme in vitro but that it has been difficult to define a PKCƐ specific subsequence to predict PKCƐ substrates. Dr. Kenny noted that there are growth inhibitors already on the market. He asked if there's any anecdotal evidence that they may affect alcohol. Dr. Messing responded that he’s not aware of any. Dr. Sinha asked if there were any interactions or impact on brain norepinephrine, as well as any sense of the impact on the prefrontal cortex (PFC). Dr. Messing said they have done no studies addressing these questions; the expense of doing so is a barrier since synthesis of these compounds is expensive, but a collaborator is working on a less expensive method for synthesis. Dr. Koob inquired about potential side effects of targeting PKCƐ in the amygdala. Dr. Messing acknowledged these were potential concerns, but noted that the knockout mice have no obvious phenotypes other than reduced anxiety-like behavior. Dr. Sanyal asked if the effects were the same in obese mice vs. lean ones, noting the prevalence of obesity in the human population; Dr. Messing explained that his lab has not yet looked at such differences. Dr. DiClemente inquired about the effects of the compound on marijuana. Dr. Messing replied that they have not yet studied that question.
Ex-officio Members’ Reports
Dr. Karen Drexler, ex-officio member from the Veterans Administration (VA), gave a report about activities at the VA. The Veterans Administration (VA)/ Department of Defense (DOD) clinical practice guidelines for substance abuse disorders are now available. These guidelines consist of 36 evidence-based recommendations grounded in a systematic review of the literature based on 12 questions. There are specific recommendations about screening, as well as about treating substance abuse disorders with medications and psycho-social interventions. The guidelines recommend the following medications: acamprosate, disulfiram, oral naltrexone and extended release injectable naltrexone, topiramate, and second line gabapentin. They also recommend five psychosocial interventions including behavioral therapy, cognitive behavioral therapy, 12-step facilitation, motivation enhancement therapy. Dr. Drexler expressed appreciation for NIAAA's support of the research that led to these evidence-based recommendations. They are currently being disseminated throughout the VA system, where AUD is often treated as part of specialty care.
Discussion: Dr. Koob noted that NIAAA believes that less than 20 percent of those with an AUD get any treatment and less than 10 percent receive any medication. Dr. Drexler commented that the VA is working on medications, confident that veterans are getting the best treatment for withdrawal, but probably not for relapse prevention. Thus, that is part of the VA’s improved quality standards. It used to be that only 6 to 7 percent of veterans received medication for alcohol use disorders. Dr. Koob said the information that medications exist for alcohol-related treatment needs to be disseminated more effectively to primary care physicians. Dr. Drexler replied that the VA would like to partner with NIAAA in this effort by disseminating it throughout the VA system.
Dr. Koob noted that NIAAA is also interested in providing a generic navigator for alcohol throughout the health care system. Robert Huebner, Ph.D., stated that NIAAA is putting together an online tool that will help people navigate the system. The tool would include questions that people can ask providers and treatment centers to assess their quality. The tool is currently in development and will be shared with Council in the future. Dr. Koob stated that NIAAA wants Council input on the tool.
Dr. Koob introduced and complimented Acting Director Patricia Powell, Ph.D., as the quiet power behind throne who facilitates the implementation of NIAAA priorities. He opened the floor for comments from Council members. Dr. Molina acknowledged Dr. Koob’s efforts to be transparent about funding and priorities, but encouraged him and NIAAA staff to tell early career investigators that NIAAA supports them. She also applauded Dr. Koob’s position on equal pay for women and encouraged him to share it with deans. Finally, she stated that alcohol affects every organ in the body. No other IC cares about alcohol. Therefore, it is important to continue to advocate for alcohol studies. Dr. Koob agreed. Despite all the attention given to opioids today, alcohol has a much greater impact on society. He encouraged Council members to be advocates about alcohol’s impact and about NIAAA’s role, so its contributions can be more widely acknowledged.
Dr. Koob stated that NIAAA has been seeing an increase in the amount of funding that people are asking for in their grant applications, especially in epidemiology, prevention and clinical grants. NIAAA can’t afford such expensive grants and therefore is examining budgets carefully. Another issue under discussion is where NIAAA should put its data. Phil Bourne of Big Data to Knowledge (BD2K) has a cloud server that is free to the ICs, and that’s where NIAAA may ultimately put its data. An investigator will pay to analyze the data from the cloud, not to pay for a server. There are other data repositories, including one on mental illnesses and another from the Psychiatric Genomics Consortium, which NIAAA is also considering using.
