Institute for Neuroplasticity Research

𝐓𝐡𝐞 𝐀𝐋𝐒 𝐝𝐫𝐮𝐠 𝐠𝐫𝐚𝐯𝐞𝐲𝐚𝐫𝐝 𝐢𝐬 𝐜𝐫𝐨𝐰𝐝𝐞𝐝

The choroid plexus (ChP): hydrodynamic bottleneck and ground zero for Alzheimer’s

The choroid plexus (ChP): hydrodynamic bottleneck and ground zero for Alzheimer’s disease https://ejournals.uni-muenster.de/fnp/article/view/9368/9664 The Institute has advanced a Dual Sequestration Hypothesis (DSH) related to the protein signatures prevalent in Alzheimer’s disease. If the DSH is correct, the ChP should enlarge and become the sentinel hydrodynamic bottleneck as synthetic particles and their protein sequestrants accumulate. This […]

Accelerating the Orphan GPCR Pipeline: GPR149 as a Case Study in Dual-Domain Target Validation

https://doi.org/10.1016/j.drudis.2026.104678 Free download of the article using this link until June 16: https://authors.elsevier.com/a/1n0uP4r9Rkz1l6 Highlights New four-pillar framework accelerates deorphanization of dark GPCR targets. (77 chars) GPR149 structural analysis identifies non-canonical ERY and DPxxF motifs. (76 chars) Path-agnostic screening bypasses traditional Gi/o signaling limitations. (75 chars) Integrated CNS and metabolic mapping reveals GPR149′s dual-domain value. (76 chars) […]

In the 1950s, my physicist father met with Albert Einstein at the Institute for Advanced Study to discuss unified field theory.

In the 1950s, my physicist father, Eugene Guth, met with Albert Einstein at the Institute for Advanced Study to discuss unified field theory. Einstein, it turned out, was more interested in the philosophy of physics than the math, a topic equally of interest to my dad. See https://michaelguth.com/family/HistoryofPhysicsbyEugeneGuth.htm Mathematics and philosophy of physics have relevance […]

Authority, Long-term Reach, and “Save” Signals

New evidence provides a stronger link between chronic anxiety and future neurocognitive decline, demanding a re-evaluation of how we approach dementia prevention in clinical practice. A major updated meta-analysis, now available in the Journal of Clinical Medicine, confirms that anxiety is significantly associated with an increased risk of all-cause dementia. This extensive study, spanning nine […]

Google Scholar Publications Michael Anthony Stephen Guth

Posted by Michael A. S. Guth on August 9th, 2026

An Independent Review of Camrelizumab-Rivoceranib Combination Therapy for the Treatment of Hepatocellular Carcinoma and Rivoceranib for Gastric Cancer. Biomedical Journal of Sci & Tech Res, 58(2) (Aug 2024). https://biomedres.us/fulltexts/BJSTR.MS.ID.009118.php
Surgical Implantation of Autologous Dopamine Neuron Progenitor Cells (DANPCs) Into the Putamen of Patients with Parkinson’s Disease, Surgical Medicine Open Access Journal, (December 2024),
Compounded Tirzepatide Therapy for Weight Loss: A Health Economics & Outcomes Research (HEOR) Analysis. Int J Pharm Compd. 2025 Jan-Feb;29(1):52-63. PMID: 39921911. (January 2025).
Stem Cell Exhaustion as a Hallmark of Aging, invited article, Cell Research and Regenerative Medicine, 1(2), (April 2025).
Mitochondrial Dysfunction, a Hallmark of Aging: Mechanisms, Consequences, and Therapeutic Strategies, Cell Research and Regenerative Medicine, invited article, (April 2025).
Nicotinamide Riboside and NAD+ Decline: Hype vs. Evidence. invited article, Novel Techniques in Nutrition and Food Science 8 (4). (August 2025). http://dx.doi.org/10.31031/ntnf.2025.08.000692.
Accelerating the Orphan GPCR Pipeline: GPR149 as a Case Study in Dual-Domain Target Validation, invited article, Drug Discovery Today (a PubMed-indexed journal), 2026 May;31(3):104678. doi: 10.1016/j.drudis.2026.104678. Epub 2026 Apr 20. PMID: 42019879 April 2026.

Alzheimer’s disease in the Plasticeneera: a clinicopathological update on the dual sequestration of amyloid and tau as hijacked innate immune responses. Free Neuropathol. 2026 Jun 22;7:14. doi: 10.17879/freeneuropathology-2026-9368. PMID: 42344202; PMCID: PMC13288216. June 2026.

Implementing Pb-212-Targeted Alpha Therapy: A Safety-First Theranostic Framework for Clinical Practice, invited article Clinical Nuclear Medicine Open (a PubMed-indexed journal), Implementing 212 Pb-Targeted Alpha Therapy: A… : Clinical Nuclear Medicine Open, July 2026, slated to appear in the September 2026 issue.
The Amyloid Trap: How Financial Entrenchment, Shareholder Pressure, and Institutional Inertia Kept Alzheimer’s Drug Development Locked in Falsified Mechanisms, forthcoming Free Neuropathology (a PubMed-indexed journal), August 2026.
Targeting TDP-43 in ALS: Regulatory Hurdles, Trial Design Deficiencies, and the Causal Evidence Gap for CTX1000, invited article, forthcoming Drug Discovery Today (a PubMed-indexed journal), July 2026. https://authors.elsevier.com/a/1nYxN4r9Rkz1wZ

The Adjuvant Paradox: Immunogenic Cell Death, T-Cell Exhaustion, and the Limits of Somatostatin Receptor-Targeted α-Therapy in Neuroendocrine Tumors, in production by Hastings Case Report (a PubMed-indexed journal) June 2026.

