Posted 20 June 2008

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Participants: Yong Shen, Sun Health Research Institute; Rob Malenka, Stanford University; Malu Tansey, U.T. Southwestern Medical School; Cynthia Lemere, Brigham and Women's Hospital and Harvard Medical School; David Szymkowski, Xencor; Jiqing Xu, University of Nebraska Medical Center; Tsuneya Ikezu, University of Nebraska Medical Center; Gregory Brewer, Southern Illinois University Medical Center; Felicia McColl, Peter Jones, Bill Watson, Prasad Gabbita, P2D; Boobalan Pachaiyappan, University of Illinois at Chicago; Fran Shaller, Gabrielle Strobel, Alzheimer Research Forum.

Note: Transcript has been edited for clarity and accuracy.

Gabrielle Strobel
Welcome back, everyone! As people continue to come, I'd like to start off by giving our panelists, including Rob Malenka, Cindy Lemere, and Tsunea Ikezu, a first round of questions/comments to each other and to guests they see in attendance—particularly from industry if they want. Then I'll open the discussion to everyone.

Rob Malenka
Very nice presentations; I learned a lot.

Malu Tansey
Rob, in your studies, you're using the TNF knockout and a soluble R1 to block the TNF actions. Do you have any thoughts on whether this is glial-derived soluble or tmTNF juxtracrine signaling?

Rob Malenka
All of our results are consistent with it being soluble TNF. Most convincing evidence for this is that we could take media from cultured neurons that were manipulated pharmacologically and then apply this to normal cultures and see clear effects that were blocked by soluble R1. Caveat to all this work is that it was done in cultured neurons, not in vivo.

Malu Tansey
That is indeed consistent with solTNF, and it would be great to see if you can extend that with DN-TNF.

Rob Malenka
I agree about trying DN-TNF. But that will be up to Dave Stellwagen, my ex-postdoc who now has his own lab.

Malu Tansey
He should be able to obtain these directly from Xencor as they are giving them out to academic collaborators.

Gabrielle Strobel
Rob, would you be interested in working with any AD mouse models? It might be interesting to compare TNFα synaptic effects in normally aging mice to aging mice that overexpress mutant human APP or mutant tau. No?

Rob Malenka
Gabrielle, that would be interesting, but my lab is pretty busy doing other projects at the moment. Of course, if you want to give me $$$$$—I can be convinced.

Cynthia Lemere
Thanks for the excellent presentations! Malu, I may have missed this, but are the DN-TNF (soluble TNF inhibitors) able to cross the blood-brain barrier (BBB)? Do the other TNF inhibitors such as infliximab or etanercept?

Malu Tansey
Cindy, to my knowledge, none of the anti-TNF biologics would be expected to cross the BBB to any significant extent because they are very large proteins. However, we have not administered these systemically in our models of neurodegeneration and checked brain penetrance. On the other hand, under conditions in which the permeability of the BBB is compromised I would not be surprised if they did cross.

Gabrielle Strobel
To Malu and our industry guests, or anyone who knows, are any biologics that are dominant-negative proteins approved as drugs or in late clinical trials? I mean generally, for indications beyond AD/PD/MS/ALS. Or would small-molecule inhibitors hitting soluble TNF selectively have to be developed?

Malu Tansey
Gabrielle, Xencor has an open IND for trials in rheumatoid arthritis. I've got no knowledge of any small molecule that would selectively neutralize solTNF. For additional questions specific to DN-TNF trials, please direct them to Dave Szymkowski who has joined the chatroom.

Gabrielle Strobel
We have a contingent of scientists from Wyeth, Merck, Genentech. Are any of you able to share what programs are ongoing in this area? And Dave, what about DN-TNF trials?

David Szymkowski
Gabrielle, our primary focus with DN-TNF biologics has been in RA. As Malu, said, we're at the IND stage. However, with Dr. Tansey and other collaborators, we are actively exploring the effects of soluble TNF inhibition in various in vivo models of neurodegeneration.

Yong Shen
Rob, TNFα was found to promote synaptic transmission during the developmental stage; however, in an AD case, while TNFα is increased, the synapses are lost. Is this due to aging versus development?

