Institute for Neuroplasticity Research

𝐓𝐡𝐞 𝐀𝐋𝐒 𝐝𝐫𝐮𝐠 𝐠𝐫𝐚𝐯𝐞𝐲𝐚𝐫𝐝 𝐢𝐬 𝐜𝐫𝐨𝐰𝐝𝐞𝐝

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 […]

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 […]

AAV9 immunogenicity as a scalability trap. PROJECT OPTIMUS to boot.

Posted by Michael A. S. Guth on August 24th, 2026

AAV9 immunogenicity as a scalability trap. PROJECT OPTIMUS to boot. The anti-AAV9 titer cutoff of ≤1:50 reflects a real immunological constraint: patients with prior AAV9 exposure mount a neutralizing immune response that reduces transduction efficiency and risks severe inflammation. https://www.sciencedirect.com/science/article/pii/S1359644626001571?dgcid=authorhttps://lnkd.in/g2YVjCDb
Pre-existing anti-AAV9 antibodies are present in roughly 30–50% of the general population, with the exact rate depending on age, geography, and assay methodology.(p19) The immediate consequence is that a meaningful proportion of otherwise eligible ALS patients will be excluded from treatment on serologic grounds alone. Applying that 30–50% background seroprevalence range directly to the ALS population – absent ALS-specific serosurvey data, which do not yet exist – implies that roughly one-third to one-half of otherwise trial-eligible patients could be excluded by the ≤1:50 titer cutoff alone, before any other eligibility criterion is applied. This figure should be treated as an extrapolation from general-population data rather than a population-specific estimate.

A related and distinct consideration is that patients who receive an irreversible, single-administration gene therapy are typically excluded from participating in essentially all other clinical trials thereafter, because of the permanent nature of the intervention. This constrains the eligible patient pool through a mechanism separate from AAV9 seroconversion: prior participation in any gene therapy trial – AAV9-based or otherwise – will limit eligibility for subsequent studies regardless of a patient’s current anti-AAV9 titer.

The longer-term scalability consideration compounds both effects. Because AAV-based gene therapies proliferate across neuromuscular indications, seroconversion rates among potential ALS patients could plausibly rise with successive exposures from other therapeutic programs, although this trend has not yet been directly measured in the ALS population and should be treated as a hypothesis rather than an established trajectory. Celosia’s commercial forecasts should model this dynamic explicitly; a therapy that works but can only be administered to a diminishing fraction of eligible patients is not, on its own, a durable therapeutic platform.

Dose optimization and regulatory imperatives

Although the KOANEWA trial follows a conventional Phase Ib safety design, its long-term success will likely hinge on adopting more rigorous dose-optimization strategies to mitigate the risks inherent to irreversible gene therapy. Figure 3 contrasts the limitations of the traditional ‘accelerated’ pipeline with an optimized framework modeled after oncological dose-selection principles, highlighting the necessity of data-driven target engagement for central nervous system (CNS) gene therapies.

A methodological audit: Where the glasses may be rose-colored

Posted by Michael A. S. Guth on August 24th, 2026

A methodological audit: Where the glasses may be rose-colored https://authors.elsevier.com/a/1nYxN4r9Rkz1wZ

The open-label problem

KOANEWA is a Phase Ib, open-label, non-randomized, single-dose study (ClinicalTrials.gov identifier: NCT07401121). The CENTAUR trial was open-label in its earliest iterations, and its 25% ALSFRS-R signal dissolved entirely under the blinded conditions of the PHOENIX Phase III trial (https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-topline-results-from-global-phase-3-phoenix-trial-of-amx0035-in-als).^(p2)^,^(p3) Because the subjective ALSFRS-R is highly susceptible to expectation bias from both patients and investigators, unblinded designs evaluating high-visibility novel gene therapies face severe validation challenges. Without a sham or vehicle control arm – which, while ethically challenging to justify in a Phase Ib safety study, is not impossible to approximate through delayed-treatment or waitlist designs – any functional signal from KOANEWA cannot be attributed to CTx1000 with statistical confidence.

