Field Loses GSM Developer Steven Wagner, 64
Quick Links
The Alzheimer’s research community has lost another notable member with the March 12 passing of Steven Wagner of the University of California, San Diego. Wagner, 64, died of heart failure after battling the condition for four months. He pioneered research on γ-secretase modulators (GSMs), coining the term. His latest iteration, GSM 776890, is set to enter AD Phase 1 trials this year.
Steven Wagner.
“He dedicated his career to developing GSMs for AD, and I am so glad he succeeded in achieving his goal of testing them in humans,” Robert Rissman at UCSD told Alzforum (full comment below).
Wagner was a biochemist by training, earning his doctoral degree at the University of Louisville, Kentucky, in 1985. He did his postdoctoral work at the University of California, Irvine, where he was part of a team that identified and purified amyloid precursor protein (Van Nostrand et al., 1989). He went on to lead the protein biochemistry program at Salk Institute Biotechnology/Industrial Associates (SIBIA) Neurosciences, San Diego, from 1991 to 1999. There he helped develop the first γ-secretase inhibitor to enter AD clinical trials (Anderson et al., 2005). These drugs were later abandoned when they worsened cognition, perhaps due to their effects on other substrates such as the signaling molecule Notch (e.g., Aug 2010 news).
In 2000, Wagner co-founded the biotech company TorreyPines Therapeutics along with Rudolph Tanzi at Massachusetts General Hospital, Boston. Wagner turned his attention to modifying, rather than inhibiting, the way γ-secretase cut APP, nudging cleavage to favor non-amyloidogenic products. He developed Notch-sparing GSMs, such as GSM-4 (Sep 2010 news). After TorreyPines shut down in 2009, Wagner moved to UCSD, where he tinkered with the structure of these GSMs, making them more water-soluble, specific, and potent (Rynearson et al., 2021). A publicly funded trial of GSM 776890 will be run by MGH and UCSD; it is expected to start enrolling this summer.
Friends and Colleagues. From left, Sam Sisodia, Rudy Tanzi, Steve Wagner, David Holtzman, Goujun Bu, Bob Vassar, and Yueming Li celebrated Wagner's 60th birthday in Chicago four years ago. [Both pictures courtesy of Rudy Tanzi.]
Friends remembered Wagner, nicknamed Wags or Waggie, for his good humor, his love of tennis and the ocean, which drew him from Kentucky to the California coast. Gopal Thinakaran at the University of South Florida, Tampa, recalls that Wagner was unfailingly generous with his time and resources. “Everyone who met Steve will remember his kindness, unassuming personality, enthusiasm, and infectious laugh,” Thinakaran wrote (full comment below).
If you knew and miss Steve Wagner, use the comment field below to share a memory or a picture to help Alzforum pay tribute to his life and legacy.—Madolyn Bowman Rogers
References
News Citations
- Lilly Halts IDENTITY Trials as Patients Worsen on Secretase Inhibitor
- New γ-Secretase Modulators Reduce Aβ42, Avoid Notch
Paper Citations
- Van Nostrand WE, Wagner SL, Suzuki M, Choi BH, Farrow JS, Geddes JW, Cotman CW, Cunningham DD. Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Nature. 1989 Oct 12;341(6242):546-9. PubMed.
- Anderson JJ, Holtz G, Baskin PP, Turner M, Rowe B, Wang B, Kounnas MZ, Lamb BT, Barten D, Felsenstein K, McDonald I, Srinivasan K, Munoz B, Wagner SL. Reductions in beta-amyloid concentrations in vivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897. Biochem Pharmacol. 2005 Feb 15;69(4):689-98. PubMed.
- Rynearson KD, Ponnusamy M, Prikhodko O, Xie Y, Zhang C, Nguyen P, Hug B, Sawa M, Becker A, Spencer B, Florio J, Mante M, Salehi B, Arias C, Galasko D, Head BP, Johnson G, Lin JH, Duddy SK, Rissman RA, Mobley WC, Thinakaran G, Tanzi RE, Wagner SL. Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention. J Exp Med. 2021 Apr 5;218(4) PubMed.