Rob Malenka
Yong, as your question implies, I do think it is important to note that all of the work on the synaptic effects of TNF was done in very young neurons (i.e., cultured neurons) or during early postnatal development. Whether TNF has the same effects in adult or aged brain is an open question. It also may be that TNF has the same effect in adult/aged brain and the increase in AMPA receptors contributes to the eventual synapse loss or dysfunction.

Jiqing Xu
I have a question to Yong. You show TNFR1 action is detrimental to neurons and can cause neuron loss. Do you have any evidence to explain why neurons from certain anatomical sources are selectively more vulnerable?

Yong Shen
Jiqing, yes. In AD, for example, R1 is increased in the cortex; in PD cases R1 is increased in the substantia nigra.

Jiqing Xu
…specifically elevated in cortex in AD?

Malu Tansey
Jiqing and Yong, our working hypothesis is that the vulnerability to death induced by TNF comes from the ratio of R1/R2 receptors in the cell, and we are actively testing that now in models of PD.

Gabrielle Strobel
Hi, Tsuneya! Feel free to type in your questions.

Tsuneya Ikezu
Hello! I enjoyed the talk of Yong and Malu very much. I have a few points that I would like to share.

Gregory Brewer
Yong, we have two recent papers that show major effects of TNFR1 and R2 with age in old rat neurons in our culture model. The effect is dramatically evident from exposure to β amyloid and TNF together.

Yong Shen
Greg, that’s a very interesting finding.

Tsuneya Ikezu
Regarding the alternative approach for modulating the TNF signaling, there are a couple of papers regarding a new type of NFκB inhibitor, which blocks its translocation: dehydroxymethylepoxyquinomicin (Kubota et al., 2007). Lovastatin was also shown to enhance neuroprotection via upregulation of TNFR2 (Dolga et al., 2008). These may fit as alternative compounds.

Yong Shen
Greg, do R1 and R2 have similar/different effects with regard to TNFα and Aβ?

Tsuneya Ikezu
Another point is that in terms of Aβ clearance, TNF not only suppresses uptake but also suppresses Aβ degradation in microglia and macrophages. Since this degradation pathway is mediated through multiple steps of endocytosis, sorting, unfolding, and site specific/non-specific processing of Aβ, there are many to be addressed in this mechanism, and some of them may be a therapeutic target as well.

Felicia McColl
As a caregiver who has seen the amazing effects of perispinal etanercept in my mom, and in others at the clinic and through forum discussion, I would like to know the reason this hasn't been researched further in a clinical trial? How do clinical trials get started? Isn't it right that Dr. Tobinick did a preliminary study, and even though placebos weren't used, the data showed improvement in all the patients, which should have been enough to justify a clinical trial. Isn't this how many trials get started? Don't researchers many times stumble across something and do a small trial to get pharma companies interested? Why do they keep saying Dr. Tobinick did it wrong?

Gabrielle Strobel
Felicia, Dr. Tobinick was invited to attend but declined. It would have been interesting to hear from him where things stand with regard to conducting a controlled, blinded trial on intrathecal etanercept. Does anyone know the latest?

Rob Malenka
Sorry, but I have to go to another meeting. Thanks for including me. I did learn a lot.

Peter Jones
Gabrielle, regarding Dr Tobinick, he has progressed.

Yong Shen
Gabrielle, there was a new study by Dr Tobinick released yesterday, but we do not know the details yet.

Peter Jones
It’s “Perispinal Etanercept Produces Rapid Improvement in Primary Progressive Aphasia: Identification of a Novel, Rapidly Reversible TNF-Mediated Pathophysiologic Mechanism,” posted in Medscape, his usual source, 06/10/2008.

Gabrielle Strobel
Were there any controls in this report on PPA?

Felicia McColl
No controls. He didn't look for this patient; she came to him for treatment as far as I know. It worked, so he wrote a publication.

Bill Watson
Over what time frame should changes in TNFα in the brain be expected after any treatment, through any portal, with etanercept? I ask because Dr. Tobinick reported seeing gross cognitive changes in AD patients 20 minutes after “perispinal” injection. It is not clear what effect placebo had in his experimental situation.

Malu Tansey
Bill W., your question is a good one. Because Rob has left, I'd say that it is likely that the rapid effects of etanercept (if they are indeed real, and if it's somehow affecting TNF levels directly or indirectly) were mediated through the gliotransmitter role of TNF and not an inflammatory component. This would be interesting and may be very different than the mechanisms that contribute to plaque deposition/removal.

