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 […]

𝐓𝐡𝐞 𝐡𝐢𝐠𝐡𝐞𝐬𝐭 𝐜𝐥𝐢𝐧𝐢𝐜𝐚𝐥 𝐭𝐫𝐢𝐚𝐥 𝐟𝐚𝐢𝐥𝐮𝐫𝐞 𝐫𝐚𝐭𝐞 𝐟𝐨𝐫 𝐚𝐧𝐲 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐢𝐧 𝐦𝐨𝐝𝐞𝐫𝐧 𝐦𝐞𝐝𝐢𝐜𝐢𝐧𝐞: 𝐇𝐨𝐰 𝐛𝐨𝐭𝐡 𝐚𝐦𝐲𝐥𝐨𝐢𝐝- 𝐚𝐧𝐝 𝐧𝐨𝐧-𝐚𝐦𝐲𝐥𝐨𝐢𝐝-𝐭𝐚𝐫𝐠𝐞𝐭𝐢𝐧𝐠 𝐭𝐡𝐞𝐫𝐚𝐩𝐢𝐞𝐬 𝐟𝐚𝐢𝐥𝐞𝐝 𝐭𝐨 𝐚𝐥𝐭𝐞𝐫 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐜𝐨𝐮𝐫𝐬𝐞 𝐢𝐧 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫’𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞

Posted by Michael A. S. Guth on August 27th, 2026

𝐓𝐡𝐞 𝐡𝐢𝐠𝐡𝐞𝐬𝐭 𝐜𝐥𝐢𝐧𝐢𝐜𝐚𝐥 𝐭𝐫𝐢𝐚𝐥 𝐟𝐚𝐢𝐥𝐮𝐫𝐞 𝐫𝐚𝐭𝐞 𝐟𝐨𝐫 𝐚𝐧𝐲 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐢𝐧 𝐦𝐨𝐝𝐞𝐫𝐧 𝐦𝐞𝐝𝐢𝐜𝐢𝐧𝐞: 𝐇𝐨𝐰 𝐛𝐨𝐭𝐡 𝐚𝐦𝐲𝐥𝐨𝐢𝐝- 𝐚𝐧𝐝 𝐧𝐨𝐧-𝐚𝐦𝐲𝐥𝐨𝐢𝐝-𝐭𝐚𝐫𝐠𝐞𝐭𝐢𝐧𝐠 𝐭𝐡𝐞𝐫𝐚𝐩𝐢𝐞𝐬 𝐟𝐚𝐢𝐥𝐞𝐝 𝐭𝐨 𝐚𝐥𝐭𝐞𝐫 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐜𝐨𝐮𝐫𝐬𝐞 𝐢𝐧 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫’𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞
Michael A. S. Guth, 𝐹𝑟𝑒𝑒 𝑁𝑒𝑢𝑟𝑜𝑝𝑎𝑡ℎ𝑜𝑙𝑜𝑔𝑦, Vol. 7 (2026).

https://ejournals.uni-muenster.de/index.php/fnp/article/view/9650

Keywords: Alzheimer’s disease, Clinical trials, Amyloid hypothesis, Drug development, CADRO, Disease-modifying therapy, Go/No Go decisions

Abstract
𝐁𝐚𝐜𝐤𝐠𝐫𝐨𝐮𝐧𝐝: Alzheimer’s disease drug development has produced a 99.6 percent failure rate for disease-modifying compounds (244 compounds tested 2002–2012, one regulatory approval; Cummings et al., 2014; Cummings, 2018)—the most sustained and costly therapeutic failure in the history of modern medicine. The field’s standard explanation is that the biology is intractable. The present analysis offers a different and more instructive diagnosis: the failure was not primarily scientific. It was institutional.

𝐎𝐛𝐣𝐞𝐜𝐭𝐢𝐯𝐞: To characterize the structural and institutional forces that sustained investment in repeatedly ineffective mechanisms of action across 567 Phase 2 and Phase 3 Alzheimer’s trials from 2010 to 2026, and to determine whether peer-reviewed alternative pathogenic frameworks were available at the time each major Go/No Go decision was made.

𝐌𝐞𝐭𝐡𝐨𝐝𝐬: Trials were identified from ClinicalTrials.gov using the following criteria: primary diagnosis of Alzheimer’s disease or mild cognitive impairment attributed to Alzheimer’s disease; Phase 2 or Phase 3; status of terminated or completed; primary completion date between January 1, 2010 and May 4, 2026. After exclusion of 70 trials not classifiable by mechanism of action, a final analytic dataset of 497 trials was classified by primary mechanism using the Common Alzheimer’s Disease Research Ontology (CADRO). A temporal alignment analysis was conducted for the 12 largest trials by enrollment (N ≥ 1,300), mapping each trial’s initiation date against the publication dates of peer-reviewed alternative mechanistic frameworks available at the time of trial launch.

Results: Amyloid-targeting approaches accounted for approximately 31 percent of the 497 classified trials, nearly all of which failed to demonstrate clinical efficacy. Among the 12 largest trials, 11 targeted amyloid pathology and 10 were terminated for futility or lack of efficacy. All 12 trials were initiated after the publication in high-impact journals of peer-reviewed alternative frameworks, including the TREM2 neuroinflammation pathway, the antimicrobial protection hypothesis, the periodontitis-associated bacterial pathogenesis hypothesis, and the GLP-1 metabolic pathways. The post-2022 period revealed that genuinely novel non-amyloid mechanisms—TREM2 agonism, GLP-1 receptor stimulation, filamin A modulation, and progranulin/sortilin restoration—also failed to produce clinical benefit at scale despite confirmed target engagement. Three establishment forces are identified as operative causes: regulatory path dependency, institutional entrenchment within grant and editorial review panels, and shareholder-driven sunk-cost pressures.