External Citations
Further Reading
Annotate
To make an annotation you must Login or Register.
Comments
University of Southern California
I will greatly miss Steve. I rarely called him Steve; most of the time I referred to him as Wags, Waggie, or Wags the Dog. He was a fantastic colleague, friend and mentor.
When he originally came to UCSD in 2009, he shared lab space with me while his space was being outfitted. We continued to work closely together thereafter. As time passed, we worked closely together on his GSM projects and the majority of the disease model testing was done together by our shared graduate student, Dr. Olga Prikhodko.
Steve dedicated his career to developing GSMs for AD, and I am so glad he succeeded in achieving his goal of testing them in humans. While it's unfortunate that he won't be able to lead the actual human studies, he passed knowing that the project (MODIFY-AD) was launching. Fairwell, Wags, thanks for all the good times! I'll miss you, buddy.
USF Morsani College of Medicine
Steve was my collaborator and a kind colleague. Everyone who met Steve will remember his kindness, unassuming personality, enthusiasm, and infectious laugh.
Even though we moved in different orbits of AD research, medicinal chemistry, and drug discovery versus cell biology and molecular pathology, Steve was genuinely excited and committed to helping us in our research. Many years ago, measuring Aβ 40 and 42 peptides was a technique accessible to only select labs. Steve generously offered to support our research by Aβ measurements in cultured cells and brain tissue. He did so for many years, generating key data that went into several publications. Whenever I asked Steve for help, be it another aliquot of his Aβ antibody or a letter of reference for a fellow, his response was, “Anything for you, brother.” I’ll miss Waggie.
K.U.Leuven and V.I.B.
I am saddened to hear that Dr. Steve Wagner passed away. I never had the pleasure of meeting him in person, but I find his work on γ-secretase modulators inspiring. My deepest condolences to his family.
TrueBinding
This is really sad news. Steve was a great person. His research on γ-secretase modulators (GSMs) is impressive. During the time at UCSD, I used to have great discussions with him regarding the AD therapies going on. His passing is a big loss in the AD field, my deepest condolences to his family.
Ludwig-Maximilians-University Munich and German Center for Neurodegenerative Diseases, Munich
Steve Wagner was a pioneer in the development of γ-secretase modulator (GSM) compounds and a leading researcher in this field. The concept of modulating γ-secretase activity to lower Aβ42 levels, to which Steve's work contributed so much, was boosted very recently, at the beginning of this year, when it became clear that CSF Aβ38 levels are associated with lower risk of AD-related changes. Also, that Aβ37 and 38 were found to inhibit aggregation of Aβ42 further clarified our understanding that GSMs have a welcome additional beneficial effect by increasing short Aβ37/38 species.
Steve was among the first to describe compounds with such an Aβ37/38-increasing/Aβ42-lowering profile and had since developed advanced GSMs with properties that justify testing them in the clinic. Not too long ago, initiated by Sam Sisodia on our annual Eibsee meeting, I got in touch with Steve by phone to explore possibilities for collaboration, and he immediately agreed to share one of his compounds for use in our GSM studies, one of which we were just preparing when the sad news of his untimely passing arrived.
It is my greatest hope that Steve's important contributions to AD drug development will pay off, and that one day we will see GSMs as effective and safe therapeutics to prevent, beneficially modify, or even cure AD.
UK Dementia Research Institute@UCL and VIB@KuLeuven
I am very sad to lose a good colleague and ally in the fight against Alzheimer’s disease. Steve Wagner was the leader in the search for γ-secretase modulators for the treatment of Alzheimer’s, and he generated with his company some very interesting compounds that showed promising results. We are going to build further on his work.
Massachusetts General Hospital
Steve Wagner was one of my very best friends and closest collaborators for the past 35 years. I remember first meeting Steve in Maratea, Italy, and then 10 years later, that beautiful sunny day in 1998 when we were walking along Nantasket beach, just south of Boston, and first conceived of the idea that since most early onset familial AD mutations in APP and the presenilin genes increase the ratio of Aβ42:Aβ40, we should screen for compounds that reverse that ratio to correct the pathogenic molecular phenotype. The idea was that by screening for small molecules that allosterically modulate γ-secretase to reverse the Aβ42:Aβ40 ratio, we might be able to help treat or prevent all cases of Alzheimers disease.
