Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB
Open accessAbstract
Methods to enhance adult neurogenesis by reprogramming glial cells into neurons enable production of new neurons in the adult nervous system. Development of therapeutically viable approaches to induce new neurons is now required to bring this concept to clinical application. Here, we successfully generate new neurons in the cortex and dentate gyrus of the aged adult mouse brain by transiently suppressing polypyrimidine tract binding protein 1 using an antisense oligonucleotide delivered by a single injection into cerebral spinal fluid. Radial glial-like cells and other GFAP-expressing cells convert into new neurons that, over a 2-month period, acquire mature neuronal character in a process mimicking normal neuronal maturation. The new neurons functionally integrate into endogenous circuits and modify mouse behavior. Thus, generation of new neurons in the dentate gyrus of the aging brain can be achieved with a therapeutically feasible approach, thereby opening prospects for production of neurons to replace those lost to neurodegenerative disease. Maimon et al. demonstrate a therapeutically viable approach, single-dose injection of a DNA drug to suppress synthesis of PTB, to generate new neurons in the aged mouse hippocampus and enhance memory after their integration into endogenous circuits.
AI snapshot
Written from the paper’s full text.
TL;DR
A single intracerebroventricular antisense oligonucleotide (ASO) injection transiently suppresses PTB and generates new neurons in the cortex and dentate gyrus of aged adult mice, with the new dentate gyrus neurons maturing and integrating into hippocampal circuits. The approach also increases neurons in human brain organoids and improves hippocampal-dependent behavior in mice, supporting a therapeutically feasible route to neuron replacement.
Key findings
- In 5-month-old GFAP-CreERT2; CAG-lox-stop-lox-tdTomato mice, PTB-ASO injection into CSF produced a 37.5-fold increase in tdTomato+, NeuN+ newly generated dentate gyrus neurons versus saline/control ASO; 15% (±5%, n=3) of total tdTomato+ cells were NeuN+, and newly induced neurons comprised 7.8% of total granular cell layer neurons.
- In aged mice injected at 1 year and analyzed two months later, PTB-ASO generated new dentate gyrus neurons comprising 4.5% of total dentate gyrus neurons, with conversion of 5% of all tdTomato-positive cells into tdTomato+, NeuN+ neurons; without PTB suppression, no new dentate gyrus neurons were detected in aged controls.
- New neurons followed a maturation time course: DCX+ immature neurons increased 26.3-fold and 49.2-fold at 1 and 2 weeks after PTB-ASO, respectively; by 2 months, 92.7% of tdTomato+ neuronal cells no longer expressed DCX, and 97% of those had converted to NeuN.
- PTB-ASO-generated dentate gyrus neurons received spontaneous excitatory and inhibitory synaptic currents and fired action potentials indistinguishable from neighboring endogenous neurons; PTB-ASO-treated aged mice performed better in Barnes maze and novel object recognition tests.
Methods
- ASOs complementary to human and murine PTB pre-mRNA were screened in mouse cells and tested for tolerability after ICV injection; two lead PTB-ASOs were used for subsequent experiments.
- New neuron generation was tracked in human brain organoids and in congenic C57BL/6 mice carrying GFAP-CreERT2 and CAG-lox-stop-lox-tdTomato reporters, with tamoxifen-induced labeling of GFAP-expressing cells followed by single-dose ICV injection of PTB-ASO or control ASO into CSF.
- Analyses included qPCR for PTB/nPTB and markers, immunofluorescence for NeuN, GFAP, DCX, Ki67, Tuj1, MAP2, SOX2, and caspase 3, morphological reconstruction, electrophysiology, and blinded behavioral assays including open field, optomotor, Barnes maze, and novel object recognition.
Limitations
- The paper states that the ASOs used are not clinical candidates, PTB suppression was less than 50% in most brain regions, and optimization for minimal toxicity and maximal efficacy is still needed; in the hippocampus, where PTB was reduced by more than 50%, robust conversion occurred even in aged mice.
- The text makes evident that the in vivo evidence is from mice, with human data limited to brain organoids in vitro; no human in vivo therapeutic validation is reported.
- Several experiments rely on small sample sizes (for example, n=3 biological repeats in multiple assays), and the aged cortex showed only limited new neuron formation compared with the dentate gyrus.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
27 of 39 cited sources checked · 9 supported · 1 flagged · accuracy not yet measured
- Interpretationcitation
Reduction in PTB triggered radial glial-like cells to convert into new granular neurons through what appears to be the typical developmental process by which new hippocampal neurons mature during development and in young adult animals.
“reduction in PTB triggered radial glial-like cells to convert into new granular neurons through what appears to be the typical developmental process by which new hippocampal neurons mature during development39 and in young adult animals40.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [39] Altman, J. & Bayer, S. A. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J. Comp. Neurol. 301, 365–381 (1990). source
- cites [40] Kempermann, G., Song, H. & Gage, F. H. Neurogenesis in the adult hippocampus. Cold Spring Harb. Perspect. Biol. 7, 9 (2015). source
- Premisecitation
Optimized ASOs to other targets have previously been shown to yield dose dependent target RNA suppression to 5% of initial level.
“optimized ASOs to other targets have previously been shown to yield dose dependent target RNA suppression to 5% of initial level13,14,48.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [13] Smith, R. A. et al. Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest. 116, 2290–2296 (2006). source
- cites [14] Kordasiewicz, H. B. et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74, 1031–1044 (2012). source
The Results section reports dose-dependent suppression of human huntingtin mRNA by an ASO, to 42% and 28% of vehicle levels at the two doses tested. It does not report suppression to 5% of initial levels or establish that result for other targets. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [48] Bennett, C. F., Krainer, A. R. & Cleveland, D. W. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu. Rev. Neurosci. 42, 385–406 (2019). source
The Alzheimer’s Disease section (page unavailable) reports dose-dependent reductions in tau expression and tau mRNA after treatment with tau-targeting ASOs. It does not report suppression of target RNA to 5% of its initial level, so the claimed magnitude is unsupported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
Transient suppression of PTB using an ASO delivered by a single injection into CSF generates new neurons in the cortex and dentate gyrus of the aged adult mouse brain.
“Here, we successfully generate new neurons in the cortex and dentate gyrus of the aged adult mouse brain by transiently suppressing Polypyrimidine-Tract-Binding-Protein-1 (PTB) using an antisense-oligonucleotide (ASO) delivered by a single injection into cerebral spinal fluid.”
Quote in the paperSubstantial claim - Findingown data
In the hippocampus of adult mice, almost all (97%) of tdTomato-expressing neurons did not accumulate detectable levels of GFAP two months after ASO injection.
“In the hippocampus of adult mice, almost all (97%) of tdTomato-expressing neurons did not accumulate detectable levels of GFAP two months after ASO injection (Figure 3a,b).”