“Some Uses and Limitations of Fuzzy Logic in Artificial Intelligence Algorithms for Reactor Control.” Nuclear Engineering and Design, 113 (1989) 99-109. (AI/ML foundational research in high-risk systems)

“A Probabilistic Foundation for Vagueness and Imprecision in Fault Tree Analysis.” IEEE Transactions on Reliability, 40:5 (December 1991) 563-571.

“Translating Higher-Order Decisions Into Flight Plans.” Journal of Operations Research, January 1994.

“Prosecution of Obscenity on Computer Networks.” Jurimetrics Journal 37:235 (1996).

“Clinical Incentives and Business Disincentives for Delayed Aging.” Clinical Business Excellence, December 2013.

“The Use of Clomiphene Citrate in Male Hormone Replacement Therapy.” Acta Medica International, 2015; 2(1):14-18. (First medical journal article on clomiphene as hormone replacement for men)

“Compounded Testosterone Troches to Optimize Health and the Testosterone Controversy.” International Journal of Pharmaceutical Compounding, 2015; 19(3):195-203. (First article in hormone replacement literature to mention testosterone troches)

“Compounding Pharmacies’ Potential to Create Graft Storage Solutions For Bypass Surgeries.” International Journal of Pharmaceutical Compounding, 2015; 19(5):373-379.

“Bioidentical Hormone Replacement Therapy for Men in the Primary Care Setting.” Quality in Primary Care, November 2016, 24(5):222-224.

“An Expert System for Curtailing Power,” West Virginia Journal of Law and Technology (March 1999), available on-line at www.wvjolt.wvu.edu.

“Prosecution of Obscenity on Computer Networks,” 37 Jurimetrics J. 235 (1996).

“A Decision Support System on the Debris Land Disposal Restrictions under the Resource Conservation and Recovery Act,” (with J. Crutcher), Waste Management, June 1996.

Book entitled Speculative Behavior and the Operation of Competitive Markets Under Uncertainty (Avebury, Ashgate Publishing Group, England, December 1994).

“Development of an Expert System: Translating Higher-Order Decisions Into Flight Plans,”

Journal of Operations Research, January 1994.

“Bang-Bang Production of Exhaustible Resources,” (with D. Reister), International Review of Economics and Business, 39:1 (January 1992) 5-20.

“A Probabilistic Foundation for Vagueness and Imprecision in Fault Tree Analysis,” IEEE Transactions on Reliability, 40:5 (December 1991) 563-571.

“A Reexamination of Arbitrage Pricing Theory (APT) under Common Knowledge Beliefs,” (with G. Philippatos), International Rev. of Economics and Business, 36:8 (August 1989) 729-746.

“Intrinsic Uncertainty and Common Knowledge Priors in Financial Economics,” Journal of Financial Research, 22:4 (Winter 1989) 269-283.

“Practical Considerations for Developing Maintenance on Instruments,” IEEE Transactions on Reliability, 38:2 (June 1989) 253-264.

“Profitable Destabilizing Speculation: A Review With Some Modern Uncertainty Theory Insights,” International Review of Economics and Business, 35:6 (June 1988) 523-538.

“An Expert System Design Incorporating Fuzzy Logic for Diagnosing Heat Imbalances in a Nuclear Power Plant,” in John Benoit and H. James Antonisse, Eds., Expert Systems in Government Symposium, (Washington, D.C.: IEEE Press, 1987). Reprinted in extended form under title “Some Uses and Limitations of Fuzzy Logic in Artificial Intelligence Algorithms for Reactor Control” in Nuclear Engineering and Design, 113 (1989) 99-109.

“Uncertainty Analysis of Rule-Based Expert Systems with Dempster-Shafer Mass Assignments,” International Journal of Intelligent Systems, 3 (June 1988) 123-139.

“Incorporating ‘Fuzzy’ Data and Logical Relations into the Design of Expert Systems for Nuclear Reactors,” in Artificial Intelligence and Other Innovative Computer Applications in the Nuclear Industry, Ed. Catherine Majumdar, (New York: Plenum Press, 1988).

“Functional Form in Finished Good Inventory Investment,” Journal of Money, Credit, and Banking, 19 (August 1987) 396-401.

“Solar Hydrogen Small User Market Penetration: Economic Potential and Barriers,” International Journal of Hydrogen Energy, 11 (1986) 1-19.

“United States Hydrogen Consumption Trends Through the Year 2000,” International Journal of Hydrogen Energy, 10:1 (1985) 1-10.

“Solar Thermal Technology Impact Assessment on Imported Petroleum,” Energy Systems and Policy, 8:1 (January 1984) 67-89.

MAGAZINE ARTICLES

“Weather Research for Trading Profits,” (with Gary Lackmann, Scott E. Kennedy, and K. Wyat Appel), The Risk Desk, May 2002.

“Research Agenda for 2002: Part III,” The Risk Desk, April 2002.

“Empirical Tests of May Spot Prices: A Special Trading Strategy Analysis,” The Desk (March 15, 2002).

“Research Agenda for 2002: Part II,” The Risk Desk, March 2002.

“Research Agenda for 2002: Part I,” The Risk Desk, Feb. 2002.

“Futures, Futures, and TVA,” The Desk (Feb. 22, 2002).

“Benefits of Accurately Determining Electricity Price Distributions: Better Risk Metrics, Beating the Market on Trades,” The Risk Desk, Jan. 2002.

“The Mythical Logic of Power Futures Markets,” The Risk Desk, Dec. 2001.

“Electricity Demand in the Digital Economy,” Energy and Power Risk Management, Nov. 2001.

“Availability Guarantees on Combined-Cycle Plants,” Power Engineering, March 2001.

“Blowing Hot and Cold,” Energy and Power Risk Management, April 2000.