Prasad
Malu, which model is the best suited AD animal model for examining small-molecule therapeutics?

Malu Tansey
Prasad, it depends on the question you want to ask: if you want to explore synaptic effects, you don't need a plaque-making mouse, but if you want to explore the TNF regulation of plaque removal and deposition, you will need a plaque-making mouse and one which also displays neurodegeneration. Bob Vassar at Northwestern has a 5xTgAD which makes lots of plaques and also shows neuronal loss (Oakley et al., 2006).

Prasad
Malu, does Bob Vassar's model show elevated TNFα in brain region...similar to the LaFerla model?

Malu Tansey
Prasad, I'm not certain but I'm willing to bet it does.... Most of them do if there is a microglial component.

Prasad
Malu, I will follow up on Vassar's model. I enjoyed this session and learnt a lot. Regards. Catch up later. Thanks.

Gregory Brewer
Tsuneya, our paper in press with Exp. Neurology with Jigisha Patel shows that NFκB translocation is even higher in old neurons than middle-age after stimulation with Aβ + TNF (dose-dependent on TNF).

Peter Jones
Here’s Tobinick’s Medscape abstract. Perispinal Etanercept Produces Rapid Improvement in Primary Progressive Aphasia: Identification of a Novel, Rapidly Reversible TNF-Mediated Pathophysiologic. Primary progressive aphasia (PPA) is an uncommon form of progressive dementia for which there exists no established treatment. The underlying pathology may be that of either frontotemporal dementia or Alzheimer's disease. Increasing evidence suggests that excess tumor necrosis factor (TNF) may play a central role in Alzheimer's disease. Additionally, excess TNF has been documented in patients with frontotemporal dementia. Excess TNF may therefore represent a therapeutic target in PPA. Etanercept, an anti-TNF fusion protein, binds to TNF, thereby reducing its biologic effect. Emerging evidence suggests that perispinal administration of etanercept may have therapeutic efficacy for Alzheimer's disease. This evidence, in combination, supports a rationale for the use of perispinal etanercept for the treatment of PPA. This report documents rapid improvement in verbal abilities, beginning within 20 minutes of perispinal etanercept, in a patient with severe PPA. With repeated weekly dosing, sustained improvement at 1 month is documented, with a more than 10-point improvement in the patient's abilities to perform activities of daily living as measured by a standardized instrument, the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory. Rapid clinical improvement in PPA following perispinal etanercept administration may be related to TNF's role as a gliotransmitter and modulator of synaptic communication in the brain. These results may provide insight into the basic pathophysiologic mechanisms underlying PPA and related forms of dementia and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in both PPA and Alzheimer's disease. Further study of this therapeutic method is indicated. Introduction Primary progressive aphasia (PPA) is an uncommon form of progressive dementia without established treatment. One third of these patients have underlying Alzheimer's disease pathology, and two thirds have pathology characteristic of frontotemporal dementia.[1] These patients characteristically present with progressive difficulty with language as the most prominent initial manifestation of the disease, which advances in an unrelenting fashion until all language abilities are lost.[2] No effective treatment has been established.[1,2] Basic science and genetic, epidemiologic, and clinical evidence suggest that excess tumor necrosis factor-α (TNF-α) may play a central role in the pathogenesis of Alzheimer's disease [3-23]. In addition, excess TNF has been documented in the cerebrospinal fluid of patients with frontotemporal dementia.[24] Excess TNF may, therefore, represent a therapeutic target in PPA. Etanercept, a recombinant dimeric anti-TNF fusion protein, binds to TNF and blocks its interaction with cell-surface TNF receptors, thereby reducing the biologic effect of excess TNF. Emerging evidence suggests that perispinal administration of etanercept may have therapeutic efficacy in Alzheimer's disease [25-29]. This evidence, in combination, supports a rationale for the use of perispinal etanercept for the treatment of PPA.

Felicia McColl
Thanks, Peter. The publication was to give researchers a clue, and to let you know what is happening, so that someone with the $$$ will do a clinical trial.

Tsuneya Ikezu
Dr. Tansey, normally a DN molecule has to be in excess amount against wt TNF to block homodimerization. How much molecular ratio (in other words, how much DN-TNF) is necessary for the inhibitory effect?