The biomarker gap

The field has converged on neurofilament light chain (NfL) as the leading surrogate end point in ALS, and NfL reduction formed the biomarker backbone of tofersen’s accelerated approval.^(p5) KOANEWA’s secondary end points include NfL in cerebrospinal fluid and plasma (ClinicalTrials.gov identifier: NCT07401121). The fundamental limitation is that NfL is a downstream marker of axonal damage: a readout of neuronal death, not of TDP-43–14-3-3 complex formation, pathological aggregate clearance, or target engagement at the molecular level. Crucially, because there is currently no validated living-patient biomarker for TDP-43 aggregate clearance itself, NfL shifts remain ambiguous: a reduction suggests slower neurodegeneration but does not confirm specific 14-3-3/degron target engagement, while an unchanged NfL cannot distinguish between a lack of molecular efficacy, an unengaged target, or poor regional biodistribution.

A more mechanistically proximal alternative is emerging. Because nuclear TDP-43 loss of function produces measurable cryptic-exon-containing RNA species (in STMN2, UNC13A, and other transcripts), these cryptic transcripts and their potential protein products are increasingly discussed as candidate biofluid biomarkers of TDP-43 functional status, distinct from NfL’s non-specific readout of neuronal injury.^(p11)^,^(p12) Developing a validated assay along these lines – whether a cerebrospinal fluid assay for cryptic RNA species, the TDP-43–14-3-3 complex itself, or a positron emission tomography (PET) ligand for TDP-43 pathology – might be as crucial to the field’s long-term progress as CTx1000 itself. Celosia’s clinical development plan should explicitly address this gap, rather than relying on NfL as a proxy for mechanism.

The exclusion criteria paradox

KOANEWA requires disease onset within two years, excludes C9ORF72 repeat expansion carriers (the most common genetic form of ALS-FTD, accounting for approximately 40% of familial and 5–10% of sporadic ALS cases^(p17)), and imposes an anti-AAV9 titer cutoff of ≤1:50 at enrollment (ClinicalTrials.gov identifier: NCT07401121). These criteria create a highly selected, non-generalizable patient population. Early-onset, non-C9ORF72, seronegative TDP-43 proteinopathy patients might respond differently from the broader sporadic ALS population in whom any eventual therapy must demonstrate real-world value. It is also worth noting that many other ALS trials already restrict enrollment to genetically defined or otherwise selected subpopulations, so KOANEWA’s recruitment feasibility is unlikely to be limited by these filters, even though the resulting evidence base will be narrow. Figure 2 illustrates the KOANEWA eligibility criteria and their non-generalizability for the ALS patient population.

Target-Specific Organs at Risk and Mitigation Strategies for 212Pb-TAT and FAP-Targeted Analogs

Posted by Michael A. S. Guth on August 19th, 2026

Guth MAS. Implementing 212 Pb-Targeted Alpha Therapy: A Safety-First Theranostic Framework for Clinical Practice. Clin Nucl Med Open. 2026;3(3):DOI: 10.1097/nm9.0000000000000092.

Table 1. Target-Specific Organs at Risk and Mitigation Strategies for Pb-212-TAT and FAP-Targeted Analogs