“Anticipating Antitrust Concerns Nets M&A Success,” Electric, Light, and Power, October 1999; (article discusses the Federal Energy Regulatory Commission’s delivered price test).

“The Role of a Risk Manager,” Energy and Power Risk Management, March 1999; (article discusses the need for financial controls managers to be independent of the head of the trading floor).

“How to Evaluate Electricity Options: Avoid Relying on Black-Scholes,” Electric, Light, and Power, December 1998.

“Value-at-Risk (VAR) is Not Enough,” Energy and Power Risk Management, Nov. 1998; (article enumerates various problems with using VAR and other risk management practices).

“Game Theory, Game Practice,” Energy and Power Risk Management, Oct. 1998; (article discusses gaming behavior leading to speculative bubbles in electricity markets).

“Expert Systems for Non-Experts,” Energy and Power Risk Management, Sept. 1998; (article discusses an expert system to explain the legal consequences of curtailing power under various electricity sales contracts).

“Drive to Compete May Result in Unexpected Legal Implications,” Energy Marketing, July-Aug. 1998, pp.8-15. Article based on talk “Jurassic Spark: Business Torts, Crimes, and Dinosaurs in Competitive Electricity Markets.”

“Exercise By Numbers,” Risk, 5:2 (February 1992) 33-37.

“𝐈𝐟 𝐲𝐨𝐮 𝐚𝐫𝐞 𝐰𝐨𝐫𝐤𝐢𝐧𝐠 𝐨𝐧 𝐬𝐨𝐦𝐞𝐭𝐡𝐢𝐧𝐠 𝐭𝐡𝐚𝐭 𝐲𝐨𝐮 𝐫𝐞𝐚𝐥𝐥𝐲 𝐜𝐚𝐫𝐞 𝐚𝐛𝐨𝐮𝐭, 𝐲𝐨𝐮 𝐝𝐨𝐧’𝐭 𝐡𝐚𝐯𝐞 𝐭𝐨 𝐛𝐞 𝐩𝐮𝐬𝐡𝐞𝐝. 𝐓𝐡𝐞 𝐯𝐢𝐬𝐢𝐨𝐧 𝐩𝐮𝐥𝐥𝐬 𝐲𝐨𝐮.” —𝐒𝐭𝐞𝐯𝐞 𝐉𝐨𝐛𝐬

Posted by Michael A. S. Guth on August 6th, 2026

True momentum does not come from forced oversight, rigid deadlines, or endless motivation hacks. When a mission genuinely resonates with your core values and intellect, the dynamic shifts entirely from external pressure to internal gravity. The destination itself acts as an irresistible force, aligning your energy naturally toward the outcome.

In complex fields like health outcomes research, market access, and life sciences strategy, this distinction becomes glaringly obvious. Navigating the hurdles of value demonstration, HTA submissions, or generating robust real-world evidence demands immense perseverance. When teams are merely complying with a mandate, every milestone feels like an uphill battle against friction and fatigue.

Conversely, when everyone involved deeply understands the human and economic impact of closing evidence gaps, the day-to-day work transforms. Obstacles stop being roadblocks and turn into puzzles waiting to be solved. Curiosity replaces obligation, and cross-functional collaboration flows without the constant need for administrative orchestration.

Cultivating this kind of pull requires leaders to connect the dots clearly between high-level strategy and tangible patient outcomes. People need to see the real-world difference their models, analyses, and publications make in the lives of patients suffering from rare diseases, oncology challenges, or chronic conditions. Purpose must be visible and palpable in every project brief.

Ultimately, the most enduring breakthroughs in biotech and healthcare do not stem from grueling push-cycles. They happen when brilliant minds are anchored to a compelling vision that makes the next logical step feel inevitable. Build environments where the destination is so meaningful that people naturally run toward it.

Targeted Alpha Therapy as Cannonballs

Posted by Michael A. S. Guth on August 6th, 2026

The landscape of peptide receptor radionuclide therapy (PRRT) is shifting toward 212Pb, which has demonstrated ORRs in patients refractory to standard beta-emitters.1,2 First-in-human studies confirm the feasibility and tolerability of this approach, with disease stabilization observed even in heavily pretreated populations.3 The potent cytotoxicity of alpha particles results from dense ionization tracks, causing irreparable DNA damage.4,5

While effective against resistant clones, this mechanism increases the risk to the pituitary gland, which expresses the constitutively active somatostatin receptor subtype 2 (SSTR2). Long-term follow-up after beta-PRRT has established baseline rates of delayed hypopituitarism (≈8%) and therapy-related myeloid neoplasms (2%–3%).6,7 Transitioning to routine practice requires a structured protocol—one that translates radiobiological principles into a practical roadmap. The protocol must embed risk mitigation at every step of the clinical pathway—from patient selection to lifetime follow-up.

Recent advances in quantitative SPECT imaging and dosimetry for 203Pb/212Pb now make personalized treatment planning clinically feasible.8–10 As the radiotheranostic field evolves toward radiohybrid systems and antibody-mimetic proteins with enhanced specificity and faster clearance, 212Pb is positioned as a primary successor for patients who fail beta-emitting therapies.11 Comprehensive reviews of the radiotheranostic landscape confirm that this principle is now gaining recognition across the field.12

For these patients and others who are refractory to standard-of-care treatment, this article provides a practice-oriented roadmap that translates complex radiobiological principles into a visually guided, step-by-step operational plan that can be implemented immediately in the multidisciplinary radio-oncology medical center. This plan or framework is built on 4 actionable pillars—advanced biomarker selection, personalized dosimetry, prospective safety monitoring, and registry science—and culminates in a consolidated Clinical Decision Pathway (see Table 2, infra).
Our objective is to equip clinicians with the specific tools and protocols needed to harness the formidable power of targeted alpha therapy (TAT) while unequivocally prioritizing patient safety.

