SHORT PRESENTATIONS
Georgios Ponirakis, PhD
Weill Cornell Medicine, Qatar
Georgios Ponirakis, PhD
Dr. Georgios Ponirakis is a clinical researcher based in Weill Cornell Medicine in Qatar. Dr. Ponikaris and his team investigated the diagnostic ability of corneal confocal microscopy (CCM) a non-invasive ophthalmic imaging biomarker of neurodegeneration for mild cognitive impairment and dementia. The ability of CCM to distinguish subjects with MCI and dementia from age-matched subjects without cognitive impairment with high accuracy was a major milestone to expand the use of CCM in dementia research.
Q&A
What is the biological link between the degree of corneal nerve damage and the severity of cognitive impairment? Do these patients have impaired vision or even visual attention?
GP: There is no direct link between corneal nerve loss and cognitive impairment. Furthermore visual alterations are related to retinal not corneal nerve degeneration. Corneal nerve degeneration is a surrogate of neurodegeneration elsewhere in the body as demonstrated by our other studies showing corneal nerve loss in a range of other peripheral neuropathies and central neurodegenerative conditions like Parkinson’s disease and multiple sclerosis.
Great talk! Is this an approach that is already used in optometry clinics? How do you see this being implemented clinically?
GP: Very good question, thank you. The Heidelberg Retina Tomograph (HRT) ophthalmic device is currently utilized in ophthamology clinics using the retinal module to assess glaucoma and the corneal module is used to image the cornea for epithelial defects and acanthomoeba infection. There are currently ~300 centres across the world using CCM to assess a wide range of peripheral neuropathies and central neurodegenerative diseases.
Elisa Calcagno, PhD
Columbia University
Elisa Calcagno, PhD
Elisa Calcagno, PhD, is an expert molecular biologist with experience on a variety of molecular, biochemical, cellular, and behavioral methods in genetically modified mouse models of Alzheimer’s disease. She completed her PhD studies in the Department of Experimental Medicine of the University of Genova (Italy) in 2019. During her PhD studies, she focused on the molecular mechanisms that regulate neuronal activity and synaptic transmission, and how these mechanisms contribute to normal learning and memory in normal conditions and neurodegenerative disorders.
Dr. Calcagno is currently working on the development of histone acetyltransferase (HAT) activators as drug candidates for the treatment of Alzheimer’s disease. The overall goal of the project is to identify an efficacious small molecule that activates HATs p300, CBP and PCAF from a library of several compounds designed in the laboratories of Drs. Arancio and Landry.
Q&A
Hi Elisa, thank you for your talk. Is there an advantage to using HAT inhibitors compared to HDAC inhibitors from a biological perspective?
EC: The advantage of using HAT activators instead of HDAC inhibitors is related to overcoming the limitations of HDAC inhibitors lacking selectivity versus different HDACs involved in memory formation, in particular HDAC1 and HDAC2 which play opposite functions in memory formation. HDAC1 is associated with the promotion of fear and extinction learning whereas HDAC2 is associated with the suppression of fear and extinction learning.
Are there other things that need to be improved to move forward with a clinical candidate?
EC: We are trying to improve the metabolic stability of the candidate.
What administration route was used to give the drug in vivo?
EC: We administered the drug intraperitoneal. However, the drug can be also given orally.
Michael Ohlmeyer, PhD
Atux Iskay Group, LLC
Michael Ohlmeyer, PhD
Michael Ohlmeyer, PhD, is Founder and VP of Chemistry of the Atux Iskay Group LLC, a platform drug development company with multiple novel PP2A activator types. The technology has application in neurodegenerative disease, inflammation and oncology. The Atux Iskay Group aims to establish or enable dedicated therapeutic focused companies with pre-clinical development compounds in each of these areas.
Previously, Dr. Ohlmeyer was Associate Professor at Mt Sinai School of Medicine where he established a network of collaborations with leading academic scientists working on fundamental PP2A biology and translational science. Dr. Ohlmeyer was co-inventor of the core technology and founding scientist of Pharmacopeia Inc., where he was Executive Director of Chemistry.
Dr. Ohlmeyer’s academic training was at Cambridge University in the UK, then subsequently at Rice University and Columbia University in the US. He has extensive drug development experience in academic and industrial settings and is located in the
NJ/NYC area.