To this end, we co-founded Neurogenetics, Inc. (DBA Torrey Pines Therapeutics), and together with Maria Kounnas and Soan Kim, performed a high-throughput screen and discovered the first non-NSAID γ-secretase modulator (GSM), a term first coined by Steve Wagner in a meeting in La Jolla with Eddie Koo, who had found the first NSAID GSM, ibuprofen, with Todd Golde. Later, as the the first clinical NSAID GSM, flurizan, failed to lower Aβ due to low potency and poor brain permeability, we developed the first non-NSAID GSM—GSM#4 (described in Kounnas et al., 2010).
Soon after Torrey Pines Therapeutics dissolved in 2010, Steve and I initiated an academic collaboration between MGH and UCSD to continue development of this new class of non-NSAID GSM. We worked with Soan Kim to design six new GSMs with improved aqueous solubility than our original GSMs. As these new GSMs showed equal or better potency to our original GSM, we used the preliminary data for these compounds, generated at MGH (under an NIA program grant) and at at Steve’s new lab at UCSD, to obtain an NIH neurotherapeutics blueprint grant and further developed this new class of GSM. Collaborators included Bill Mobley and Robert Rissman at UCSD and Can (Martin) Zhang in my lab at MGH.
With funding from the NIH and Cure Alzheimers Fund, we developed this new class of GSM through several generations until we found a powerful allosteric modulator GSM that opens the docking site of γ-secretase to preferably favor the production of Aβ40 and 38 over the more amyloidogenic Aβ42. We then recruited Kevin Rynearson (UCSD) to help develop our final lead clinical candidate, GSM 776890, guided by an excellent lead development team (LDT) that was provided by the NIH Neurotherapeutics Blueprint program.
Over the past year, we worked closely with the Larry Refolo and Laurie Ryan at the NIA, the Cure Alzheimers Fund, and the LDT, to progress our lead clinical candidate into planned NIH-funded Phase 1 clinical trials (MODIFY trial) at UCSD, with Howard Feldman, Doug Galasko, and the ADCS and MGH. We hope to have our single-ascending and multiple-ascending-dose Phase 1 clinical trials of GSM776890 initiating this summer.
It is heartbreaking that Steve will not be here to see these clinical trials be initiated. Steve is the true father of GSMs. His entire career was passionately dedicated to getting us to this moment. All of us who have partnered with Steve, from our labs at MGH and UCSD, to the Blueprint LDT to the ADCS, will be diligently working to progress this lead GSM through clinical development. Our goal is to see Steve’s dream come true with a GSM that will hopefully safely and efficaciously help prevent new cases of Alzheimer’s disease.
On a personal note, all who knew Steve knew that his brilliance was only surpassed by his kindness, generosity, and indomitable spirit. All of us who cherished him as a close friend, including Sam Sisodia, and all who have partnered with Steve over the past decades, will continue to help make his dream come true. Steve Wagner was a bright ray of light in the Alzheimer’s disease research world. May his light shine brightly on all who have loved working with him and may we someday see his noble and extraordinary life’s work come to fruition. Rest in peace, my friend. We will never forget you.
References:
Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E, Zhang X, Ahn K, Nguyen P, Comer D, Mao L, Yu C, Pleynet D, Digregorio PJ, Velicelebi G, Stauderman KA, Comer WT, Mobley WC, Li YM, Sisodia SS, Tanzi RE, Wagner SL. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron. 2010 Sep 9;67(5):769-80. PubMed.
University of Rhode Island
Steve and I were postdocs during the same time period in Dennis Cunningham's lab at UC Irvine. Back then, in the late 1980s, the AD field was exploding with the cloning of the APP gene. During this period, we purified and biochemically characterized the APP protein (known as protease nexin-2 back in the day).
I have many fond memories about the exciting science but also the very frequent laughs. Subsequently, Steve and I continued to work together as he moved over to the corporate side (SIBIA) and I remained in academia. Although our interests then diverged in the ADRD field, we remained in contact and would catch up at meetings. It is sad to lose someone so young. R.I.P.