Quote in the paperSubstantial claim - Findingown data
The number of cells expressing the neuronal protein marker NeuN was slightly elevated in PTB-ASO treated organoids compared with control ASO treated organoids.
“The number of cells expressing the neuronal protein marker NeuN was slightly elevated (Figure 1g,h).”
Quote in the paperSubstantial claim
- Findingown data
Two months after PTB-ASO injection (at a final age of 5 months), an obvious increase in tdTomato+, NeuN+ neurons was identified in the granular layer of the dentate gyrus.
“In sharp contrast, two months after PTB-ASO injection (at a final age of 5 months), an obvious increase in tdTomato+, NeuN+ neurons was identified in the granular layer of the dentate gyrus (Figure 2d; Supplementary Videos 1&2).”
Quote in the paperSubstantial claim - Findingown data
Measurement of other intrinsic membrane properties were also consistent with tdTomato-positive cells possessing membrane properties indistinguishable from neighboring tdTomato-negative cells.
“Measurement of other intrinsic membrane properties were also consistent with tdTomato-positive cells possessing membrane properties indistinguishable from neighboring tdTomato-negative cells (Table 1).”
Quote in the paperSubstantial claim - Findingown data
Electrophysiological recordings from tdTomato-positive neurons in the granule cell layer of the dentate gyrus revealed spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) that were indistinguishable from endogenous tdTomato-negative neurons.
“Electrophysiological recordings obtained from tdTomato-positive neurons in the granule cell layer of the dentate gyrus (Figure 6a) revealed spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs), indicating the presence of afferent glutamate and GABA synaptic inputs, respectively (Figure 6b), that were indistinguishable from endogenous tdTom”
Quote in the paperSubstantial claim - Findingcitation
In tamoxifen-induced GFAP-CreERT2, CAG-lox-stop-lox-tdTomato mice, 0.4% of the tdTomato-expressing cell population also expressed NeuN+ two months after saline or control ASO injection into CSF.
“In tamoxifen-induced GFAP-CreERT2, CAG-lox-stop-lox-tdTomato mice, 0.4% of the tdTomato-expressing cell population also expressed NeuN+ two months after saline or control ASO injection into CSF (Figure 2d), consistent with the known low rate of ongoing neurogenesis in the dentate gyrus of young adult mice29.”
Quote in the paperSubstantial claim - Findingnone given
Suppression of PTB was also demonstrated to be sufficient to generate new human neurons in brain organoids in vitro.
“Suppression of PTB was also demonstrated to be sufficient to generate new human neurons in brain organoids in vitro.”
Quote in the paperSubstantial claim - Findingown data
Glial cells can switch identities to become new neurons in the healthy adult mouse brain.
“Our evidence establishes that glial cells can switch identities to become new neurons in the healthy adult mouse brain.”
Quote in the paperSubstantial claim - Findingown data
Morphology of newly generated neurons strongly depended on the brain region, with converted neurons acquiring morphologies matching granular, pyramidal, or cortical neurons characteristic of each region.
“It is notable that morphology of the newly generated neurons strongly depended on the brain region in which they were generated (Extended Data Figure 4), with the converted neurons acquiring morphologies matching that characteristic of granular, pyramidal, or cortical neurons, respectively, that are representative for neurons of each region.”
Quote in the paperSubstantial claim - Findingreasoning
Newly induced neurons comprise 7.8% of the total neurons of the granular cell layer (GCL) in the entire dentate gyrus of these 5 months old mice.
“Correcting for this, we calculated that newly induced neurons comprise 7.8% of the total neurons of the granular cell layer (GCL) in the entire dentate gyrus of these 5 months old mice (Figure 2g).”
Quote in the paperSubstantial claim - Findingown data
Only 25.5% (±4.9%, n=7) of endogenous GFAP-expressing astrocytes expressed tdTomato.
“Counting also revealed that only 25.5% (±4.9%, n=7) of endogenous GFAP-expressing astrocytes expressed tdTomato.”
Quote in the paperSubstantial claim - Findingown data
tdTomato positive neurons generated in response to PTB ASO injection mature morphologically over one week to two months, rather than initially appearing as morphologically mature neurons.
“Second, using a Cre/tdTomato glial marking system, we established that the tdTomato positive neurons generated in response to PTB ASO injection mature morphologically over a time course of one week to two months, rather than initially appearing as the morphologically mature neurons that would be produced by artifactually marking existing neurons.”
Quote in the paperSubstantial claim - Findingown data
PTB-mediated production of new neurons was also supported by a PTB-ASO-dependent increase in DCX in brain organoids.
“PTB-mediated production of new neurons was also supported by a PTB-ASO-dependent increase in DCX in brain organoids (Extended Data Figure 9).”
Quote in the paperSubstantial claim - Findingown data
Without PTB suppression no new neurons were detected in the dentate gyrus of aged mice.
“As expected, without PTB suppression no new neurons were detected in the dentate gyrus of these aged mice (Extended Data Figure 5).”
Quote in the paperSubstantial claim - Findingown data
At early time points (1 week and 2 weeks) after ICV injection of PTB ASOs, most of the tdTomato expressing cells with neuronal character in hippocampi of PTB-ASO treated mice had morphological characteristics expected of newly generated neurons.
“At these early time points, most of the tdTomato expressing cells with neuronal character in hippocampi of PTB-ASO treated mice had morphological characteristics expected of newly generated neurons.”
Quote in the paperSubstantial claim - Findingown data
No differences between PTB and control ASO treated groups were seen in stress related behaviors in open field assays that included distance traveled, velocity of movement, and time spent in the open.
“Using observers blinded to the treatment ASO, no differences between PTB and control ASO treated groups were seen in stress related behaviors46 in open field assays that included distance traveled, velocity of movement, and time spent in the open (Figure 7a,b,c).”
Quote in the paperSubstantial claim - Findingown data
Over a subsequent six week period, DCX-positive neurons in PTB ASO injected mice decreased by three fold.
“Over a subsequent six week period, DCX-positive neurons in PTB ASO injected mice decreased by three fold (Figure 4b,e), as expected if many initial DCX-positive neurons had matured.”
Quote in the paperSubstantial claim - Findingown data
ASO-mediated transient suppression of PTB improved mouse memory in Barnes maze and novel object recognition assays.
“Fifth, ASO-mediated transient suppression of PTB improved mouse memory (in Barnes maze and novel object recognition assays), an outcome consistent with production of new functional neurons, but inconsistent with existing neurons artifactually labeled with tdTomato.”
Quote in the paperSubstantial claim - Findingown data
PTB ASO injection into the adult mouse nervous system generated a transient 49.2 fold increase in new immature (DCX-positive) neurons 2 weeks post suppression of PTB.