Q&A
You mentioned other PP2A inhibitors and their disadvantages. Have any of these been tested in clinical studies?
Thank you for your talk. I have two questions: What biomarker would you look to use in human studies? How would you know you are hitting PP2A in a human patient?
Lauren Gandy, PhD cand.
Rensselaer Polytechnic Institute
Lauren Gandy, PhD cand.
Lauren Gandy is a PhD candidate in the Chemistry & Chemical Biology Dept at Rensselaer Polytechnic Institute. Her dissertation topic explores if the presence of herpes virus inhibits or promotes the prion-like spread of tau pathology in Alzheimer’s disease. She received the Rensselaer Graduate Fellowship upon entry into program in 2017 and was then awarded the NIA Alzheimer’s Disease Clinical and Translation Research Grant from 2018 to 2020.
Prior to coming to Rensselaer, she graduated with honors in 2017 from the University of Central Florida with a B.S. in Forensic Biochemistry and a B.A. in French. During her time there, she conducted research on gunshot residue analysis at the National Center for Forensic Science and published an undergraduate thesis on the didactic representation of Enlightenment ideology in 17th and 18th century French science fiction. She was awarded the Order of Pegasus, the most prestigious and significant award a student can attain at UCF, her graduating year in recognition of her leadership, academic, community service, and research accomplishments.
Q&A
Hi Lauren, can you provide additional information and data on herpes virus in AD and other neurodegenerative diseases?
LG: Thank you for your question. More data about herpes virus in AD can be found this 2018 Itzhaki review, including her own very interesting papers, a study by Loveheim et al. in Alzheimer’s & Dementia, 2015 (https://pubmed.ncbi.nlm.nih.gov/25043910/) and a nation-wide study in Taiwan by Tzeng et al. in Neurotherapies, 2018 (https://pubmed.ncbi.nlm.nih.gov/29488144/). For other neurodegenerative diseases, I recommend the review by Hogestyn et al. in Neural Regeneration Research, 2018.
Do other viruses have gD1 or is this a specific feature of herpes 1?
LG: Thank you for your question. Glycoprotein D appears specific to the alphaherpesvirinae family, present on cell surfaces in herpes simplex virus types 1 and 2, though some like varicella-voster virus lack it. Refer to “Entry of Herpesviruses into Cells: The Enigma Variations” by Krummenacher, Carfi, Eisenberg and Cohen for more information, link: https://www.ncbi.nlm.nih.gov/books/NBK6257/.
Hi, I’m curious to know what are the next critical experiments that you plan to perform. Great talk!
LG: Thank you for your question. We next plan to further characterize the structural details of gD-heparan sulfate, gD-tau and ternary interactions using NMR, SPR and MS.
Shruti Shalini, PhD
University of Delhi
Shruti Shalini, PhD cand.
Shruti Shalini is a PhD candidate at Dr. B R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India. Her area of research is focused on the development of small molecules with disease-modifying potential for the treatment of Alzheimer’s disease (AD). She is currently working on her thesis entitled “Development of potential multifunctional agents from natural and synthetic sources for the treatment of Alzheimer’s disease: A detailed in-vitro and in-vivo investigation “. Her academic credentials include Bachelors in Microbiology and Masters in Biomedical Sciences.
In her PhD tenure, she is exposed to research in drug designing and development, performing various enzyme based drug screening assays. Currently, she is screening the best active compounds on SHSY-5Y cells for their neuroprotective properties and also on scopolamine-induced mice model of Alzheimer’s disease.
Shruti has been a co-author on five research papers in reputed journals (Med Chem Comm, Neurotoxicity Research, European Journal of Medicinal Chemistry, Bioorganic & Medicinal Chemistry and Bioorganic Chemistry Journal), where she contributed in the in-vitro assessment of the biological properties of the synthesized derivatives.
Q&A
Have you looked at the effect of compound 12 on synaptic markers or neurodegeneration?
Thank you for this suggestion. It would have been interesting to explore this aspect. However, in the case of our study, we have planned it for future to have more detailed investigation.
Hi, can you clarify why you studied the interaction of your compounds with copper.
Thank you for pointing this out. Metal dyshomeostasis in the body, especially in the brain, can be a critical mechanism for neurodegenerative processes, including oxidative stress generation or amyloid plaques aggregation. Therefore, the ability of our synthesized compound 12 to chelate bio-metals like Cu(II) and Fe(II) was performed by UV−vis spectroscopy.