The fundamental biophysical mechanism that confers this agent’s high potency—alpha particle-induced DNA damage—is illustrated in Figure 1. Because an alpha particle is actually a helium nucleus (2 protons and 2 neutrons), it is much heavier than a lone proton, which is why it acts like a “cannonball,” causing that clustered, irreparable double-strand break, as illustratesd in Figure 1. High-resolution conceptual modeling illustrates the “bulkier” clustered damage characteristic of alpha radiation compared with the single-strand nicks typically associated with beta particles.

“𝐈𝐧𝐟𝐨𝐫𝐦𝐞𝐝 𝐜𝐨𝐧𝐬𝐞𝐧𝐭 𝐢𝐬 𝐧𝐨𝐭 𝐣𝐮𝐬𝐭 𝐭𝐡𝐞 𝐬𝐢𝐠𝐧𝐢𝐧𝐠 𝐨𝐟 𝐚 𝐟𝐨𝐫𝐦. 𝐈𝐧𝐟𝐨𝐫𝐦𝐞𝐝 𝐜𝐨𝐧𝐬𝐞𝐧𝐭 𝐢𝐬 𝐚𝐛𝐨𝐮𝐭 𝐚 𝐭𝐡𝐨𝐫𝐨𝐮𝐠𝐡 𝐩𝐫𝐨𝐜𝐞𝐬𝐬 𝐨𝐟 𝐜𝐨𝐦𝐦𝐮𝐧𝐢𝐜𝐚𝐭𝐢𝐨𝐧 𝐛𝐞𝐭𝐰𝐞𝐞𝐧 𝐩𝐚𝐭𝐢𝐞𝐧𝐭 𝐚𝐧𝐝 𝐩𝐫𝐨𝐯𝐢𝐝𝐞𝐫.”

Posted by Michael A. S. Guth on August 5th, 2026

“𝐈𝐧𝐟𝐨𝐫𝐦𝐞𝐝 𝐜𝐨𝐧𝐬𝐞𝐧𝐭 𝐢𝐬 𝐧𝐨𝐭 𝐣𝐮𝐬𝐭 𝐭𝐡𝐞 𝐬𝐢𝐠𝐧𝐢𝐧𝐠 𝐨𝐟 𝐚 𝐟𝐨𝐫𝐦. 𝐈𝐧𝐟𝐨𝐫𝐦𝐞𝐝 𝐜𝐨𝐧𝐬𝐞𝐧𝐭 𝐢𝐬 𝐚𝐛𝐨𝐮𝐭 𝐚 𝐭𝐡𝐨𝐫𝐨𝐮𝐠𝐡 𝐩𝐫𝐨𝐜𝐞𝐬𝐬 𝐨𝐟 𝐜𝐨𝐦𝐦𝐮𝐧𝐢𝐜𝐚𝐭𝐢𝐨𝐧 𝐛𝐞𝐭𝐰𝐞𝐞𝐧 𝐩𝐚𝐭𝐢𝐞𝐧𝐭 𝐚𝐧𝐝 𝐩𝐫𝐨𝐯𝐢𝐝𝐞𝐫.” —𝐃𝐫. 𝐀𝐚𝐫𝐨𝐧 𝐅𝐢𝐧𝐤 If a patient consents to a physician’s 3rd choice for treatment, rather than his first two preferences, does that consent operate as an instruction telling the physician to proceed with the consented treatment? Can a physician refuse a treatment, because it is not his first or second choice?

Yes, that consent operates as an instruction to proceed with that specific option, but only if the physician still considers it a medically appropriate choice. A physician can refuse to provide a treatment if they believe it falls below the standard of care, but they cannot refuse a treatment simply because it was not their personal first or second preference.

The Dynamics of Selecting a 3rd-Choice Treatment
The Scope of Instruction: When a physician presents three viable medical options, they are confirming that all three options fit within the boundaries of acceptable medical practice. By selecting the third choice, the patient is instructing the doctor: “Of the acceptable paths you offered, this is the only one I authorize you to perform.”

The Limit of the Instruction: The patient’s choice does not force the doctor to perform the procedure blindly. If the patient’s medical condition changes rapidly and makes the third choice dangerous or ineffective, the physician’s professional obligation requires them to halt and re-evaluate.

Why a Physician Cannot Refuse Simply Over “Preferences”
The Offered Options Rule: If a physician offers a treatment as a viable option, they have already validated it as a medically sound choice. Refusing to perform it simply because the patient didn’t pick Option 1 or Option 2 is a violation of the shared decision-making process.

The Threshold of Refusal: A physician can only legally and ethically refuse a treatment if it is medically futile, violates their professional judgment, falls outside their scope of competence, or if they have a profound moral/conscientious objection (which must be declared upfront, with the patient safely transferred to another provider).

Patient Autonomy Controls the Choice: In medicine, the physician’s role is to establish the boundary of what is medically safe and effective. Within that safe boundary, the patient’s values, lifestyle, and preferences dictate which option is chosen.

𝐓𝐡𝐞 𝐀𝐋𝐒 𝐝𝐫𝐮𝐠 𝐠𝐫𝐚𝐯𝐞𝐲𝐚𝐫𝐝 𝐢𝐬 𝐜𝐫𝐨𝐰𝐝𝐞𝐝

Posted by Michael A. S. Guth on August 5th, 2026

Since 1995, when the FDA approved riluzole for amyotrophic lateral sclerosis (ALS) – offering a median survival extension measured in weeks – more than 60 compounds have advanced to clinical evaluation, with the overwhelming majority failing to demonstrate efficacy.^(p1) It is worth distinguishing, within that graveyard, between uninformative ‘failed’ trials that lacked biomarkers and left little beyond a null clinical result, and ‘negative’ trials that incorporated biomarkers and therefore still yielded interpretable mechanistic information even without clinical benefit.