“Fourth, independent of Cre/tdTomato marking, PTB ASO injection into the adult mouse nervous system generated a transient 49.2 fold increase in new immature (DCX-positive) neurons 2 weeks post suppression of PTB.”
Quote in the paperSubstantial claim - Findingown data
In 1.2 year old PTB-ASO injected mice there was a 19.8 fold increase in DCX positive cells even when compared with control ASO injected young adult (5 month old) mice.
“Indeed, in 1.2 year old PTB-ASO injected mice there was a 19.8 fold increase in DCX positive cells even when compared with control ASO injected young adult (5 month old) mice in which some endogenous neurogenesis was still occurring.”
Quote in the paperSubstantial claim - Findingown data
PTB suppression in the human organoid model induced a 50-100% increase in new neurons.
“Third, PTB suppression in the human organoid model, a well-established in vitro model of neurodevelopment, induced 50–100% increase in new neurons.”
Quote in the paperSubstantial claim - Findingown data
Current injections into tdTomato-positive neurons provoked action potentials similar to those from tdTomato-negative cells.
“Furthermore, current injections into tdTomato-positive neurons provoked action potentials similar to those from tdTomato-negative cells (Figure 6c).”
Quote in the paperSubstantial claim - Findingown data
Reduction in GFAP mRNA was coupled with induction of NeuN mRNA in human brain organoids.
“Reduction in GFAP mRNA was coupled with induction of NeuN mRNA (Figure 1f), similar to what was found after PTB suppression in cultured mouse astrocytes (Figure 1b).”
Quote in the paperSubstantial claim - Findingown data
The PTB-ASO treated group escaped the Barnes maze more rapidly compared to the control ASO-treated group.
“However, using a Barnes maze test that scored the time required to find an escape hole during four days of training, as well as a final fifth day44, the PTB-ASO treated group escaped the maze more rapidly compared to the control ASO-treated group (Figure 7e).”
Quote in the paperSubstantial claim - Findingown data
It also induced a similar increase in neurons in the CA1 region of the hippocampus.
“It also induced a similar increase in neurons in the CA1 region of the hippocampus, which developed a morphology expected of pyramidal neurons (Extended Data Figure 4).”
Quote in the paperSubstantial claim - Findingown data
A significant enhancement was recorded in the time spent near novel objects in PTB-ASO injected mice compared to those injected with a control ASO.
“Using a novel object recognition test45 to monitor hippocampal function, a significant enhancement was recorded in the time spent near novel objects in PTB-ASO injected mice compared to those injected with a control ASO (Figure 7f,g).”
Quote in the paperSubstantial claim - Findingown data
The addition of either ASO to culture media of primary murine astrocytes rapidly suppressed PTB mRNA.
“The addition of either ASO to culture media of primary murine astrocytes rapidly suppressed PTB mRNA (Figure 1c).”
Quote in the paperSubstantial claim - Findingown data
Single PTB-ASO injection into CSF produced new neurons that comprised 4.5% of the total neurons in the dentate gyri of aged (14 months old) mice.
“Remarkably, single PTB-ASO injection into CSF produced new neurons that comprised 4.5% of the total neurons in the dentate gyri of aged (14 months old) mice (Figure 2d,g), with conversion of 5% of all tdTomato-positive cells into tdTomato+, NeuN+ expressing neurons (Figure 2f).”
Quote in the paperSubstantial claim - Findingown data
We have generated new neurons in the cortex and hippocampus of the normal aged adult mouse brain by a transient, partial suppression of PTB using an ASO delivered by a therapeutically viable single dose injection into CSF.
“We have generated new neurons in the cortex and hippocampus of the normal aged adult mouse brain by a transient, partial suppression of PTB using an ASO delivered by a therapeutically viable single dose injection into CSF.”
Quote in the paperSubstantial claim - Findingown data
New neurons convert from radial glia or astrocytes, not from artifactual activation of the tdTomato reporter in neurons already present.
“five lines of evidence demonstrate that new neurons convert from radial glia or astrocytes, not from artifactual activation of the tdTomato reporter in neurons already present.”
Quote in the paperSubstantial claim - Findingown data
Single injection into CSF of a PTB mRNA-targeting ASO induced a 10 fold higher increase in NeuN expressing tdTomato+ cells in the first and fourth layers of the cortex.
“Single injection into CSF of a PTB mRNA-targeting ASO induced a 10 fold higher increase in NeuN expressing tdTomato+ cells in the first and fourth layers of the cortex (Figure 2b), each displaying a neuronal morphology similar to endogenous cortical neurons (Figure 2c).”
Quote in the paperSubstantial claim - Findingown data
Axons and dendrites were significantly elevated in PTB-ASO treated organoids compared with control ASO treated organoids.
“Furthermore, axons and dendrites (measured by axonal marker Tuj1 (Extended Data Figure 3a,b) or dendritic marker MAP2 (Figure 1i,j,k,l)) were significantly elevated in PTB-ASO treated organoids compared with control ASO treated organoids.”
Quote in the paperSubstantial claim - Findingown data
Conversion of 5% of all tdTomato-positive cells into tdTomato+, NeuN+ expressing neurons in aged mice.
“Remarkably, single PTB-ASO injection into CSF produced new neurons that comprised 4.5% of the total neurons in the dentate gyri of aged (14 months old) mice (Figure 2d,g), with conversion of 5% of all tdTomato-positive cells into tdTomato+, NeuN+ expressing neurons (Figure 2f).”
Quote in the paperSubstantial claim - Findingown data
One and two weeks after PTB ASO injection into 5 month old mice, doublecortin (DCX) was present in 26.3 and 49.2 times (respectively) as many cells as found 1 and 2 weeks after injection of a control ASO.
“Furthermore, one and two weeks after PTB ASO injection into 5 month old mice, doublecortin (DCX), a protein expressed in developing immature neurons, but silenced as those neurons mature37, was present in 26.3 and 49.2 times (respectively) as many cells as found 1 and 2 weeks after injection of a control ASO (Figure 4b,e).”
Quote in the paperSubstantial claim - Findingown data
No DCX-containing immature neuron present in dentate gyri one week and two weeks after PTB ASO injection contained GFAP bundles.
“As mature astrocytes are well established42 to accumulate starburst bundles of GFAP filaments that fill the central cell bodies (e.g., see Figure 3a), we determined that no DCX-containing immature neuron present in dentate gyri one week and two weeks after PTB ASO injection contained GFAP bundles (Figure 5a,b; Supplementary video 5).”
Quote in the paperSubstantial claim - Findingown data
There were no differences between the two treatment groups in an optomotor assay.
“Similarly, there were no differences between the two treatment groups in an optomotor assay (Figure 7d).”