David Szymkowski
Tsuneya, good question. DN works (as the name implies) by a dominant-negative mechanism. It's a mass action exchange effect. In other words, equimolar or slight excess DN-TNF eliminates the majority of native soluble TNF. The Science (Steed et al., 2003) and J. Immunology (Zalevsky et al., 2007) papers give the details.

Malu Tansey
Tsuneya, the stoichiometry tells us that a twofold excess should work, but you can drive it with larger amounts. The 2003 Science paper demonstrates this in detail.

Tsuneya Ikezu
Thank you, Malu. I have to leave for another appointment. Thank you for inviting me to the discussion panel.

Yong Shen
Malu, are there any similar/different effects of TNFα on different types of neurons? For example, dopamine neurons versus cortical neurons?

Malu Tansey
Yong, there is definitely a difference in sensitivity of DA neurons versus cortical. DA neurons are much more sensitive, but if you couple it with Aβ you can really affect them adversely, consistent with your data....

Bill Watson
Malu, what results have implicated the gliotransmitter role of TNFα in AD?

Malu Tansey
Bill W., your question about what data implicate TNF as a gliotransmitter in AD: I would say some of the LTP data in brain slices and clinically, the Tobinick data, but it's not clear how the etanercept is getting to the sites in the brain....

Gregory Brewer
Bill, we show neuroprotective effects of low-dose TNF for middle-age neurons against Aβ toxicity (Patel and Brewer, 2008).

Bill Watson
Gregory, in vivo?

Gregory Brewer
Yes, in culture...but old neurons are killed by doses that are protective in middle-age neurons, and it is TNF receptor dependent.

Gabrielle Strobel
Yong, in your talk you made a case for a number of potential targets besides TNFα —FADD, TRADD, NFκB, Apaf-1? Do you know if there is any drug discovery around those?

Yong Shen
Gabrielle, yes. For example, several companies are working on NFκB as a target, but there are several side effects on toxicity.

Boobalan Pachaiyappan
I've a general question for either Dr. Yong Shen or Dr. Malu. I have a feeling that TNFα1 inhibitors can make a huge impact on late-AD patients and BACE1 inhibitor on early-AD patients. How do you see this? Also, can one envision the synergistic effect by combining these inhibitors?

Yong Shen
Boobalan, we need a chemist to create the idea of a combination of a BACE inhibitor and a TNFα inhibitor.

Boobalan Pachaiyappan
Dr. Shen, in theory, if a combination inhibitor can be made, how do you envision the outcome?

Yong Shen
Boobalan, Aβ may be decreased and TNFα-induced inflammation may be diminished.

Prasad
Malu/Yong, has anyone looked at the effects of TNFα inhibition on α- or β-secretase activity in vivo?

Malu Tansey
Boobalan, I like your idea, too, but again, we must be very cautious not to affect TNF signaling in areas of the brain where it is protective against neurotoxicity or excitotoxicity. Lindvall's work with TNF antibodies after stroke in rat models says that TNF is important for hippocampal neuroblast survival. So my feeling is that targeted delivery may be in order and regulated delivery even better...but we gotta start somewhere.

Gregory Brewer
Malu, our 2001 paper with John Viel showed that microglia from old rat brains made much more TNF in response to Aβ than microglia from young brains (Viel et al., 2001).

Malu Tansey
Greg, that is very interesting and consistent with some of the data emerging from our lab that the microglia may become dysfunctional as one ages.... We should not be neuron-centric but also consider that the neighborhood matters (as Don Cleveland likes to say!).

Gregory Brewer
Malu, I agree. We need a TNF modulator, not a blocker. A little inflammation is part of the protective stress response. We need something like Namenda that only acts when there is excess TNF.

Peter Jones
Is it appropriate to use etanercept on AD patients, as it does not cross the BBB yet lowers the immune system?

Yong Shen
Peter, the concern I have is the way etanercept is given; it may cause injury to patients, especially with continuous use.

Gregory Brewer
Peter, our conclusion in our J. Neurosci. Res. paper urges caution with etanercept because of blocking the remaining protective effect of TNFα.