Organ/Tissue	SSTR2/FAP Expression	Primary Radiation Risk	Proactive Mitigation and Monitoring Strategy
Pituitary Gland	High (SUVmax ≈ 15–25)	Hypopituitarism (central hypothyroidism, hypogonadism, adrenal insufficiency)	Pre-Tx: Quantify Tumor-to-Pituitary SUV ratio. Dosimetry: Establish/respect absorbed dose limit (e.g., < 15 Gy). Monitoring: Baseline and annual pituitary axis panel (TSH/fT4, morning cortisol, testosterone/estradiol, LH/FSH) for ≥ 10 years.
Bone Marrow	Low (progenitor cell subsets)	Cytopenias; Therapy-Related Myeloid Neoplasms (t-MDS/AML)	Dosimetry: Apply red marrow absorbed dose constraints. Monitoring: Pre-cycle CBC with differential; annual CBC and peripheral blood smear for ≥ 5–10 years post-therapy.
Kidneys	Very Low	Chronic nephropathy	Mitigation: Mandatory renoprotective amino acid infusion during therapy. Monitoring: Baseline and annual serum creatinine / eGFR.
Vasculature (FAP-specific)	Atherosclerotic plaques	Plaque Instability / Accelerated Atherosclerosis	Imaging: Baseline FAPI-PET screening for vascular ‘hot spots’ to quantify atherosclerotic burden. Exclusion: Consider exclusion of patients with diffuse vascular uptake (e.g., SUVmax > 10 in major vessels) pending safety data.
Lungs (FAP-specific)	Fibrotic tissues (IPF)	Radiation-induced pneumonitis / Exacerbation of fibrosis	Pre-Tx: Detailed respiratory history; consider high-resolution chest CT if clinically indicated. Monitoring: Baseline and periodic pulmonary function tests (PFTs) in patients with known interstitial lung disease or significant FAPI uptake in lung parenchyma.
Liver (FAP-specific)	Cirrhosis / Fibrosis	Radiation-induced liver disease (RILD); Hepatic failure	Pre-Tx: Baseline LFTs and FibroScan (stiffness). Imaging: FAPI-PET to assess “background” hepatic uptake.
Joints (FAP-specific)	Activated Synovium (RA/OA)	Synovitis / Radiation-induced joint inflammation	Pre-Tx: Detailed history of inflammatory arthropathy; consider rheumatology consultation for patients with active RA/OA. Monitoring: Assessment of joint pain/swelling post-therapy in patients with high baseline joint uptake on FAPI-PET.
Uterus (FAP-specific)	Gravid Uterine Stroma	Fetal radiation exposure	Exclusion: Mandatory pregnancy testing; highly effective contraception protocols per radiopharmaceutical clinical trial standards.
Other Endocrine Tissues	Pancreatic Islets (Alpha cells), Thyroid	Subclinical dysfunction / Metabolic effects	Monitoring: Consider baseline and periodic assessment of glucose metabolism (HbA1c) and thyroid function (TSH).

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 17th, 2026

For the next two weeks or so, my article “Targeting TDP-43 in ALS: Regulatory hurdles, trial design deficiencies, and the causal evidence gap for CTx1000″ is available for reading and downloading for free at this link: https://www.sciencedirect.com/science/article/pii/S1359644626001571?dgcid=author

After that, the article will go behind a journal paywall for a year or more.

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.

Keywords: TDP-43; amyotrophic lateral sclerosis (ALS); gene therapy; 14-3-3 protein; biomarker; clinical trial design; AAV9 (adeno-associated virus serotype 9)

𝐈𝐬 𝐓𝐃𝐏-𝟒𝟑 𝐭𝐡𝐞 𝐥𝐲𝐧𝐜𝐡𝐩𝐢𝐧 𝐟𝐨𝐫 𝐟𝐢𝐧𝐝𝐢𝐧𝐠 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐟𝐨𝐫 𝐀𝐋𝐒?

Posted by Michael A. S. Guth on August 16th, 2026

𝐈𝐬 𝐓𝐃𝐏-𝟒𝟑 𝐭𝐡𝐞 𝐥𝐲𝐧𝐜𝐡𝐩𝐢𝐧 𝐟𝐨𝐫 𝐟𝐢𝐧𝐝𝐢𝐧𝐠 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐟𝐨𝐫 𝐀𝐋𝐒? Two pathologies, one protein The field has increasingly recognized that TDP-43 dysfunction operates through two parallel mechanisms. The cytoplasmic gain-of-function toxicity that CTx1000 directly targets is only half the story. Equally consequential is the loss of normal nuclear TDP-43 function, particularly its role in RNA splicing regulation: nuclear depletion of TDP-43 leads to the inclusion of unannotated or cryptic exons in transcripts encoding key neuronal survival regulators, including STMN2 and UNC13A.