Quote in the paperNot a substantial claim - Findingown data
There was a 16-fold increase over control ASO injected mice in tdTomato-positive+ axons extending from neurons in the dentate gyrus into the Mossy fiber path and into the hippocampal CA3 area.
“There was also a 16-fold increase over control ASO injected mice in tdTomato-positive+ axons extending from neurons in the dentate gyrus into the Mossy fiber path (Figure 4f,h,i) and into the hippocampal CA3 area (Figure 4f,j), consistent with successful integration into the hippocampal circuit.”
Quote in the paperSubstantial claim - Findingown data
PTB-ASO treatment increased total DCX area in human organoids 1 month after treatment.
“Total DCX area in either PTB-ASO or control treated organoids. Data are presented as fold change mean +/− SEM (control: 1 +/− 0.09; PTB-ASO mean: 1.43 +/− 0.13; n=4 biological repeats, two tailed t test *p=0.042).”
Quote in the paperSubstantial claim - Findingown data
PTB-ASO increased Ki67 positive cells in dentate gyrus of 5-month-old mice.
“Total Ki67 positive cells per dentate gyrus of a 5 months old mouse 2 months post ICV delivery of PTB-ASO or control ASO. Data are presented as mean +/− SEM (control: 1.25 +/− 0.75; PTB-ASO mean: 5.75 +/− 2.3; n=4 biological repeats).”
Quote in the paperSubstantial claim - Findingown data
Malat1-ASO reduced Malat1 mRNA levels in human organoids at 2 and 4 weeks after addition.
“(2 weeks control mean: 1 +/− 0.04; 2 weeks post Malat1-ASOs mean: 0.11 +/− 0.03; 4 weeks control mean: 1 +/− 0.1; 4 weeks post Malat1-ASOs mean: 0.1 +/− 0.02; n=3 biological repeats).”
Quote in the paperNot a substantial claim - Findingown data
PTB suppression was less than 50% in most brain regions.
“PTB suppression was less than 50% in most brain regions, while optimized ASOs to other targets have previously been shown to yield dose dependent target RNA suppression to 5% of initial level13,14,48.”
Quote in the paperSubstantial claim - Findingown data
PTB-ASO treatment did not significantly alter SOX2 positive cell numbers in human organoids.
“Quantification of the total SOX2 positive cells per organoid area treated with PTB-ASO compared to ASO control. Data are presented as mean +/− SEM (control mean: 436.7 +/− 17.82; PTB-ASO mean: 406.3 +/− 19.89; n=3 biological repeats).”
Quote in the paperSubstantial claim - Findingown data
In the hippocampus, where PTB was reduced by more than 50%, robust glia-to-neuron conversion was documented even in aged mice.
“In the brain region where PTB was reduced by more than 50% (the hippocampus), we document robust glia-to-neuron conversion even in aged mice”
Quote in the paperSubstantial claim - Findingown data
PTB-ASO injection into CSF induced a low number of new neurons in the cortex of aged (1.2-year-old) mice.
“Injection of ASO to suppress PTB into the cerebral spinal fluid induces a low number of new neurons in the aged mouse cortex. (a,b) Representative immunofluorescence image (a) from 1.2 years old mouse cortex taken 2 months post-ICV injection of PTB-ASO2 into mice carrying both a CAG-lox-stop-lox-tdTomato gene and a tamoxifen-inducible GFAP-CreERT2 transgene.”
Quote in the paperSubstantial claim - Findingown data
Malat1-ASO was detectable in human organoids 1 month after application.
“Representative immunofluorescence images from 5-month-old human organoids taken 1-month post-Malat1-ASO application to the organoid culture medium. Images show a view of (green) a Malat1-ASO (visualized by indirect immunofluorescence) or (blue) DAPI staining for DNA; experiment was reproduced three times, independently, with similar results.”
Quote in the paperNot a substantial claim - Findingown data
PTB-ASO increased Ki67 mRNA levels in human organoids 1 month after treatment.
“Ki67 mRNA levels measured by qPCR, 1 month after the addition of either PTB-ASO2 or control ASO to the human organoid culture medium. Data are presented as fold change mean +/− SEM (control: 1 +/− 0.35; PTB-ASO mean: 4.193 +/− 1.19; n=3 biological repeats).”
Quote in the paperSubstantial claim - Findingown data
PTB-ASO treatment increased TUJ1 protein in human organoids 1 month after treatment.
“Total TuJ1 area in PTB-ASO treated organoids compared to control ASO. Data are presented as fold change mean +/− SEM (control mean: 1 +/− 0.21; PTB-ASO mean: 1.73 +/− 0.33; n=3 biological repeats).”
Quote in the paperSubstantial claim - Findingown data
PTB-ASO treatment did not increase caspase 3 protein area in human organoids.
“Total caspase 3 (CC3) protein area in PTB-ASO treated organoids compared to control ASO. Data are presented as fold change mean +/− SEM (control mean: 1 +/− 0.21; PTB-ASO mean: 0.79 +/− 0.19; n=4 biological repeats).”
Quote in the paperSubstantial claim - Findingown data
Cy3-Malat1-ASO was detectable in 5-month-old human organoids 1 week after addition to culture medium.
“Representative immunofluorescence images from a 5-month-old human organoid taken 1-week post Cy3-Malat1-ASO addition to the culture medium. Images show a view of (red) Cy3-Malat1-ASO (visualized by direct immunofluorescence) or (blue) DAPI staining for DNA; experiment was reproduced two times, independently, with similar results.”
Quote in the paperNot a substantial claim - Premisecitation
Introduction of 2 or more mismatches abrogates activity of RNase H dependent ASOs.
“Recognizing that introduction of 2 or more mismatches abrogates activity of RNase H dependent ASOs19, we used the Bowtie algorithm to identify 196 candidate 20mer ASOs with 100% complementarity to both human and murine PTB pre-mRNAs and which did not match any other region within the human or murine genomes even with allowing a 2 base mismatch.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Vickers, T. A. et al. Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J. Biol. Chem. 278, 7108–7118 (2003). source
- Interpretationown data
Radial glial-like cells and other GFAP-expressing cells convert into new neurons that over a two-month period acquire mature neuronal character in a process mimicking normal neuronal maturation.
“Radial glial-like cells and other GFAP-expressing cells convert into new neurons that over a two-month period acquire mature neuronal character in a process mimicking normal neuronal maturation.”
Quote in the paperSubstantial claim - Interpretationown data
Generation of new neurons in the dentate gyrus of the aging brain can be achieved with a therapeutically feasible approach.
“Thus, generation of new neurons in the dentate gyrus of the aging brain can be achieved with a therapeutically feasible approach, thereby opening prospects for production of neurons to replace those lost to neurodegenerative disease.”
Quote in the paperSubstantial claim - Interpretationown data
The enhanced production of new neurons is inconsistent with artifactual marking of mature neurons.