Peter Jones
Do you have an opinion on CSVS as a way past the BBB? Here is another quote from Tobinick: “The cerebrospinal venous system (CSVS), a term coined by me, plays a central role in the vascular circulation of the brain, the spinal cord, and the nerve roots. Detailed knowledge of the CSVS is therefore of consequence when considering therapeutic intervention for diseases involving these structures. The seminal work regarding the anatomy and physiology of the CSVS was done by Oscar Batson, a pioneering professor at the University of Pennsylvania, in the 1940s. Although ‘Batson's Plexus’ has achieved widespread recognition, much of his highly important work never achieved the scientific dissemination it deserved. Perhaps the use of highly potent and selective biologic therapeutics capable of transport via the CSVS (as described in my pending patent applications) will help illuminate the brilliance of Dr. Batson's early discoveries.” From: The Cerebrospinal Venous System: Anatomy, Physiology, and Clinical Implications. By Edward Tobinick. Source MedGenMed 2006; 8(1):53. Abstract: There is substantial anatomical and functional continuity between the veins, venous sinuses, and venous plexuses of the brain and the spine. The term "cerebrospinal venous system" (CSVS) is proposed to emphasize this continuity, which is further enhanced by the general lack of venous valves in this network. The first of the two main divisions of this system, the intracranial veins, includes the cortical veins, the dural sinuses, the cavernous sinuses, and the ophthalmic veins. The second main division, the vertebral venous system (VVS), includes the vertebral venous plexuses which course along the entire length of the spine. The intracranial veins richly anastomose with the VVS in the suboccipital region. Caudally, the CSVS freely communicates with the sacral and pelvic veins and the prostatic venous plexus. The CSVS constitutes a unique, large-capacity, valveless venous network in which flow is bidirectional. The CSVS plays important roles in the regulation of intracranial pressure with changes in posture, and in venous outflow from the brain. In addition, the CSVS provides a direct vascular route for the spread of tumor, infection, or emboli among its different components in either direction.

Malu Tansey
Peter, I wouldn't be surprised if etanercept is getting in because the BBB is probably leaky in AD patients (and in other neurodegenerative diseases like PD and others with chronic neuroinflammation)...but it would be nice to show this by labeling it.

Peter Jones
Does any scientist here support Dr. Tobinick?

Malu Tansey
Peter, I think the finding, if true, would be incredibly interesting. It needs to be confirmed because it has potential. If one is worried about the immune system, some of the solTNF selective inhibitors should be tried. He should contact Xencor if he is interested in more selective and hence possibly safer drugs. To understand the mechanism, perhaps we need to do more studies in animal models.

Gabrielle Strobel
Malu, is the data available now sufficient to recommend follow-up with a controlled, blinded human trial at this point?

Malu Tansey
Gabrielle, I'm not a neurologist nor a clinician so I can't advise but I'd like to see one done. More importantly, we could do the animal experiments to better understand the mechanism. We're considering it but as Rob mentioned, $$$ would be needed.

Gabrielle Strobel
The Alzforum received a comment to this discussion pointing out a recent paper that reports acute psychosis in three people receiving etanercept for RA (comment on Live Discussion page). To the scientists/clinicians here, is this a surprise? Or have psychiatric side effects been known before for the existing antiTNF biologics?

Yong Shen
Gabrielle, this is not a surprise because TNFα does involve some schizophrenia-type syndrome.

Cynthia Lemere
Yong and Malu, is TNF upregulated during sprouting and regeneration?

Yong Shen
Cynthia, that’s a good question. I have not seen the data yet, but I assume, during the regeneration, there might also have to be an inflammation response, so I wouldn't be surprised if TNFα is changed.

Malu Tansey
Cindy, do you mean centrally or peripherally (regeneration)?

Cynthia Lemere
Malu, I'm thinking more of sprouting. One can see sprouting of neurons following bungarotoxin treatment in goldfish optic tectum in brain, for example. I think some APP tg mice have been shown to have sprouting as well. May be a last-ditch effort by the neuron to survive.

Malu Tansey
Cindy, your question is a very good one on sprouting and regeneration. I'm not aware that anyone has looked directly, but in terms of hippocampal sprouting, it will be a good thing to have around (Olle Lindvall’s data).

Gabrielle Strobel
Cindy, has not Carl Cotman published fairly extensively about sprouting, as well? This is an old literature, but I think it's generally thought to happen in AD brain like you say, no?