The most recent casualty is instructive. In September 2022, the FDA granted accelerated approval to AMX0035 (sodium phenylbutyrate-taurursodiol) after the Phase II CENTAUR trial demonstrated a 25% attenuation in ALS Functional Rating Scale-Revised (ALSFRS-R) decline.^(p2)^,^(p3) However, in March 2024, the blinded Phase III PHOENIX trial reported a primary end point p-value of 0.667 – indicating no difference from placebo (https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-topline-results-from-global-phase-3-phoenix-trial-of-amx0035-in-als) – prompting Amylyx Pharmaceuticals to voluntarily withdraw the product from the market (https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-formal-intention-to-remove-relyvrior/albriozatm-from-the-market-provides-updates-on-access-to-therapy-pipeline-corporate-restructuring-and-strategy).^(p4) CENTAUR/PHOENIX is a good example of the ‘negative but informative’ category: the blinded failure mechanistically clarified the fragility of open-label ALSFRS-R signals, even though it was a clinical disappointment.

The therapeutic arithmetic is unforgiving. Riluzole and edaravone offer only modest slowing of disease progression. Tofersen’s 2023 accelerated approval for SOD1-ALS represents a genuine precision medicine advance, but it applies to fewer than 2% of all ALS patients.^(p5) For the remaining 98% – the overwhelming majority with sporadic TAR DNA-binding protein 43 (TDP-43) proteinopathy – no approved therapy stops or reverses neurodegeneration. Median survival from symptom onset remains 24 to 48 months.

Into this landscape arrives CTx1000, an adeno-associated virus serotype 9 (AAV9)-based gene therapy developed by Celosia Therapeutics, a Macquarie University (Australia) spin-out. AAV9 was selected primarily for its efficient transduction of neurons and glia, not simply for its capacity to cross the blood–brain barrier. CTx1000 is currently known only by this code name and does not yet have a generic name or an approved commercial brand name.

Foust et al. demonstrated that AAV9 transduction is markedly age-dependent: intravascular delivery in neonatal animals transduces motor neurons and dorsal root ganglia efficiently, whereas in adult animals the same route shifts toward predominantly astrocytic transduction with comparatively limited neuronal uptake.^(p6) This is a material caveat for ALS, a disease of mid-to-late adult life, and for KOANEWA’s intracisternal magna (ICM) delivery route specifically, which was chosen to improve neuronal and glial distribution relative to peripheral intravenous dosing. In early 2026, Celosia dosed its first patient in the KOANEWA Phase Ib trial of CTx1000, which uses a 14-3-3θ fusion degron protein to selectively target pathological TDP-43.

𝐓𝐚𝐫𝐠𝐞𝐭𝐢𝐧𝐠 𝐓𝐃𝐏-𝟒𝟑 𝐢𝐧 𝐀𝐋𝐒: 𝐑𝐞𝐠𝐮𝐥𝐚𝐭𝐨𝐫𝐲 𝐡𝐮𝐫𝐝𝐥𝐞𝐬, 𝐭𝐫𝐢𝐚𝐥 𝐝𝐞𝐬𝐢𝐠𝐧 𝐝𝐞𝐟𝐢𝐜𝐢𝐞𝐧𝐜𝐢𝐞𝐬, 𝐚𝐧𝐝 𝐭𝐡𝐞 𝐜𝐚𝐮𝐬𝐚𝐥 𝐞𝐯𝐢𝐝𝐞𝐧𝐜𝐞 𝐠𝐚𝐩 𝐟𝐨𝐫 𝐂𝐓𝐱𝟏𝟎𝟎𝟎

Posted by Michael A. S. Guth on August 5th, 2026

𝐓𝐚𝐫𝐠𝐞𝐭𝐢𝐧𝐠 𝐓𝐃𝐏-𝟒𝟑 𝐢𝐧 𝐀𝐋𝐒: 𝐑𝐞𝐠𝐮𝐥𝐚𝐭𝐨𝐫𝐲 𝐡𝐮𝐫𝐝𝐥𝐞𝐬, 𝐭𝐫𝐢𝐚𝐥 𝐝𝐞𝐬𝐢𝐠𝐧 𝐝𝐞𝐟𝐢𝐜𝐢𝐞𝐧𝐜𝐢𝐞𝐬, 𝐚𝐧𝐝 𝐭𝐡𝐞 𝐜𝐚𝐮𝐬𝐚𝐥 𝐞𝐯𝐢𝐝𝐞𝐧𝐜𝐞 𝐠𝐚𝐩 𝐟𝐨𝐫 𝐂𝐓𝐱𝟏𝟎𝟎𝟎, Michael A.S. Guth,

Drug Discovery Today, Volume 31, Issue 5, 2026, 104752, ISSN 1359-6446,

https://doi.org/10.1016/j.drudis.2026.104752.

https://www.sciencedirect.com/science/article/pii/S1359644626001571

Highlights

• Over 60 amyotrophic lateral sclerosis (ALS) drug failures since 1995 underscore a persistent trial graveyard.

• CTX1000’s degron fusion selectively clears toxic cytoplasmic TDP-43 – in mice.

• The open-label KOANEWA trial lacks a control arm and validated biomarkers.

• Moving to Phase III without a TDP-43 biomarker risks replicating past failures.

• CTX1000 and VTx-002 parallel trials will together settle the TDP-43 causal architecture.