“This strikingly enhanced production of new neurons is inconsistent with artifactual marking of mature neurons.”
Quote in the paperSubstantial claim - Study design and conductown data
Preliminary toxicity assay after ICV injection into CSF of healthy adult mice determined that each ASO was well tolerated with no overt changes in body weight, overall health, spontaneous activity, and gross motor behavior.
“We identified those which most effectively reduced PTB mRNA levels in a mouse cell line with effective ASO uptake (murine 4T1 cells) and then conducted a preliminary toxicity assay after intracerebroventricular (ICV) injection into CSF of healthy adult mice to determine that each was well tolerated with no overt changes in body weight, overall health, spontaneous activity, and gross motor behavior”
Quote in the paperSubstantial claim - Interpretationown data
PTB ASO-dependent generation of new neurons appears to trigger the typical maturation process by which new neurons are generated during development and adult neurogenesis.
“Thus, PTB ASO-dependent generation of new neurons appears to trigger the typical maturation process by which new neurons are generated during development39 and adult40 neurogenesis.”
Quote in the paperSubstantial claim - Interpretationown data
New neurons were induced by reduction in PTB expression in human brain organoids mediated by free uptake of an ASO to trigger catalytic degradation of PTB mRNA.
“Hence, new neurons were induced by reduction in PTB expression in human brain organoids mediated by free uptake of an ASO to trigger catalytic degradation of PTB mRNA.”
Quote in the paperSubstantial claim - Interpretationown data
Suppression of PTB by at least 50% may be required to initiate efficient conversion in other brain regions.
“suggesting that suppression by at least this amount may be required to initiate efficient conversion in other brain regions.”
Quote in the paperSubstantial claim
- May combine two claims. 34
- Classified as probably not a substantial claim. 16
- The quote only partly states this claim. 2
May combine two claims.
PremisecitationASO injection is a current standard of care for spinal muscular atrophy and is in five ongoing Phase I trials in ALS, Parkinson's, and Alzheimer's diseases and in Phase III trials for inherited ALS and Huntington's disease.
“ASO injection is a current standard of care for the fatal childhood disease spinal muscular atrophy15 and is in five ongoing Phase I trials in ALS, Parkinson’s, and Alzheimer’s diseases and in Phase III trials for inherited ALS from a mutation in superoxide dismutase16,17 and for Huntington’s disease18.”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [15] Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017). source
The Background identifies nusinersen as an antisense oligonucleotide, and Trial Design and Treatment describes its intrathecal injection in infants with spinal muscular atrophy. The Conclusions report improved survival and motor function, but the paper does not establish that ASO injection is a current standard of care. The claims about trials in other diseases are attached to other citations, not this one. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [16] Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12, 435–442 (2013). source
The citation is attached to the claim about Phase III trials for inherited SOD1 ALS. The cited paper instead describes its SOD1 ALS study as a randomised Phase I trial (Abstract, Methods), and the Introduction calls it a first-in-human study. It does not establish the claimed Phase III status. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [17] Miller, T. et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 383, 109–119 (2020). source
- cites [18] Leavitt, B. R. & Tabrizi, S. J. Antisense oligonucleotides for neurodegeneration. Science 367, 1428–1429 (2020). source
The Abstract reports an approved ASO therapy for spinal muscular atrophy and ongoing trials in ALS, Parkinson’s, and Alzheimer’s disease. The clinical-trials section identifies a phase 3 Huntington’s disease trial, but places the SOD1-mutant ALS trial in phase 1/2a, not phase 3; it also does not establish a total of five ongoing phase I trials. The copy provides no page numbers for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe dentate gyrus of the hippocampus is the brain region where the most active neurogenesis has been documented to take place.
“The dentate gyrus of the hippocampus is the brain region where the most active neurogenesis has been documented to take place23–25.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [23] Altman, J. & Das, G. D. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319–335 (1965). source
- cites [24] Ming, Gli & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702 (2011). source
The Introduction (page unavailable) identifies the dentate gyrus as one of two regions where adult neurogenesis is active under normal conditions. It also identifies the subventricular zone as active and does not say that neurogenesis is most active in the dentate gyrus. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [25] Zhao, C., Deng, W. & Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008). source
The Main Text (indexed as Abstract; no page available) identifies the subgranular zone of the hippocampal dentate gyrus as a site where adult neurogenesis is clearly demonstrated. It also identifies the subventricular zone as such a site, but does not say that neurogenesis is most active in the dentate gyrus. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationASO injection into CSF is a therapeutically viable approach that was initiated 14 years ago and validated to yield effective delivery to neurons and glial cells throughout the rodent and non-human primate nervous systems.
“ASO injection into cerebral spinal fluid (CSF) is a therapeutically viable approach that was initiated 14 years ago13 and validated to yield effective delivery to neurons and glial cells throughout the rodent13 and non-human primate14 nervous systems.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [13] Smith, R. A. et al. Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest. 116, 2290–2296 (2006). source
- cites [14] Kordasiewicz, H. B. et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74, 1031–1044 (2012). source
The Results section on non-human primates reports that ASOs infused into rhesus monkeys’ CSF reached neurons across many brain and spinal-cord regions and reduced huntingtin mRNA. It does not establish delivery to glial cells in the primates; the reported astrocyte uptake appears in the separate rodent results. The ‘14 years ago’ and rodent portions of the sentence are attached to citation 13, not this source’s citation 14. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationRadial glial cells, stem cell precursors, and astrocytes all express GFAP and are found in the dentate gyrus.
“Radial glial cells, stem cell precursors, and astrocytes - all reported to express GFAP (reviewed in ref.26) - are found in the dentate gyrus2,27,28.”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [26] Song, H., Berg, D. A., Bond, A. M. & Ming, Gli Radial glial cells in the adult dentate gyrus: what are they and where do they come from? F1000Res. 7, 277 (2018). source
- cites [2] Bond, A. M., Ming, G. L. & Song, H. Adult mammalian neural stem cells and neurogenesis: five decades later. Cell Stem Cell 17, 385–395 (2015). source
- cites [27] Song, H., Stevens, C. F. & Gage, F. H. Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39–44 (2002). source
- cites [28] Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe known low rate of ongoing neurogenesis in the dentate gyrus of young adult mice.
“consistent with the known low rate of ongoing neurogenesis in the dentate gyrus of young adult mice29.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [29] Morgenstern, N. A., Lombardi, G. & Schinder, A. F. Newborn granule cells in the ageing dentate gyrus. J. Physiol. 586, 3751–3757 (2008). source
The section “Sharp decrease in adult neurogenesis in the ageing brain” reports newly generated dentate granule cells in 2-month-old mice, supporting ongoing neurogenesis in young adults. It reports a roughly 40-fold decline by 10 months, but does not characterize the rate in young adult mice as low. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationMAP2 is a marker for mature dendrites.