I wonder if the synthesis of your compounds is scalable or will need to be optimized.
For industrial purpose, more optimization would be required.
Biyue Zhu, PhD cand.
Massachusetts General Hospital
Biyue Zhu, PhD cand.
Biyue Zhu is an exchange PhD student doing research at Dr. Chongzhao Ran’s Lab at Massachusetts General Hospital. Her research is focused on developing imaging probes and therapeutics for Alzheimer’s disease.
Q&A
What is known about obatoclax? Is this a drug that has been approved for other indications?
BZ: Obatoclax is an inhibitor of Bcl-2 protein that showed promise in treating various types of cancer. It has been tested in phase III clinical trials.
Hi Biyue, can you clarify how SPEED screening works?
BZ: SPEED is based on testing the changed antibody binding to target epitope before and after compound treatment. For dot blotting immunoassay as an example, Aβ protein with or without compound treatment was immobilized on a nitrocellulous membrane using Bio-Dot Microfiltration Apparatus. Each strip including 5-6 duplications was assigned to corresponding antibody recognition for epitope of interest (EOI). After routine dot blotting procedures, the chemiluminescence readout from control group (without tested ligand) was normalized to 1.0, and the alteration effect for EOI was quantified using the ratio between the two groups.
Ajinkya Sase, PhD
University of Pennsylvania
Ajinkya Sase, PhD
Ajinkya Sase is a 4th-year postdoctoral researcher in Dr. Elizabeth A. Heller’s lab at the University of Pennsylvania, Philadelphia, USA. He received his Masters of Science degree in microbiology from India in 2007. He then shifted his academic focus towards neuroscience and started his PhD work in neuroproteomics lab of Dr. Gert Lubec at the Medical University of Vienna, Austria.
Ajinkya has expertise in rodent behavioral paradigms and protein biochemistry. His thesis focused on identifying the effect of novel Dopamine Transporter (DAT) inhibitors on cognitive performance and investigating related GPCR’s.
His current research focuses on epigenetic remodeling in memory and stress behavior.
Q&A
What is known about cdk5 in human brain?
Have any differences in expression between observed between sexes?
Yes, there is a difference in the expression of Cdk5 between the sexes. I would direct you to our last publication for more information. https://www.biologicalpsychiatryjournal.com/article/S0006-3223(18)32054-7/fulltext.
Hi, how do you explain this sex difference from an evolutionary point of view? What does it mean?
Can you tell us more about cdk5 in the brain of AD patients or other neurodegenerative diseases?
Anna Stoll, PhD
Michigan State University
Anna Stoll, PhD
Anna Stoll was first introduced to the world of neuroscience and Parkinson’s disease research during her undergraduate degree by a molecular toxicology professor studying the correlation between pesticide exposure and Parkinson’s disease. This led her to a master’s program in biological sciences with a concentration in neurodegenerative diseases before attending the Department of Pharmacology and Toxicology at Michigan State University where she is a 4th year PhD candidate.
Anna joined the Sortwell laboratory to study the role of neuroinflammation in the progression of Parkinson’s disease and determine whether microglia are a potential target for disease modifying therapeutics. Through this work, she has come to realize the importance of drug discovery and have gained the desire to continue drug discovery research in neurodegenerative diseases.
Q&A
Can you tell us more if this drug has been tested in clinical trials for Neurodegenerative diseases?
Thank you for the question. As of right now I do not believe that this drug has been tested in clinical trials for neurodegenerative disease but as of last year it is FDA approved for tenosynovial giant cell tumor.
Do you know if is possible to measure CSF1R in the brain? Any CSF or PET biomarkers? Thank you and great talk!
Thank you for the question. I believe that there are labs that have been using and working on PET radiotracers that would be specific for the CSF1R. I do not believe that at this time they are being used in the clinic. For CSF analysis lots of different inflammatory markers are used to understand the changes in microglial levels and activation states.
Elisa Zuccarello, PhD
Columbia University
Elisa Zuccarello, PhD
Elisa Zuccarello is an expert medicinal chemist and a pharmacologist with experience in design and synthesis of small molecules, generation and optimization of leading compounds for drug discovery and lead optimization of novel small molecules. She completed her PhD studies at the Department of Pharmaceutical Sciences at the University of Catania (Italy) in 2016. There, she designed and synthesized hybrid ligands of sigma receptors releasing NO for cancer treatment. Moreover, she designed and synthesized pro-drugs for the modulation of opioid activity, sigma 1 receptors, and HDAC activity for the treatment of neuropathic pain. Finally, she contributed to the synthesis of 4-Nitro-2,1,3-benzoxadiazole derivatives as potential fluorescent sigma receptor probes.