Johns Hopkins University
It was through Steve Wagner that I assimilated a valuable concept. We were both working on γ-secretase inhibitors when our paths crossed at a poster I had up during the 2002 AAIC meeting in Stockholm, 20 years ago. He was at Bristol Myers-Squibb and I at AstraZeneca. My poster was on the enzymology of γ-secretase using a competitive active site inhibitor. We had a skilled chemistry team at AZ who could plow through the patent literature and come up with compounds we could use as benchmarks in our lead identification studies.
Turns out that we were using a BMS compound at the time which was the example on the poster. Steve walked up, read the poster, then looked at me, and in red-faced anger, veins visible in his neck, remarked, “How the ***** did you guys figure out our lead clinical compound?” I smiled and said, “Really? I didn’t know that. But now I know a lot more about our benchmark inhibitor.”
It was later that day that it came to me—a new philosophy that I’ve shared with colleagues in every position I’ve had over the past 20 years: “There’s no such thing as a true competitor in this business, just varying degrees of collaboration. Ultimately, we all learn from each other.”
Steve and I developed a subsequent friendship. I’m glad that I had the opportunity to share this memory and its impact with him, the last time we had dinner together at a Mexican restaurant when I was in San Diego in February 2018.
NuPharmAdvise LLC
From his role in Sibia and mine at Bristol-Myers Squibb, Steve and I led the discovery effort that resulted in the first γ-secretase inhibitor to enter clinical trials. From this early relationship, we became friends and a number of years later we again became collaborators on Steve's BPN γ-secretase modulator project, which eventually led to the current GSM clinical candidate.
Through all of these projects, Steve sustained and, at every opportunity, articulated an enduring belief in γ-secretase as a central target for Alzheimer's disease. Even when the going got tough, Steve's belief and enthusiasm never wavered. As a person he was thoughtful, kind, and generous with his time. I was shocked and deeply saddened to learn of his untimely passing.
ADvantage Neuroscience Consulting LLC
I am saddened to hear of Steve’s passing. He was one of the true pioneers in γ-secretase drug discovery.
With the close of the recent AD/PD meeting, I am reminded of the first AD/PD meeting I attended. It was in Sorrento and I was there to give an update on the Lilly γ-secretase inhibitor program. I was particularly excited about the session as Steve was going to talk immediately after on their γ-secretase modulators.
Making it more exciting, I flew over to Sorrento thinking it would be my collaborator on GSM’s speaking after me. Lilly was signing a deal to work on GSMs with Steve’s company as I was in flight. Imagine my surprise when just before the session Steve came over and sheepishly said that the deal fell through. These things happen all the time in industry, and we laughed about it at later meetings. Lilly eventually abandoned its GSM programs due to intractable toxicity with structures, but Steve and his colleagues persisted. I look forward to following the progression of this GSM in the clinic.
RIP Dr. Wagner.
Adjunct Professor of Pharmacology, Northwestern University
From his earliest published research on protease nexin-1 to his recent work on GSMs, Steve was a superb scientist and a prolific collaborator and contributor to the Alzheimer's field. More importantly, he was a kind and generous friend and colleague to so many of us.
Steve was very helpful and supportive back in1996 to 2003, the early years of Acumen. I tried to persuade big pharma that amyloid oligomers really were the likely AD trigger and an excellent drug target. Steve would tell me that some company would eventually partner with us. It took a while, but he was right.
Steve's untimely passing is very sad, but it brings back memories that I will long cherish.
Medical University of South Carolina
I am at loss for words to describe the loss of Steve Wagner, who did some great biochemistry with the identification of protease nexin I, identifying it as APP, and demonstrating the drop of Aβ in AD CSF. The field has lost a dedicated scientist. I hope that GSMs will prove to be efficacious and stay as his legacy.
University of Chicago
I have not met Dr. Wagner in person, but I had the pleasure to get involved in some of his research works on GSM, and I also received his generous support for my study by analyzing Aβ peptides in our samples. Thank you!
RIP, Dr. Wagner.