“contained MAP2 (Supplementary video 4), a marker for mature dendrites38.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Kosik, K. S. & Finch, E. A. MAP2 and tau segregate into dendritic and axonal domains after the elaboration of morphologically distinct neurites: an immunocytochemical study of cultured rat cerebrum. J. Neurosci. 7, 3142–3153 (1987). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationDoublecortin (DCX) is a protein expressed in developing immature neurons, but silenced as those neurons mature.
“doublecortin (DCX), a protein expressed in developing immature neurons, but silenced as those neurons mature37”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [37] Van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002). source
The Methods (page unavailable) list the neuronal markers examined but do not mention doublecortin or DCX. The paper discusses maturation of newly generated neurons and possible shutdown of GFP expression (Abstract, page unavailable), not whether DCX expression is silenced as neurons mature. Searches for “doublecortin DCX” and immature-neuron marker expression found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIt is well accepted that neurogenesis sharply decreases in the aged mammalian nervous system, with no new neurons detectable in mice by 10 months of age.
“It is well accepted that neurogenesis sharply decreases in the aged mammalian nervous system29–31, with no new neurons detectable in mice by 10 months of age29,31.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [29] Morgenstern, N. A., Lombardi, G. & Schinder, A. F. Newborn granule cells in the ageing dentate gyrus. J. Physiol. 586, 3751–3757 (2008). source
The ‘Sharp decrease in adult neurogenesis in the ageing brain’ section reports an approximately 40-fold reduction between 2- and 10-month-old mice, supporting the decline. But it also says GFP-positive newborn neurons were observed at all time points, and the ‘Complex morphological traits’ section describes neurons born in 10-month-old mice. The claim that none were detectable by that age is therefore contradicted. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [30] Sorrells, S. F. et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381 (2018). source
The paper’s Abstract reports a sharp early decline in hippocampal neurogenesis in humans and a decline during juvenile development in macaques. It does not report that no new neurons are detectable in mice by 10 months of age; that species-specific claim is unsupported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [31] Heine, V. M., Maslam, S., Joëls, M. & Lucassen, P. J. Prominent decline of newborn cell proliferation, differentiation, and apoptosis in the aging dentate gyrus, in absence of an age-related hypothalamus-pituitary-adrenal axis activation. Neurobiol. Aging 25, 361–375 (2004). source
Classified as probably not a substantial claim.
PremisecitationThe process by which newly generated neurons in normal development are incorporated into the granular cell layer is well established and involves expression of specific markers and development of defined neuronal morphology.
“The process by which newly generated neurons in normal development are incorporated into the granular cell layer is well established and involves expression of specific markers and development of defined neuronal morphology24,26,34,35.”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [24] Ming, Gli & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702 (2011). source
The Development of Neural Stem Cells in the Adult Brain section (page unavailable) describes immature neurons migrating into the dentate granule cell layer, extending dendrites and axons, and following a stereotyped course of integration. It also mentions developmental marker expression, but primarily describes adult neurogenesis; it does not establish the claimed marker-defined process for normal development generally. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [26] Song, H., Berg, D. A., Bond, A. M. & Ming, Gli Radial glial cells in the adult dentate gyrus: what are they and where do they come from? F1000Res. 7, 277 (2018). source
The ‘Classic homogeneous radial glia-like cell population model’ section describes adult-born neuroblasts expressing DCX, developing a bipolar shape, migrating into the granule cell layer, and maturing into Prox1-positive neurons. The ‘Origin of adult neural stem cells’ section describes markers during embryonic development, but does not establish the same marker-and-morphology sequence for neurons incorporated during normal development. The claim blends the paper’s adult neurogenesis account with its developmental account. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [34] Toni, N. et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat. Neurosci. 11, 901–907 (2008). source
The Results describe morphological maturation of adult-born granule-cell axons and compare their mature boutons with those of neurons born during early postnatal development. But the paper does not establish a process of incorporation into the granule cell layer during normal development or describe the expression of specific developmental markers; GFP was introduced to label the cells. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [35] Zhao, C., Teng, E. M., Summers, R. G., Ming, G. L. & Gage, F. H. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 26, 3–11 (2006). source
The Results section (‘Elaborate dendritic arborization of newborn cells within 3 weeks’; page not supplied) places newborn neurons in the granule cell layer, identifies neuronal-marker expression (NeuN), and describes their developing morphology. The Discussion defines four morphological maturation stages. But the Introduction says the timing and duration of these features were not clear, so calling the process ‘well established’ overstates the paper; its principal focus is adult mouse neurogenesis, although it also compares postnatal neurons. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationHuman brain organoids are a scaled-down, three-dimensional model of the human brain, mimicking various developmental features, including generation of new neurons by their conversion from radial glia and incorporation into neuronal network.
“Human brain organoids are emerging as a scaled-down, three-dimensional model of the human brain, mimicking various developmental features, including generation of new neurons by their conversion from radial glia20 and incorporation into neuronal network21.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [20] Di Lullo, E. & Kriegstein, A. R. The use of brain organoids to investigate neural development and disease. Nat. Rev. Neurosci. 18, 573–584 (2017). source
- cites [21] Trujillo, C. A. et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell 25, 558–569 (2019). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAn unresolved controversy is whether the apparent generation of new neurons from astrocytes in earlier reports may actually reflect endogenous neuronal precursors or mature neurons mistakenly labeled by various fluorescent marking schemes, as opposed to transdifferentiation from glia.
“An unresolved controversy41 is whether the apparent generation of new neurons from astrocytes in earlier reports7 may actually reflect endogenous neuronal precursors or mature neurons mistakenly labeled by various fluorescent marking schemes, as opposed to transdifferentiation from glia.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [41] Wang, L.-L., Garcia, C. S., Zhong, X., Ma, S. & Zhang, C.-L. Rapid and efficient in vivo astrocyte-to-neuron conversion with regional identity and connectivity? Preprint at bioRxiv https://doi.org/10.1101/2020.08.16.253195 (2020). source
The Introduction and Discussion (pages unavailable) report that endogenous neurons can be mislabeled as astrocyte-converted neurons by less stringent reporter methods, supporting the mature-neuron alternative. Our copy does not establish that the apparent new neurons instead came from endogenous neuronal precursors. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [7] Barker, R. A., Götz, M. & Parmar, M. New approaches for brain repair—from rescue to reprogramming. Nature 557, 329–334 (2018). source
The discussion accompanying Figure 3 (pp. 8–9) describes endogenous neurogenesis and reports glia-to-neuron conversion, but does not discuss a controversy over the origin of the reported neurons. Searches for fluorescent mislabeling and for neuronal precursors being mistaken for glial-derived neurons found no passage addressing that concern. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataPTB-ASO enhanced production of tdTomato expressing neurons 37.5 times in the dentate gyrus and 10 times in the cortex or CA1 of reporter mice.