This splicing dysregulation, observed in patient postmortem tissue, might be a driver of neurodegeneration that is at least as proximal as cytoplasmic aggregation itself, and antisense oligonucleotides (ASOs) designed to correct UNC13A cryptic splicing have already been shown to rescue synaptic function in TDP-43-depleted human neurons, providing independent, complementary evidence for the causal importance of TDP-43 loss-of-function.

A therapy that clears cytoplasmic aggregates without restoring nuclear splicing function – or, worse, one that inadvertently exacerbates nuclear depletion – might produce incomplete or even detrimental clinical outcomes. CTx1000’s 14-3-3θ/degron design was purposely engineered to preserve functional nuclear TDP-43 while removing the harmful cytoplasmic form. However, the underlying mechanistic selectivity has so far been demonstrated as preferential rather than absolute – the fusion protein shows higher affinity for pathological versus physiological TDP-43, rather than binding pathological TDP-43 exclusively – and its behavior in aged human neurons remains an open empirical question.

One line of evidence supporting a causal role for TDP-43 in disease is the existence of pathogenic mutations in the gene encoding TDP-43 itself, TARDBP, in a subset of familial ALS.(p14) These rare mutations demonstrate that TDP-43 dysfunction can be sufficient to cause motor neuron disease, although whether they model the far more common sporadic proteinopathy remains uncertain. Some TARDBP mutations seem to enhance cytoplasmic aggregation, whereas others primarily impair nuclear localization and splicing activity, so the existence of the mutations does not by itself resolve the gain-of-function versus loss-of-function debate.

A secondary concern warrants clear recognition. If TDP-43 aggregation is not a cause but a marker of upstream problems, then removing it – even selectively – might leave the root cause of neurodegeneration untouched. This structural risk echoes the adjuvant paradox in neuroinflammatory disease, where clearing protective protein deposits without resolving the underlying substrate dismantles a sequestration response, leaving the toxic agent free to accelerate injury.

Whether cytoplasmic TDP-43 aggregates similarly perform any protective sequestration function is, at present, an unresolved and largely unc

Cancer is a syndrome of diseases

Posted by Michael A. S. Guth on August 15th, 2026

“Cancer is not one disease but many diseases. We call them all ‘cancer’ because they share a fundamental feature: the abnormal growth of cells.”

—The Emperor of All Maladies by Siddhartha Mukherjee

If you had a neuroendocrine tumor, would you be willing to try a radioactive drug as a small part of your treatment?

Posted by Michael A. S. Guth on August 11th, 2026

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

If you had a 𝐧𝐞𝐮𝐫𝐨𝐞𝐧𝐝𝐨𝐜𝐫𝐢𝐧𝐞 𝐭𝐮𝐦𝐨𝐫 𝐢𝐧 𝐲𝐨𝐮𝐫 𝐬𝐭𝐨𝐦𝐚𝐜𝐡, 𝐬𝐦𝐚𝐥𝐥 𝐢𝐧𝐭𝐞𝐬𝐭𝐢𝐧𝐞, 𝐚𝐩𝐩𝐞𝐧𝐝𝐢𝐱, 𝐜𝐨𝐥𝐨𝐧, 𝐩𝐚𝐧𝐜𝐫𝐞𝐚𝐬, 𝐥𝐮𝐧𝐠𝐬, 𝐚𝐝𝐫𝐞𝐧𝐚𝐥 𝐠𝐥𝐚𝐧𝐝𝐬, 𝐭𝐡𝐲𝐫𝐨𝐢𝐝, 𝐩𝐢𝐭𝐮𝐢𝐭𝐚𝐫𝐲, 𝐫𝐞𝐜𝐭𝐮𝐦, 𝐛𝐫𝐞𝐚𝐬𝐭, 𝐨𝐫 𝐩𝐫𝐨𝐬𝐭𝐚𝐭𝐞, 𝐰𝐨𝐮𝐥𝐝 𝐲𝐨𝐮 𝐰𝐚𝐧𝐭 𝐭𝐨 𝐭𝐫𝐲 𝐚 𝐫𝐚𝐝𝐢𝐨𝐚𝐜𝐭𝐢𝐯𝐞 𝐝𝐫𝐮𝐠 as (a small) part of the treatment?