Sarah Mattson, Ph.D., commented that grant budget issues affect younger investigators. She noted that investigators are being encourage to enroll larger numbers of subjects, but getting less support from NIH. She asked if investigators could leverage Dr. Koob’s comments to persuade their institutions to provide more support for studies. Adolf Pfefferbaum, M.D., stated that institutions have no other funds to provide. Dr. Sanyal commented that another issue is that different consortia use different case definitions, so it’s difficult to cross-consortia analyses. He asked if there was any effort to develop some consensus around data harmonization, common data elements and case definitions that might provide more “bang for the buck.” Dr. Koob explained that there are efforts underway to do so, e.g., the liver consortium is trying to develop common elements of diagnosis and measures. Previously, a Council subcommittee developed the definition for binge drinking widely used in alcohol research.
Dr. Sloan raised a budget concern, noting that as direct costs go up, indirect costs also go up. Yet NIH has been extremely reluctant to negotiate. Dr. Koob replied that indirect costs are determined not by NIH, but by DoD. High indirect rates, in some cases as much as 100 percent, put everyone on soft money at risk. NIAAA is seeing $1 million requests on a regular basis, and is cutting them back. One strategy to address the issue of ballooning budgets is to standardize dependent variables, another is look at existing cohorts that can be used, and a third is the increasing use of the U mechanism which forces investigators to work together on these variables. The era of Big Science and precision medicine demands large groups of subjects. NIAAA will continue to emphasize young investigators and health disparities in its grantsmanship. The Institute also needs to better understand the success rates of its National Research Service Awardees (NRSAs). Dr. Weisner commented that some institutions are cutting back on letting people write grant applications. She also asked if there was any discussion within NIH about institutions giving the Pharmaceutical Research and Manufacturing Association (PhRMA) firms and foundations lower rates, so that NIH is subsidizing PhRMA. Joe Martinez, Ph.D, suggested that the Institute provide information about sample size considerations (e.g., effects size needed) to investigators as a budgeting guideline. Dr. Koob responded that this is part of the new reproducibility guidelines that are being given to study sections. For example, ICs are just beginning to grapple with the requirement that gender be considered in all samples. Dr. Bautista commented that this is the first time that study sections are having to consider reproducibility as well as the inclusion of both sexes and using the female gender as a variable, but NIH does not require it to be powered. It depends on the type of analysis in the study. Dr. Koob explained that there is no difference in the success rates in R01s and R21s. The purpose of the R21 is to generate data for an R01. Young investigators should write an R01 if they have data. Dr. DiClemente commented that the R21 grant has a lower budget than an R01, so people think they could be more successful with a lower budget and are saving big projects for the R01. NIH needs to get the word out that an R01 doesn’t need to be $1 million. Tatiana Foroud, Ph.D. asked if it was true there was no difference in paylines between a modular grant and one under $500,000. Dr. Bautista answered that there is no difference in the review between those with modular and detailed budgets; it depends on the IC director. Dr. Sanyal inquired if there was a sense that the increase in costs was driven by the advent of more sophisticated technologies where investing in common services might reduce the cost of individual applications or by inflated salaries. Dr. Koob said this issue was being investigated. Dr. Hingson commented that grant budgets are increasing, but funding has been flat so that NIH can fund fewer grants. Applications to conduct secondary analyses are usually not reviewed well by study sections because they’re not seen as innovative, even though they can be. Both Drs. Koob and Weisner agreed that secondary analyses were valuable, and Dr. Koob asked Dr. Powell to make a note about following up on promoting greater use of secondary analyses. Dr. Hingson noted that his division has a policy research program, much of which can use surveillance data. Peggy Murray, Ph.D., interjected that for the resource-rich ABCD study, CRAN is making a strong effort to make the data available as soon as possible in order to encourage secondary analysis. Dr. Weisner added that health care data is another valuable source for secondary analyses. Dr. Sinha returned to the discussion of alcohol as a brain disease. She made the point that it’s important to remember that people do recover. There is a need for more studies on relapse and recovery. She will make comments related to this on the draft of the strategic plan, and asked what will happen once NIAAA receives Council members’ comments. Dr. Koob responded that NIAAA will develop a summary of the NIAAA changes to the Strategic Plan to the Council.
Pamela Walters, Al-anon Family Group Headquarters, thanked NIAAA and Council on behalf of Al-Anon members for all they do. She shared a podcast comments to highlight the struggles faced by people whose family members are alcoholics. Tracy Ober from the Headquarters of Alcoholics Anonymous also thanked NIAAA for its excellent work. She announced that AA is searching for a replacement for a Class A (non-alcoholic) trustee on its Board. She invited Council members to consider themselves or colleagues for the position.
The meeting adjourned at 3:47 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.