“First, production of tdTomato expressing neurons was enhanced 37.5 times in the dentate gyrus (and 10 times in the cortex or CA1) of reporter mice in which PTB expression was reduced with a PTB targeting ASO.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWithin 3 days of ASO addition, conversion into neurons was initiated, with reduced PTB expression accompanied by a sharp reduction in GFAP-encoding mRNA and induction of the neuronal-specific NeuN mRNA.
“Within 3 days, conversion into neurons was initiated, with reduced PTB expression accompanied by a sharp reduction in GFAP-encoding mRNA (an astrocytic marker) and induction of the neuronal-specific NeuN mRNA (Figure 1c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBy 2 months post-ICV injection, the vast majority (92.7%) of tdTomato+ cells with neuronal morphology no longer expressed DCX, 97% of which had converted to expression of the mature neuronal marker NeuN.
“By 2 months post-ICV injection, the vast majority (92.7%) of tdTomato+ cells with neuronal morphology no longer expressed DCX, 97% of which had converted to expression of the mature neuronal marker NeuN (Figure 4d, Extended Data Figure 10).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter an additional six weeks the tdTomato+ neurons had developed long dendritic processes which extended into the Perforant pathway and contained MAP2.
“In comparison to the short dendritic branching in immature neurons present 2 weeks post-ICV of PTB-ASO (Figure 4a,d), after an additional six weeks the tdTomato+ neurons had developed long dendritic processes which extended into the Perforant pathway (Figure 4f,g) and contained MAP2 (Supplementary video 4), a marker for mature dendrites38.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPTB-ASOs penetrated the organoids and reduced PTB mRNA levels.
“PTB-ASOs penetrated the organoids (Figure 1e) and reduced PTB mRNA levels (Figure 1f).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTwo weeks following ICV injection with PTB-ASO in 1.2 year old mice, many DCX positive cells were present, while there was a complete absence of DCX positive cells present in any of the age matched, control ASO injected mice.
“Consistent with this interpretation, two weeks following ICV injection with PTB-ASO in 1.2 year old mice, many DCX positive cells were present, while there was a complete absence of DCX positive cells present in any of the age matched, control ASO injected mice (Figure 4e, Extended Data Figure 8).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUnbiased counting of total tdTomato+ expressing cells throughout the dentate gyrus revealed a 37.5-fold increase (compared with saline or control ASO injected mice) in newly generated neurons identified as tdTomato+, NeuN+ cells, with 15% (± 5%, n=3) of total tdTomato+ cells also NeuN+.
“Unbiased counting of total tdTomato+ expressing cells throughout the dentate gyrus revealed a 37.5-fold increase (compared with saline or control ASO injected mice) in newly generated neurons identified as tdTomato+, NeuN+ cells, with 15% (± 5%, n=3) of total tdTomato+ cells also NeuN+ (Figure 2d,e,f, Supplementary Video 3).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataKi67 was elevated in the dentate gyri of both 5 month or 1.2 year old PTB-ASO injected mice and in PTB-treated human brain organoids.
“Instead, Ki67, a marker for cell proliferation33, was elevated in the dentate gyri of both 5 month or 1.2 year old PTB-ASO injected mice (Extended Data Figure 7a-c) and in PTB-treated human brain organoids (Extended Data Figure 7d), consistent with proliferation of precursor cells stimulated to divide by homeostatic mechanisms that maintain the levels of glia, including astrocytes32.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWith PTB ASO injection, limited new neuron formation was observed in the cortex of aged mice, at a rate similar to what was seen in younger mice.
“With PTB ASO injection, limited new neuron formation was observed in the cortex of these aged mice (Extended Data Figure 6), at a rate similar to what was seen in younger mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataConversion to neurons did not affect the pool of GFAP-expressing cells, as no difference was observed in the total number of GFAP or nestin expressing cells in the human organoid model or in GFAP-positive cells in the dentate gyri of PTB-ASO treated animals.
“Conversion to neurons did not, however, affect the pool of GFAP-expressing cells, as no difference was observed in the total number of GFAP or nestin expressing cells in the human organoid model (Figure 3c) or in GFAP-positive cells in the dentate gyri of PTB-ASO treated animals (Figure 3c,d,e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWidespread Malat1-ASO presence was observed within the organoids, accompanied by 85% reduction of Malat1 mRNA levels at both 2- and 4-weeks post-treatment.
“Widespread Malat1-ASO presence was observed within the organoids, accompanied by 85% reduction of Malat1 mRNA levels at both 2- and 4-weeks post-treatment (Extended Data Figure 2).”
Quote in the paperNot a substantial claim- Rests on an assumption: The use of ASOs to modulate gene expression in human organoids has not previously been reported.
May combine two claims.
Findingown dataThey were located exclusively in the basal layer of the dentate gyrus and exhibited shorter and less complex dendritic branches than those of tdTomato expressing neurons at 2 months post ASO injection.
“They were located exclusively in the basal layer of the dentate gyrus and exhibited shorter and less complex dendritic branches (Figure 4a,c) than those of tdTomato expressing neurons at 2 months post ASO injection (Figure 4a,d), the latter of which had acquired dendritic morphologies similar to those of mature, endogenous neurons34–36.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data~30% of the tdTomato+ cells exhibited morphologic characteristics expected of radial glial cells but had hybrid neuronal/glial character, with a DCX+ cell body sharing dendrites with GFAP filaments.
“However, ~30% of the tdTomato+ cells exhibited morphologic characteristics expected of radial glial cells (Figure 5a,c) [including triangular shaped cell bodies located near the sub granular zone and bushy radial dendrites extending through the granular cell layer26] but had hybrid neuronal/glial character, with a DCX+ cell body sharing dendrites with GFAP filaments, as would be expected for cells”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataReduction of PTB mRNA was observed 72 hours post ICV injection, followed by induction of neuronal PTB (nPTB) 15 days post injection.
“Reduction of PTB mRNA was observed 72 hours post ICV injection, followed by induction of neuronal PTB (nPTB) 15 days post injection (Extended Data Figure 1b,c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNeither the number of pluripotent cells (SOX2+) nor those with caspase 3 activation was changed by PTB-ASO treatment.
“Neither the number (Extended Data Figure 3c,d) of pluripotent cells (SOX2+) nor those with caspase 3 activation (Extended Data Figure 3e) was changed by PTB-ASO treatment.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataNewly generated neurons in granular cell layer, CA1, and cortex 2 months post-PTB-ASO ICV have region-specific morphologies.