Conclusion: The 567-trial record constitutes a structural verdict on a model of drug development that was never designed to solve a problem of this complexity. The uniformity of negative results across all mechanism categories—amyloid, tau, neuroinflammation, metabolic, and synaptic—points toward deeper problems of disease definition, intervention timing, and endpoint validity that institutional and financial pressures have prevented the field from confronting. The Dominantly Inherited Alzheimer Network (DIAN) biomarker data demonstrates that pathology precedes symptoms by 15–25 years; the 2025 DIAN Trials Unit (DIAN-TU) extension provides the first evidence that treatment before symptom onset may delay dementia. Prevention trials in asymptomatic at-risk populations represent the only strategy the accumulated trial record has not yet refuted.

A new oral pill drug for pancreatic cancer extends life on average 13.2 months compared to 6.7 months for harsh chemotherapy.

Posted by Michael A. S. Guth on August 26th, 2026

A new oral pill drug approved by the FDA for treatment of pancreatic cancer extends life on average 13.2 months compared to 6.7 months for harsh chemotherapy. The drug operates through a first-in-class “molecular glue” tricomplex mechanism that targets the active, GTP-bound “ON” state of both mutant and wild-type RAS proteins. [1, 2, 3]

The FDA approved the drug for treating advanced metastatic pancreatic cancer after the landmark RASolute 302 phase 3 trial demonstrated that it nearly doubled the median overall survival time compared to standard chemotherapy (13.2 months vs. 6.7 months). [4, 5, 6]

Step-by-Step Mechanism of Action

Chaperone Binding (Bicomplex Formation)Daraxonrasib is an oral small molecule that first binds non-covalently to an abundant cellular helper/chaperone protein called cyclophilin A (CypA) inside the cell. This binding forms an initial binary complex.

Steric Blockade (Tricomplex Formation)The newly formed CypA-daraxonrasib structure creates a highly specific, complementary surface that physically “glues” itself to RAS superfamily proteins (including KRAS, HRAS, and NRAS). This results in a stable ternary (tri-complex) structure.

Shutting Down the “ON” Signal Unlike first-generation RAS inhibitors that only bind to the inactive “OFF” (GDP-bound) state, the drug targets RAS in its active “ON” (GTP-bound) state. By physically locking onto RAS(ON), the large tricomplex creates a steric barrier that blocks RAS from binding to its downstream effectors.

Pathway Suppression

By breaking the connection between RAS and its effectors, the drug successfully shuts down the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR cell signaling cascades. Without these signals, the uncontrolled proliferation and survival of the tumor cells are halted, prompting cell death. [1, 10]

Why It Is Considered a “Landmark” Discovery

Multi-Selective / Pan-RAS Target: Over 90% of pancreatic cancers are driven by RAS mutations, but they vary by subtype (e.g., G12D, G12V, G12R, Q61X). Previous drugs could only target single mutations (like KRAS G12C).

The new drug is a pan-RAS inhibitor that works across almost all major variants, bypassing decades of failure in trying to target “undruggable” RAS variants.

Bypasses Tumor Resistance: Cancers often develop resistance to “OFF-state” drugs by rapidly looping back into active signaling. Because daraxonrasib targets the active state directly, it curbs this adaptive resistance loop. [10]

The Goal of Achieving Medicare-for-All

Posted by Michael A. S. Guth on August 25th, 2026

BRIAHNA JOY GRAY: Let’s talk about something like Medicare for All, which Bernie has already done the work of making popular. It went from a 37% approval prior to 2016 to enjoying 90% approval among Democrats, high 60s% approval among independents, and 49% approval among Republicans even.

If you have a so-called socialist, a DSA candidate like AOC, who, by the way, now says that she is not a member of the national DSA. Right? She says, “I’m a member of the New York DSA, but not the national DSA,” which is not a thing you can do. That’s not a real thing. These are the kind of pivots that are getting made. And for what? For, I believe, a presidential run, but that’s really a vice presidential run. If our ambitions have gone from electing someone who will fight for and win Medicare for All to getting a socialist in the White House as the vice president, and that person is actively saying that Hakeem Jeffries should be Speaker of the House, when just this past week Hakeem Jeffries says that he does not support Medicare for All?

Then again, what are we doing? My previous image of the left winning and then having Black people come over— do I want this neutered version of the left to be the face of the left? And to shift Black people into what is another version of the status quo so that all those Black people in South Carolina, in Jim Clyburn’s district— Jim Clyburn, who takes more money from the pharmaceutical industry than any other member of Congress— can continue to deny them a right to healthcare so that it has some of the lowest health outcomes in the entire country that mirror some of those in the Global South, in the richest country in the history of the world? Is that what this work that I’m doing, that we’re all doing, and that the— collective left has been doing is for?

Look, I too would like to not be living an Upton Sinclair novel. That being said, that is not my job. I didn’t quit the law firm and take a pay cut ’cause I wanted to go back to the Clinton years.

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.

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𝐓𝐡𝐞 𝐀𝐋𝐒 𝐝𝐫𝐮𝐠 𝐠𝐫𝐚𝐯𝐞𝐲𝐚𝐫𝐝 𝐢𝐬 𝐜𝐫𝐨𝐰𝐝𝐞𝐝

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