The therapeutic landscape for amyotrophic lateral sclerosis (ALS) has been characterized by decades of clinical trial failures, often attributed to biological heterogeneity, end-point insensitivity, and a profound evidence gap regarding target engagement. With TAR DNA-binding protein 43 (TDP-43) aggregation emerging as a hallmark feature in the vast majority of ALS cases, new precision-medicine modalities – most notably the proteolysis-targeting chimera (PROTAC) CTx1000 – aim to address the underlying causal pathology through selective degradation of mislocalized TDP-43. This review critically evaluates the regulatory hurdles and trial design deficiencies that have historically undermined ALS clinical development, and incorporates the dual sequestration hypothesis as a framework to interpret the convergence of TDP-43 pathology across neurodegenerative diseases. It concludes that it is imperative that the field adopts more rigorous biomarker-led methodologies, and that although target-specific degraders offer a sophisticated technological leap, their success depends on addressing fundamental knowledge gaps in target engagement, age-dependent vector tropism, and trial design architecture.

A microscopic-scale missile system designed to hunt down and destroy rogue cancer cells

Posted by Michael A. S. Guth on July 30th, 2026

Imagine a microscopic-scale missile system designed to hunt down and destroy rogue cancer cells one by one, while leaving healthy tissue completely untouched. That is the revolutionary promise of targeted alpha therapy, a cutting-edge field of medicine using specialized radioactive particles. By attaching these powerful alpha emitters to targeting molecules, doctors can deliver localized radiation directly to tumors with pinpoint accuracy.

While the science sounds futuristic, bringing these treatments into everyday hospitals requires solving major engineering and logistical puzzles. Because alpha particles pack an incredible punch over a tiny microscopic distance, handling them safely demands specialized shielding, strict facility guidelines, and meticulous tracking from the moment they are manufactured. Ensuring the safety of both hospital staff and patients is the absolute top priority before these therapies can become widely available.

One of the biggest challenges in this field is making sure the radioactive medicine stays exactly where it is supposed to be inside the body. Advanced safety protocols and specialized molecular carriers are designed to lock the radioactive atoms in place, preventing them from wandering off into healthy organs. This precision engineering is what separates targeted radiation from traditional, broader treatments that often cause widespread side effects.

Translating these complex therapies into routine clinical care takes a massive team effort involving doctors, physicists, pharmacists, and safety experts working hand in hand. Every single hospital workflow—from preparation to administration and waste disposal—must be carefully mapped out and rehearsed. Building this robust infrastructure is the key to transforming experimental breakthroughs into reliable, mainstream medical options.

My latest peer-reviewed, PubMed-indexed paper detailing a comprehensive safety framework for implementing Lead-212-targeted alpha therapy is now officially published and openly available in Clinical Nuclear Medicine Open. This work represents a vital step toward making advanced radiopharmaceuticals safer and more accessible for the patients who need them most. Anyone interested in the future of cancer care should read the full article and join the conversation.

https://www.ovid.com/jnls/cnmo/fulltext/10.1097/nm9.0000000000000092~implementing-212-pb-targeted-alpha-therapy-a-safety-first

Successful integration of Lead-212-targeted alpha therapy into routine clinical practice

Posted by Michael A. S. Guth on July 30th, 2026

Targeted alpha therapy (TAT) represents a transformative shift in precision oncology, offering high linear energy transfer over extremely short cellular paths to eradicate treatment-resistant malignancies. However, translating these powerful radioisotopes from the bench to the bedside introduces complex operational and toxicological bottlenecks. Chief among these is the management of transient daughter radionuclides like Lead-212 and its progeny, which can break away from chelator complexes and redistribute unpredictably throughout non-target organs.

To address these vulnerabilities, clinical researchers must implement rigorous safety-first frameworks that prioritize multi-point physiological monitoring alongside optimized chelation chemistry. Standardized handling protocols are no longer optional adjuncts; they form the foundational baseline required to mitigate systemic toxicity while preserving the therapeutic index of alpha-emitting platforms. Without these procedural guardrails, the clinical adoption of novel radiopharmaceuticals risks being derailed by preventable safety events.

Furthermore, integrating advanced dosimetric modeling into daily clinical workflows bridges the gap between pre-clinical assumptions and real-world patient exposures. True clinical translation requires precise patient-specific dosimetry rather than generalized activity prescriptions, accounting for heterogeneous tumor uptake and varying clearance rates. This level of granularity ensures that therapeutic efficacy is maximized while protecting vulnerable healthy tissues from cumulative radiotoxicity.

Scaling this infrastructure demands unprecedented cross-functional coordination between nuclear medicine physicians, medical physicists, radiation safety officers, and hospital administrators. Facilities must overhaul their containment and waste management systems to handle short half-life alpha emitters safely and efficiently. Overcoming these logistical hurdles is critical to establishing a reliable, reproducible standard of care across diverse healthcare settings.

Ultimately, the successful integration of Lead-212-targeted alpha therapy into routine clinical practice depends on our collective commitment to structural rigor and transparent safety reporting. As my newly published work in Clinical Nuclear Medicine Open outlines, establishing standardized safety-first operational frameworks now will pave the way for sustainable innovation in targeted radiopharmaceuticals. We invite colleagues and stakeholders to review the complete open-access methodology to help advance the field responsibly.

https://www.ovid.com/jnls/cnmo/fulltext/10.1097/nm9.0000000000000092~implementing-212-pb-targeted-alpha-therapy-a-safety-first

Targeting TDP-43 in ALS: Regulatory Hurdles, Trial Design Deficiencies, and the Causal Evidence Gap for CTx1000