Cynthia Lemere
Yes, I believe so. It would be interesting to know if these TNF inhibitors have any effect on sprouting in vivo.

Malu Tansey
Cindy, if you or anyone else is interesting in looking, we may be able to provide some reagents.

Yong Shen
Greg, the TNFα you used to treat neurons—is this soluble TNFα?

Gregory Brewer
Yong, yes—10-1000 ng/ml soluble TNFα. You all might be interested in our findings in cultured neurons, young and old, with and without anti-TNFR1 or R2 antibodies: the best correlation for neuron survival was not the nuclear NFκB, but the cytoplasmic ratio of its downstream action on Bcl-2/Bax ratio.

Malu Tansey
Greg, I'm not surprised, as TNF signaling to apoptotic pathways may be stronger than the opposing NFκB counterarm depending on strength of activation and duration of R1 versus R2 during any given stimulus, plus the signaling proteins intracellularly that modulate those responses.

Prasad
Malu, has anyone looked at the effects of TNFα inhibition on α- or β-secretase activity in vivo?

Malu Tansey
Prasad, in our paper coming out soon (we hope), we looked at inhibition of solTNF with lenti-DN-TNF. We did not see significant effects on BACE mRNA or protein, but a negative result is difficult to interpret when you're grinding up brains...limit of detectability is poor.

Peter Jones
I am stating here, after much research I challenge Dr. Tobinick in his claims with the use of etanercept for Alzheimer’s and all the other diseases he has claimed in the past. The entire works are fiction. The AD caregiver community is vulnerable to this because of the dearth of therapies in AD. There may be some truth to inflammation as a causation in the pathology in AD, but to come out with this magic potion. It is time that the AD research community regrouped. Dr. Tobinick is a dermatologist. Any person from neuroscience willing to challenge Dr. Tobinick?

Fran Shaller
Peter Jones, have you met with Dr. Tobinick or have you witnessed the post-injection reaction of any of his patients?

Cynthia Lemere
Peter, scientists and clinicians have an obligation to perform rigorous, scientifically sound clinical trials before announcing to the world that they have found the types of effects Dr. Tobinick described. Even preclinical trials must be rigorous and scientifically sound. Until this is done, the results may mislead patients and their families into believing in something that has not been validated and may put them at risk.

Peter Jones
I am sorry to intrude in your discussion, but Dr. Tobinick has entered into your domain and is messing with your research and AD patients.

Gabrielle Strobel
Peter, to reply to your call on scientists to refute Dr. Tobinick. Very few in the AD scientific community have embraced Dr. Tobinick's methods or claims, or his successive tapping of one disease market after another, now apparently moving on to some tauopathies where the treatment situation is even more dire than in AD. But there is genuine and broad-based interest in the concept of developing drugs against TNFα—doing so in the right way. No one likes to publicly attack a person, but I think you will see, are already seeing, research effort going in the direction of rigorously studied TNFα drugs that are approvable.

Malu Tansey
Peter J., discoveries about mechanism and potential for therapeutic intervention will have to take place by doing the necessary preclinical studies, so we should focus on taking his observations and rigorously testing the hypothesis with mechanistic studies.

Cynthia Lemere
Malu, I completely agree.

Peter Jones
Dr. Tobinick should be discounted completely; he is delaying the advances in this area. He has nothing to offer.

Fran Shaller
If he has "nothing to offer," then my eyes are lying to me.

Gabrielle Strobel
Let's move on. Does anyone have further questions or ideas regarding Yong's and Malu's research?

Peter Jones
I apologise for my interference. Please, scientists, Google Tobinick and see what comes up. You will all advance with real science.

Cynthia Lemere
Sorry, I have to go now. Thanks everyone!

Gabrielle Strobel
Bye, Cindy; thanks for coming!

Yong Shen
Bye, Cynthia; thanks for participating.

Malu Tansey
Cindy, talk later! To members of industry, educate me: what would it take in terms of preclinical evidence to have your company move forward with an approved biologic for a CNS application?

Gabrielle Strobel
Hi Steve, are you still there? Perhaps you could take Malu's question?