The emerging clinical dataset highlights excellent short-term tolerability for 212Pb-TAT, with adverse events primarily consisting of low-grade nausea, fatigue, and manageable lymphocytopenia.3,17,18,21 However, long-term toxicities are typically delayed and insidious. The pituitary gland is the prime organ at risk due to high SSTR2 expression in the anterior pituitary, with diagnostic [68Ga]Ga-DOTATATE PET/CT consistently showing uptake in the sella turcica. While beta-PRRT carries an ≈ 8% risk of delayed pituitary dysfunction over 5–10 years,4 the higher relative biological effectiveness (RBE) of alpha particles could substantially increase this risk. Preclinical models provide direct evidence of alpha particle-induced endocrine disruption.

Long-term radiotoxicity studies with [212Pb]Pb-TCMC (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane)-rituximab in murine models of Non-Hodgkin lymphoma demonstrate that renal toxicity may emerge months after treatment. Quelven et al (2025) observed significant increases in urea and creatinine at 4–6 months post-therapy, with histopathologically confirmed renal damage.26 Notably, toxicity was reduced by optimizing specific activity, suggesting that careful dose optimization and extended follow-up are essential for 212Pb-based therapies.

Therapy-related myeloid neoplasms/acute myeloid leukemia (t-MDS/AML) occur in 2%–3% of beta-PRRT patients with latency of several years7—a risk plausibly heightened with alpha-emitters due to potent energy deposition in hematopoietic stem cells.4,5 The bystander effect expands the potential “at-risk” tissue volume beyond cells with direct radiopharmaceutical uptake, meaning healthy cells adjacent to targeted cells may suffer collateral damage via intercellular signaling.14

First-in-human phase 0 studies of prostate-specific membrane antigen (PSMA)-targeted 212Pb ligands confirm safety and feasibility in heavily pretreated populations. While therapeutic efficacy was not expected at microdose levels, the favorable safety profile supports further dose-escalation trials.

An unexpected safety advantage of 212Pb-labeled radiopharmaceuticals is their inherent antimicrobial potency. Studies with [212Pb]Pb-dotamtate demonstrated a ≥ 6-log reduction in colony-forming units for microorganisms, including S. aureus and C. albicans, within 6 hours of exposure, at absorbed doses below 1.01 kGy.28 This “self-sterilizing” property adds an additional layer of pharmaceutical safety, reducing the risk of microbial contamination in drug product vials.

Activate to view larger image,

𝐓𝐚𝐫𝐠𝐞𝐭𝐢𝐧𝐠 𝐓𝐃𝐏-𝟒𝟑 𝐢𝐧 𝐀𝐋𝐒: Causal Driver, Toxic Passenger, or Loss-of-Function Crisis?

Posted by Michael A. S. Guth on August 10th, 2026

https://authors.elsevier.com/a/1nYxN4r9Rkz1wZ

TDP-43 is the most common neuropathological signature of ALS and one of the two most common pathologies in frontotemporal dementia (FTD), alongside fused in sarcoma (FUS) proteinopathy.10,11 Its cytoplasmic mislocalization and aggregation are observed in approximately 97% of all ALS cases, both sporadic and familial, with the notable exceptions of SOD1-linked disease and FUS-associated ALS.11 This near-universality makes it a compelling therapeutic target. It also makes the absence of any approved TDP-43-directed therapy nearly two decades after its identification as an ALS/FTD disease protein in 2006 a central puzzle of ALS drug development.10 ALS clinical trials as a field span more than three decades, dating to the 1993 discovery of SOD1 mutations, but dedicated TDP-43-directed therapeutic development is a more recent, roughly 20-year effort dating from Neumann et al.’s 2006 report.10