Posted by Michael A. S. Guth on July 29th, 2026

𝐀𝐦𝐲𝐨𝐭𝐫𝐨𝐩𝐡𝐢𝐜 𝐥𝐚𝐭𝐞𝐫𝐚𝐥 𝐬𝐜𝐥𝐞𝐫𝐨𝐬𝐢𝐬 (𝐀𝐋𝐒) 𝐢𝐬 𝐚 𝐟𝐚𝐭𝐚𝐥 𝐧𝐞𝐮𝐫𝐨𝐝𝐞𝐠𝐞𝐧𝐞𝐫𝐚𝐭𝐢𝐯𝐞 𝐝𝐢𝐬𝐞𝐚𝐬𝐞. 𝐌𝐞𝐝𝐢𝐚𝐧 𝐬𝐮𝐫𝐯𝐢𝐯𝐚𝐥 𝐟𝐫𝐨𝐦 𝐬𝐲𝐦𝐩𝐭𝐨𝐦 𝐨𝐧𝐬𝐞𝐭 𝐢𝐬 𝟐𝟒 𝐭𝐨 𝟒𝟖 𝐦𝐨𝐧𝐭𝐡𝐬, 𝐚𝐧𝐝 𝐟𝐨𝐫 𝐦𝐨𝐬𝐭 𝐩𝐚𝐭𝐢𝐞𝐧𝐭𝐬, 𝐧𝐨 𝐚𝐯𝐚𝐢𝐥𝐚𝐛𝐥𝐞 𝐭𝐡𝐞𝐫𝐚𝐩𝐲 𝐦𝐞𝐚𝐧𝐢𝐧𝐠𝐟𝐮𝐥𝐥𝐲 𝐬𝐥𝐨𝐰𝐬 𝐭𝐡𝐚𝐭 𝐝𝐞𝐜𝐥𝐢𝐧𝐞.

Since riluzole’s 1995 approval — which extended median survival by only weeks — more than 60 compounds have entered clinical trials for ALS, and nearly all have failed. Some of these were uninformative failures: trials without biomarkers that ended in a null result and little else. Others were negative but scientifically useful, generating real mechanistic insight even without clinical benefit.

The most recent example is instructive. AMX0035 won accelerated FDA approval in 2022 after a Phase 2 trial showed a 25% slowing of functional decline. Two years later, the confirmatory Phase 3 trial found no difference from placebo, and the manufacturer withdrew the drug from the market. It’s a case study in how fragile early open-label signals can be once tested under full blinding.

Tofersen, approved in 2023, is a genuine precision-medicine breakthrough — but it treats a specific genetic mutation found in under 2% of ALS patients. The remaining 98%, whose disease involves sporadic TDP-43 protein pathology, still have no therapy that stops or reverses neurodegeneration.

My new article in Drug Discovery Today examines this history and asks what it would take for a new therapy to break the pattern — starting with CTx1000, a gene therapy now in early human testing. Link: https://authors.elsevier.com/sd/article/S1359-6446(26)00157-1

“𝐓𝐡𝐞 𝐪𝐮𝐞𝐬𝐭𝐢𝐨𝐧 𝐢𝐬 𝐧𝐨𝐭 𝐰𝐡𝐚𝐭 𝐲𝐨𝐮 𝐥𝐨𝐨𝐤 𝐚𝐭, 𝐛𝐮𝐭 𝐰𝐡𝐚𝐭 𝐲𝐨𝐮 𝐬𝐞𝐞.” — 𝐇𝐞𝐧𝐫𝐲 𝐃𝐚𝐯𝐢𝐝 𝐓𝐡𝐨𝐫𝐞𝐚𝐮

Posted by Michael A. S. Guth on July 28th, 2026

“𝐓𝐡𝐞 𝐪𝐮𝐞𝐬𝐭𝐢𝐨𝐧 𝐢𝐬 𝐧𝐨𝐭 𝐰𝐡𝐚𝐭 𝐲𝐨𝐮 𝐥𝐨𝐨𝐤 𝐚𝐭, 𝐛𝐮𝐭 𝐰𝐡𝐚𝐭 𝐲𝐨𝐮 𝐬𝐞𝐞.” — 𝐇𝐞𝐧𝐫𝐲 𝐃𝐚𝐯𝐢𝐝 𝐓𝐡𝐨𝐫𝐞𝐚𝐮 For decades, Alzheimer’s research has looked at the same data: amyloid plaques, tau tangles, neuroinflammation. But what if we have been seeing it wrong?

Two underappreciated forces—chronic stress and an oral bacterium called P. gingivalis—may be converging on the same vulnerable brain circuits, accelerating neurodegeneration in ways that neither factor alone can explain.
This “dual-hit” model reframes Alzheimer’s not as a single pathological cascade, but as an interaction between host vulnerability and environmental exposures. It asks a different question: not how do we treat late-stage dementia? but why do some brains age better than others?

Cellular Senescence: Persistent exposure to P. gingivalis toxins promotes the early accumulation of senescent (aging, non-dividing) cells in structural tissues like bone and oral mucosa, accelerating local tissue breakdown and bone resorption.

Are you looking at someone with Alzheimer’s disease? Or do you see beyond the disease to possible causes?

Metabolic Disruption: P. gingivalis alters the gut microbiome and systemic oxidative pathways, which is strongly associated with increased insulin resistance and elevated risk for metabolic complications during aging.

If you’d like, I can elaborate on:
Specific oral hygiene and nutritional strategies to lower P. gingivalis risk.
The connection between periodontal health and cardiovascular aging.