I am saddened by Steve's rather sudden passing. He has been a very good friend, colleague, and golf partner since I moved to UCSD more than 20 years ago. When he joined the faculty at UCSD some years later, he brought with him a unique set of skills that's uncommon in academia. He is one of the prime movers behind the R&D efforts on developing GSMs for AD therapeutics. His high energy, can-do attitude and genuine collegiality greatly benefited UCSD and surrounding institutions. UCSD and the AD community will sorely miss him.
University of Florida
I am saddened to hear of “Waggie's” passing. Steve and I shared roots in Louisville, Kentucky, though we did not meet until our interest in Alzheimer’s disease brought us together professionally in the mid-1990’s. Our shared passion for Kentucky basketball and horse racing forged an immediate connection. Steve had relentless energy and dedication toward finding effective drugs for AD, which will be sorely missed.
Indiana University School of Medicine
Indiana University School of Medicine
National Institute on Aging, National Institutes of Health
We were shocked and saddened to hear of the demise of Steve Wagner. As others have noted, Steve was a pillar of the AD research community and a pioneer of GSMs. We gratefully recall his significant contributions to our research years ago while we elucidated interactions between APP and tacrine (or Cognex), the initial FDA-approved drug for AD and known to inhibit the activity of the enzyme cholinesterase.
At that time, there were parallel hypotheses and lines of research focused on the amyloid and cholinergic pathways, which were largely separate and without recognition of a converging path. When we discovered the APP-reducing properties of tacrine, we needed to confirm such activity by measuring the secretion of other proteins that were not members of the APP superfamily, to evaluate whether the reduction of secreted APP (sAPP) was exclusive. We needed help, and Steve suggested secreted protease nexin 1 (PN1). His laboratory had developed a 125I-thrombin-PN-1-binding assay, which was not based on alike immune affinity techniques that we were using to detect levels of sAPP. We were thus able to establish that the apparent reduction of sAPP was not a general action of tacrine on all proteins or a non-specific Western blotting effect. Not only did Steve suggest the PN1 target, but also he also generously assisted by personally undertaking the assays in his laboratory. The data clearly demonstrated that tacrine significantly reduced APP but not PN1 levels (Lahiri et al., 1994). We could not have established this without Steve's contribution. His support gave us confidence.
Beyond tacrine, we investigated other cholinesterase inhibitors (ChEIs), both acetyl- and butyryl-, and discovered that select ChEIs could reduce APP, thus potentially reducing toxic Aβ peptides (Lahiri et al., 1998). We characterized the non-cholinergic mechanism of action via which this select group, which included phenserine (Shaw et al., 2001; Greig et al., 2005; Lahiri et al., 2007), could achieve, and then developed analogs that lacked ChEI activity (posiphen), and advanced these into clinical trials (Lahiri et al., 2007; Becker et al., 2018). Along the way, Steve's mind and creativity were often helpful to us. Over the last three decades, on encountering one another at conferences, we were continuously impressed by his intellect and warmth. Steve was a good and generous friend. Although our laboratories moved into other areas, Steve's early contributions and benevolence linger forever in our minds.
References:
Lahiri DK, Lewis S, Farlow MR. Tacrine alters the secretion of the beta-amyloid precursor protein in cell lines. J Neurosci Res. 1994 Apr 15;37(6):777-87. PubMed.
Lahiri DK, Farlow MR, Sambamurti K. The secretion of amyloid beta-peptides is inhibited in the tacrine-treated human neuroblastoma cells. Brain Res Mol Brain Res. 1998 Nov 20;62(2):131-40. PubMed.
Shaw KT, Utsuki T, Rogers J, Yu QS, Sambamurti K, Brossi A, Ge YW, Lahiri DK, Greig NH. Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7605-10. PubMed.
Greig NH, Utsuki T, Ingram DK, Wang Y, Pepeu G, Scali C, Yu QS, Mamczarz J, Holloway HW, Giordano T, Chen D, Furukawa K, Sambamurti K, Brossi A, Lahiri DK. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17213-8. PubMed.
Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki T, Giordano T, Sambamurti K, Greig NH. The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther. 2007 Jan;320(1):386-96. PubMed.