The unresolved mechanistic question is whether TDP-43 aggregation is a cause of motor neuron death, a consequence of upstream insults (such as glutamate excitotoxicity, mitochondrial dysfunction, or RNA metabolism dysregulation), or—critically—a downstream epiphenomenon that obscures a primary loss-of-function pathology.12 Riluzole centered on glutamate; edaravone targeted oxidative stress. Whether these modest effects reflect incomplete target engagement or the fundamental irrelevance of their targets to disease causation remains unanswered; for riluzole specifically, “target engagement” is itself difficult to define precisely given the drug’s several proposed mechanisms and the absence of a settled consensus on which one is primarily responsible for its clinical effect. A successful CTx1000 program would, for the first time, provide empirical evidence that TDP-43 proteinopathy is causally necessary—not merely correlative—for motor neuron loss in sporadic ALS, representing a genuine paradigm shift in the field’s understanding of disease mechanism.

Two Pathologies, One Protein. The field has increasingly recognized that TDP-43 dysfunction operates through two parallel mechanisms. The cytoplasmic gain-of-function toxicity that CTx1000 directly targets is only half the story. Equally consequential is the loss of normal nuclear TDP-43 function, particularly its role in RNA splicing regulation: nuclear depletion of TDP-43 leads to the inclusion of unannotated or cryptic exons in transcripts encoding key neuronal survival regulators, including STMN2 and UNC13A.13,14 This splicing dysregulation, observed in patient postmortem tissue, may be a driver of neurodegeneration that is at least as proximal as cytoplasmic aggregation itself, and antisense oligonucleotides (ASOs) designed to correct UNC13A cryptic splicing have already been shown to rescue synaptic function in TDP-43-depleted human neurons, providing independent, complementary evidence for the causal importance of TDP-43 loss-of-function.^14,15 A therapy that clears cytoplasmic aggregates without restoring nuclear splicing function—or, worse, one that inadvertently exacerbates nuclear depletion—might produce incomplete or even detrimental clinical outcomes. CTx1000’s 14-3-3θ/degron design was purposely engineered to preserve functional nuclear TDP-43 while removing the harmful cytoplasmic form. However, the underlying mechanistic selectivity has so far been demonstrated as preferential rather than absolute—the fusion protein shows higher affinity for pathological versus physiological TDP-43 rather than binding pathological TDP-43 exclusively—and its behavior in aged human neurons remains an open empirical question.⁹

Google Scholar Publications Michael A. S. 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.

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

AAV9 immunogenicity as a scalability trap. PROJECT OPTIMUS to boot.

A methodological audit: Where the glasses may be rose-colored

The open-label problem

The biomarker gap

The exclusion criteria paradox

Target-Specific Organs at Risk and Mitigation Strategies for 212Pb-TAT and FAP-Targeted Analogs

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

𝐈𝐬 𝐓𝐃𝐏-𝟒𝟑 𝐭𝐡𝐞 𝐥𝐲𝐧𝐜𝐡𝐩𝐢𝐧 𝐟𝐨𝐫 𝐟𝐢𝐧𝐝𝐢𝐧𝐠 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐟𝐨𝐫 𝐀𝐋𝐒?

Cancer is a syndrome of diseases

If you had a neuroendocrine tumor, would you be willing to try a radioactive drug as a small part of your treatment?

𝐓𝐚𝐫𝐠𝐞𝐭𝐢𝐧𝐠 𝐓𝐃𝐏-𝟒𝟑 𝐢𝐧 𝐀𝐋𝐒: Causal Driver, Toxic Passenger, or Loss-of-Function Crisis?

Google Scholar Publications Michael A. S. Guth

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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

The open-label problem

The biomarker gap

The exclusion criteria paradox

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Calendar

Links

Archives

Recent Comments