#AlzheimersDisease #Neuroscience #HealthyAging #BrainHealth #Stress #OralHealth #PorphyromonasGingivalis #Neuroinflammation #CognitiveResilience

𝐈𝐧 𝐭𝐡𝐞 𝐰𝐨𝐫𝐥𝐝 𝐨𝐟 𝐛𝐢𝐨𝐦𝐞𝐝𝐢𝐜𝐚𝐥 𝐫𝐞𝐬𝐞𝐚𝐫𝐜𝐡, 𝐰𝐞 𝐟𝐫𝐞𝐪𝐮𝐞𝐧𝐭𝐥𝐲 𝐬𝐩𝐞𝐧𝐝 𝐝𝐞𝐜𝐚𝐝𝐞𝐬 𝐬𝐭𝐚𝐫𝐢𝐧𝐠 𝐝𝐢𝐫𝐞𝐜𝐭𝐥𝐲 𝐚𝐭 𝐞𝐱𝐩𝐚𝐧𝐬𝐢𝐯𝐞 𝐜𝐥𝐢𝐧𝐢𝐜𝐚𝐥 𝐝𝐚𝐭𝐚𝐬𝐞𝐭𝐬 𝐰𝐡𝐢𝐥𝐞 𝐜𝐨𝐦𝐩𝐥𝐞𝐭𝐞𝐥𝐲 𝐦𝐢𝐬𝐬𝐢𝐧𝐠 𝐭𝐡𝐞 𝐬𝐭𝐫𝐮𝐜𝐭𝐮𝐫𝐚𝐥 𝐜𝐨𝐧𝐧𝐞𝐜𝐭𝐢𝐨𝐧𝐬 𝐬𝐭𝐚𝐫𝐢𝐧𝐠 𝐛𝐚𝐜𝐤 𝐚𝐭 𝐮𝐬. When scientific fields remain tightly siloed—treating systemic health, chronic stress, and neurodegeneration as entirely separate universes—we risk treating isolated symptoms while missing the integrated biological reality. “The question is not what you look at, but what you see.” ― Henry David Thoreau

Real breakthroughs rarely emerge from finding entirely new data points in the laboratory; instead, they come from fundamentally changing how we look at the data we already possess. By refusing to cross traditional disciplinary boundaries, researchers trap themselves in legacy frameworks that obscure how peripheral and central systems interact over the human lifespan. True scientific progress requires stepping back from specialized myopia to observe the broader environmental and physiological pressures acting on biological systems.

This institutional inertia often blinds investigators to the true nature of chronic multi-system pathologies that do not fit neatly into a single medical specialty. When complex conditions are viewed through a single narrow lens, the cumulative impact of overlapping risk factors goes entirely unrecognized by traditional diagnostic models. Expanding our analytical perspective allows us to perceive the subtle, multi-hit trajectories that precede clinical disease onset.

Challenging these entrenched silos is essential if we want to move beyond stagnant treatment paradigms and address the root causes of cognitive aging. By welcoming interdisciplinary frameworks, the scientific community can begin to bridge the artificial gaps separating immunology, endocrinology, and neurology. This broader perspective ultimately revitalizes how we evaluate clinical evidence and design preventive interventions.

Looking forward to sharing more on how cross-disciplinary blind spots shape our understanding of cognitive aging soon. These ongoing inquiries highlight the urgent need for a more unified approach to translational research and clinical trial design. Engaging with these deeper conceptual challenges will help redefine the future landscape of preventive health strategy.

𝐓𝐡𝐞 𝐀𝐋𝐒 𝐝𝐫𝐮𝐠 𝐠𝐫𝐚𝐯𝐞𝐲𝐚𝐫𝐝 𝐢𝐬 𝐜𝐫𝐨𝐰𝐝𝐞𝐝

The choroid plexus (ChP): hydrodynamic bottleneck and ground zero for Alzheimer’s

Accelerating the Orphan GPCR Pipeline: GPR149 as a Case Study in Dual-Domain Target Validation

In the 1950s, my physicist father met with Albert Einstein at the Institute for Advanced Study to discuss unified field theory.

Authority, Long-term Reach, and “Save” Signals

Google Scholar Publications Michael Anthony Stephen Guth

Targeted Alpha Therapy as Cannonballs

𝐓𝐡𝐞 𝐀𝐋𝐒 𝐝𝐫𝐮𝐠 𝐠𝐫𝐚𝐯𝐞𝐲𝐚𝐫𝐝 𝐢𝐬 𝐜𝐫𝐨𝐰𝐝𝐞𝐝

A microscopic-scale missile system designed to hunt down and destroy rogue cancer cells

Successful integration of Lead-212-targeted alpha therapy into routine clinical practice

Targeting TDP-43 in ALS: Regulatory Hurdles, Trial Design Deficiencies, and the Causal Evidence Gap for CTx1000

“𝐓𝐡𝐞 𝐪𝐮𝐞𝐬𝐭𝐢𝐨𝐧 𝐢𝐬 𝐧𝐨𝐭 𝐰𝐡𝐚𝐭 𝐲𝐨𝐮 𝐥𝐨𝐨𝐤 𝐚𝐭, 𝐛𝐮𝐭 𝐰𝐡𝐚𝐭 𝐲𝐨𝐮 𝐬𝐞𝐞.” — 𝐇𝐞𝐧𝐫𝐲 𝐃𝐚𝐯𝐢𝐝 𝐓𝐡𝐨𝐫𝐞𝐚𝐮

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𝐓𝐡𝐞 𝐀𝐋𝐒 𝐝𝐫𝐮𝐠 𝐠𝐫𝐚𝐯𝐞𝐲𝐚𝐫𝐝 𝐢𝐬 𝐜𝐫𝐨𝐰𝐝𝐞𝐝

The choroid plexus (ChP): hydrodynamic bottleneck and ground zero for Alzheimer’s

Accelerating the Orphan GPCR Pipeline: GPR149 as a Case Study in Dual-Domain Target Validation

In the 1950s, my physicist father met with Albert Einstein at the Institute for Advanced Study to discuss unified field theory.

Authority, Long-term Reach, and “Save” Signals

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