Malu Tansey
Gabrielle, the reason I ask is because I'm curious whether they would have to unequivocally know the mechanism of action (gliotransmitter versus pro-inflammatory cytokine driving neurotoxicity) before moving forward? If so, we and others need to do much more work, and we should get going.

Gabrielle Strobel
Our scheduled time has passed, but all who are still interested are most welcome to stay and chat. The room will stay open. But before people start dropping out, I'd like to invite Yong and Malu to make a wish: which study/trial would you like to see done next if funding was no issue? What would be most informative next? That can be your concluding statement.

Yong Shen
We would like to try clinical studies by using a protein-based and small-molecule-based TNFα inhibitor and see whether cognition in AD patients improves. We would also like to test approved drugs in MCI patients to see if we can slow the conversion from MCI to AD.

Malu Tansey
Gabrielle, if you mean preclinical study, I'd like to see clear-cut effects of centrally or peripherally administered TNF inhibitors (solTNF selective versus non-selective) in rodent models where neuropathology can be examined histologically and behavior outcomes can be measured objectively. In patients, we may need to do much more work and perhaps use the solTNF selective inhibitors in MS as proof of concept that we can modulate the course of an inflammatory condition without affecting immunity or synaptic plasticity (cognition).

Gabrielle Strobel
Malu, it’s unfortunate, though no surprise, that the industry scientists cannot speak here. But that so many came, from at least five companies, suggests that they are actively interested.

Malu Tansey
Gabrielle, absolutely, no problem. I understand and appreciate their interest and their hard work in this area. For all these neurodegenerative diseases with chronic inflammation, I'd like to see early diagnosis so we can run neuroprotective trials!

Gabrielle Strobel
Amen to early diagnosis! Go biomarkers! We'll host a Webinar/town hall meeting on early diagnosis next month. Yong, by approved, do you mean etanercept, infliximab etc.?

Yong Shen
Gabrielle, yes, or experimental BACE inhibitor. We just need to figure out how to give it to the patient. Realistically, small molecules may be easier to get approval for.

Malu Tansey
Yong, my concern with small molecules is that they are going to go everywhere in the brain and would be expected to inhibit TNF signaling where it may have protective roles…like hippocampus.

Yong Shen
Malu, it’s true, but we want to see in the disease state which one has the more important role. Maybe at a young stage a BACE inhibitor is not appropriate but at an older age is sensible.

Gabrielle Strobel
Malu, as a practical matter, how would you target a biologic to a subarea of the brain?

Malu Tansey
It may be possible to do targeted delivery via minipump or via gene transfer of DN-TNF.... Then all you have to do is get through the regulatory hurdles of viral vectors :-).

Fran Shaller
Malu, if AD starts in the hippocampus, is it possible that the TNF signaling is malfunctioning at that level?

Malu Tansey
Fran, it is possible that TNF signaling in the brain antagonizes trophic factor pathways (insulin-like growth factor-1, or IGF-1, perhaps) that get the brain into an energy crisis. Some have suggested that AD is type 3 diabetes. As you know, TNF is involved in the insulin resistance in diabetes. This is speculative but worth looking into.... To those doing AD research, I'm curious to know whether anyone is looking at the effects of TNF signaling on GLUT transporters in cortical neurons? Yong?

Yong Shen
Malu, yes.

Malu Tansey
Yong, good, because I have a feeling that TNF is playing very different roles at various stages in the neuronal dysfunction and pathology, which may be very different. Synaptic, APP processing, and glucose utilization effects may precede all the late events that involve plaque deposition where TNF may be playing other roles in regulation of microglia activation, etc. And, of course, TNF may be required if one is to do immunotherapy, as many have shown that microglia must step up to the plate to remove plaque.... It is very complex!

Yong Shen
Malu, indeed. Let's continue to keep in touch and we will chat more about this later.

Gabrielle Strobel
I have to leave, but that does not mean you do. Yong and Malu, thank you both tremendously for your texts, presentations, and the significant preparation going into today. Thank you, audience, for your interest. The Alzforum will stay on this topic.

Malu Tansey
Yong, sounds like a great idea. Will do. Unless others have additional questions for us, we should also get back to pushing back the frontiers of science or at least get back to work.... To all, if anyone has questions, please feel free to e-mail us: malu.tansey@utsouthwestern.edu.

Yong Shen
I also welcome questions: yong.shen@sunhealth.org.