At the conclusion of her PhD work, she joined the labs of Drs. Arancio and Landry at Columbia University where she is currently working as a post-doctoral Research Scientist on the development of phosphodiesterase type 5 (PDE5) inhibitors and histone acetyltransferase (HAT) activators as drug candidates for the treatment of Alzheimer’s disease.
Q&A
What biomarkers would be the best fit for PDE5 inhibitors?
EZ: Biomarkers tailored to assessing synaptic function are ideal for our studies. This is a field in rapid evolution. I am fascinated by PET imaging for SV2A, which allow to measure synaptic density in the living human brain. I know that a team in Yale is currently using the PET technique to assess Alzheimer’s disease drugs. An additional biomarker assessing synaptic function that could be used is Neurogranin that is shed into CSF under circumstances of synaptic degeneration in Alzheimer’s disease. Pharmaco-EEG is another method that is closely connected with synaptic transmission and could be used to monitor drug efficacy. I should also add that one could monitor cGMP concentrations in CSF.
Do you anticipate any side effects of this approach?
EZ: A key advantage of using PDE5 inhibitors is the paucity of side effects that has already been shown with the marketed inhibitors against peripheral diseases. This was the reason why we decided to develop PDE5 inhibitors as drugs against Alzheimer’s Disease. For instance, PDE5 inhibitors are currently administered chronically to subjects with pulmonary hypertension and they might save their lives. With respect to observed adverse events of marketed PDE5 inhibitors, they include mild vasodilatory effects such as headache, flushing, dyspepsia, and nasal congestion or rhinitis, hypothension (if nitrates are given concurrently), transient visual impairment (probably due to lack of specificity vs. PDE6 which is not inhibited by our compounds). To this end, it should be said that although Aβ is primarily accumulating in the CNS, Aβ is also present in the blood of patients affected by Alzheimer’s Disease and other neurological disorders characterized by abnormal Aβ production. Intriguingly, systemic Aβ potentiates vasoconstriction not only in cerebral vasculature but also in other districts of the vascular system. Moreover, hypertension is often associated with Alzheimer’s Disease. Thus, it is very appealing to think that PDE5 inhibitors might counteract not only CNS symptoms, but also vascular symptoms that often affect Alzheimer’s Disease patients.
Another side effects of PDE5 inhibitors has been priapism which has been reported to occurr in a few cases. However, the current view about the cause of priapism is that it is likely due to a dysregulation of PDE5 function following down-regulation of the NO pathway, a phenomenon that is also caused by Aβ increase, such that, paradoxically, PDE5 inhibitors have been proposed as therapeutic agents against priapism.
Hi Elisa, when do you think that you will have a lead compound to be moved in late preclinical studies?
EZ: Thanks for this question. Columbia University has recently licensed these compounds to a medium size pharmaceutical company with the commitment to move them quickly to late preclinical and clinical studies. Additionally, I have developed a library of new PDE5 inhibitors with the aim of further improving their physicochemical properties that might serve as backup compounds in our PDE5 campaign.
Priyanka Das Pinky, PhD
Auburn University
Priyanka Das Pinky, MD, PhD cand.
Priyanka Das Pinky is a PhD candidate from the department of drug discovery and development in Auburn University, Auburn, AL. She also has an MD degree from Bangladesh. Priyanka is working on several projects for understanding the mechanism of learning and memory deficits and opportunity for newer drug development in Alzheimer’s disease. She has also worked on prenatal drug abuse and its effect on learning and memory of adolescent offspring. Priyanka has published several review and research articles. In future, she wants to join academia to pursue her interest in the neuropharmacology and drug development.
Q&A
Given your findings in mice, what biomarkers would you predict most affected in a human trial of troriluzole?
PDP: Unfortunately, neurophysiological parameters are not readily measurable in humans. However, synaptic biomarkers (eg, SNAP-25, neurogranin) may be relevant to the data presented, have the potential to be assessed in CSF, and are likely to be impacted.