Becker RE, Greig NH, Lahiri DK, Bledsoe J, Majercik S, Ballard C, Aarsland D, Schneider LS, Flanagan D, Govindarajan R, Sano M, Ferrucci L, Kapogiannis D. (-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer's Disease. Curr Alzheimer Res. 2018 Jan 10; PubMed.
ADvantage
I first met Steve at the conference on "Serine proteases and their serpin inhibitors in the nervous system," held in Maratea, Italy, in 1989. At the meeting I also met, for the first time, Bill Van Nostrand and their postdoc mentor, Dennis Cunningham. Steve described protease nexin I, Bill spoke about protease nexin 2 (later that year to be reported as the APP with the KPI domain), and I spoke about α1-antichymotrypsin, a serpin and an acute-phase protein tightly bound to Aβ deposits in plaques.
Since then, I ran into Steve at numerous meetings throughout the years and always had nice conversations. He left us much too early, but his contributions to neuroscience and AD will last. Condolences to his family and friends.
University of California, San Diego
Steve Wagner, who passed away on March 12, 2022, after a sudden illness, is deeply mourned by friends and colleagues at UCSD, his academic home for the past decade, and by the many people whose lives he touched.
Steve trained in biochemistry and cell biology and did early research on APP, identifying critical aspects of the KPI form. He then worked in various pharmaceutical settings, most notably at SIBIA, where he led pioneering efforts for small-molecule discovery against Aβ pathways. After continuing these efforts under two other small companies, Steve moved to UCSD, where his set of skills and knowledge in drug discovery was invaluable and highly prized. At UCSD, Steve continued to pursue his research to develop γ-secretase modulators (GSMs), obtaining Blueprint funding from NIH, followed by additional sources such as the Cure Alzheimer’s Foundation.
With a combination of deep understanding and persistence, he developed a series of GSMs on a novel backbone, the most potent of which shows highly promising properties in cell and animal models and is soon to enter Phase 1 studies in humans. This is a remarkable achievement for a laboratory in an academic setting, and the incredibly detailed and rigorous background research gives us hope for developing a successful clinical program.
We remember Steve as an intense, passionate, and incredibly detail-oriented and meticulous scientist, who generously shared his time and expertise with many colleagues at UCSD. He cared deeply for technicians and junior colleagues, and even when criticizing an idea or grant proposal, almost always found something positive to say. Steve’s enthusiasm for life is well-remembered by colleagues and friends who recall dinners, golfing, and other events where his personality stood out. A memorial fund is being established in his name at UCSD.
Uppsala University
Uppsala University
We remember Steve’s way of sharing his home with us during our occasional visits to San Diego. Staying with him in his house in La Jolla left warm memories for life. We gratefully remember his significant contributions to our research when we published a paper together in Nature Medicine years ago, on decreased α-secretase-cleaved APP in members of the Swedish mutation family. We had planned a major follow-up on a large number of AD cases, which unfortunately never happened.
Steve had great skills and knowledge in drug discovery. His research aimed at developing γ-secretase modulators, a drug target we believe has great future promise for primary prevention of Alzheimer’s disease.
Steve’s excitement for science and his warm and friendly personality stood out, and we will always remember him.
Neurocrine Biosciences
I was one of the medicinal chemists who helped Steve's group discover the first non-NSAID, highly potent small-molecule GSMs at Neurogenetics/TorreyPines Therapeutics from 2002-2008. He was the type of leader who had an open-door policy and always made himself available for serious discussions or just a friendly chat. The first time I met him, his passion for his work was evident by the excitement in his voice when he talked about his research. I always left his office feeling empowered and motivated to carry out the work we had discussed. He took each advancement in our research as a huge victory no matter how small, and never cast a negative light on what we had achieved. I regret that I was not able to continue to work with Steve after the closing of TPTX, but I had great admiration for his belief in GSMs and his continued work to find new GSMs and push them to the clinic. His friendly personality and his love and passion for science made him one of a kind. He was a world-class scientist and a good friend. He is missed by so many.
Make a Comment
To make a comment you must login or register.