“Morphology of newly generated neurons in different brain regions, 2 months post-PTB-ASO ICV administration. Representative immunofluorescence images of (left) granular cell layer, (middle) CA1, and (right) cortex, 2 months post-ICV injection of PTB-ASO2 into mice carrying both a CAG-lox-stop-lox-tdTomato gene and a tamoxifen-inducible GFAP-CreERT2 transgene.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPTB mRNA in hippocampus was reduced at 3 days but returned to control levels by 15 days after PTB-ASO injection.
“(control mean: 1 +/− 0.04; 3 days post PTB-ASOs mean: 0.61 +/− 0.08; 15 days post PTB-ASOs mean: 1.18 +/− 0.24; n=3 biological repeats.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataPTB-ASO ICV delivery increased DCX expression in dentate gyrus of 1.5-year-old mice 2 weeks post injection.
“DCX expression levels 2 weeks post-PTB-ASO ICV delivery into 1.5 years old mice. Four representative images and insets of 1.5 years old mice dentate gyrus at 2 weeks post ICV delivery of (upper) control or (lower) PTB-ASO. (Green) DCX (visualized by indirect immunofluorescence); (blue) DAPI stain for DNA; experiment was reproduced three times, independently, with similar results.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datanPTB mRNA in hippocampus was reduced at 3 days and increased at 15 days after PTB-ASO injection.
“(control mean: 1 +/− 0.03; 3 days post PTB-ASOs mean: 0.63 +/− 0.04; 15 days post PTB-ASOs mean: 1.75 +/− 0.33; n=3 biological repeats).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn control-ASO injected mice, no tdTomato+ NeuN+ neurons were detected in the dentate gyrus of 1.2-year-old mice, whereas some were detected at 5 months.
“Quantification of the tdTomato+ & NeuN+ neurons (iNeurons) in the granular cell layer 2 months post ICV injection of control-ASO at 5 months or 1.2 years old mice. Data are presented as fold change mean +/− SEM. (control 5 months mean: 1 +/− 0.35; Control 1.2 years old mean: 0 +/− 0; n=8, n=5 brain slides per each condition, n=3, n=1, respectively).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPTB-ASO injection increased tdTomato+ NeuN+ cells in dentate gyrus of 5-month-old mice at 2 weeks and more at 2 months.
“Quantitation of total tdTomato+, NeuN+ positive cells per dentate gyrus area of 5 months old mice 2 weeks or 2 months post PTB-ASO or control ICV injection into mice Data are presented as mean +/− SEM (control: 1.33 +/− 0.66; 2 weeks PTB-ASO mean: 3.16 +/− 1.59; 2 months PTB-ASO mean: 28.88 +/− 4.87; n=3, n=3, n=4, respectively; **, One way ANOVA with Tukey’s multiple comparisons, **p=0.0013).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe new neurons functionally integrate into endogenous circuits and modify mouse behavior.
“The new neurons functionally integrate into endogenous circuits and modify mouse behavior.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataUnbiased counting was used to quantify tdTomato+ expressing cells.
“Unbiased counting of total tdTomato+ expressing cells throughout the dentate gyrus revealed a 37.5-fold increase (compared with saline or control ASO injected mice) in newly generated neurons identified as tdTomato+, NeuN+ cells, with 15% (± 5%, n=3) of total tdTomato+ cells also NeuN+ (Figure 2d,e,f, Supplementary Video 3).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataBehavioral assays were performed with observers blinded to the treatment ASO.
“Using observers blinded to the treatment ASO, no differences between PTB and control ASO treated groups were seen in stress related behaviors46 in open field assays that included distance traveled, velocity of movement, and time spent in the open (Figure 7a,b,c).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationMature astrocytes are well established to accumulate starburst bundles of GFAP filaments that fill the central cell bodies.
“As mature astrocytes are well established42 to accumulate starburst bundles of GFAP filaments that fill the central cell bodies (e.g., see Figure 3a)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Eliasson, C. et al. Intermediate filament protein partnership in astrocytes. J. Biol. Chem. 274, 23996–24006 (1999). source
May combine two claims.
Interpretationown dataWithin two months post-ICV injection of PTB-ASO into CSF newly generated neurons are sufficiently integrated into endogenous circuits to be capable of receiving both glutamate and GABA inputs and firing action potentials that are indistinguishable from the neighboring endogenous granular cell layer neurons.
“These results indicate that within two months post-ICV injection of PTB-ASO into CSF newly generated neurons are sufficiently integrated into endogenous circuits to be capable of receiving both glutamate and GABA inputs and firing action potentials that are indistinguishable from the neighboring endogenous granular cell layer neurons.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationNovel object recognition test monitors hippocampal function.
“Using a novel object recognition test45 to monitor hippocampal function”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] Heyser, C. J. & Chemero, A. Novel object exploration in mice: not all objects are created equal. Behav. Process. 89, 232–238 (2012). source
May combine two claims.
Interpretationown dataThe memory improvement is consistent with production of new functional neurons and inconsistent with existing neurons artifactually labeled with tdTomato.
“an outcome consistent with production of new functional neurons, but inconsistent with existing neurons artifactually labeled with tdTomato.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataOver a two month period the new neurons acquire mature neuronal character and functionally integrate into endogenous circuits, with dendrites extending into the Perforant path and receiving inhibitory (GABA) and excitatory (glutamate) inputs, and axons extending into CA3 and sending action potentials which modify hippocampal-dependent mouse behavior.
“Over a two month period the new neurons acquire mature neuronal character and functionally integrate into endogenous circuits, with dendrites extending into the Perforant path and receiving inhibitory (GABA) and excitatory (glutamate) inputs, and axons extending into CA3 and sending action potentials which modify hippocampal-dependent mouse behavior.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationKi67 is a marker for cell proliferation.
“Ki67, a marker for cell proliferation33”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Gerdes, J. et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J. Immunol. 133, 1710–1715 (1984). source
May combine two claims.
Interpretationown dataA single ICV injection of an ASO to suppress PTB induces new neurons in the dentate gyrus of the adult mouse brain with no depletion in total GFAP-expressing cell number.
“Thus, a single ICV injection of an ASO to suppress PTB induces new neurons in the dentate gyrus of the adult mouse brain with no depletion in total GFAP-expressing cell number.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataNew neurons generated by a transiently lowered PTB level appear to derive from conversion of a glial progenitor, including at least two different progenitors (radial glia for granular neurons and human neurons in organoids; astrocytes for cortical and pyramidal neurons).
“In each example we document, the new neurons generated by a transiently lowered PTB level appear to derive from conversion of a glial progenitor, including at least two different progenitors (radial glia for granular neurons and human neurons in organoids; astrocytes for cortical and pyramidal neurons).”
Quote in the paperSubstantial claim- Rests on an assumption: Human organoids are a well-established in vitro model of neurodevelopment.
May combine two claims.
Interpretationown dataNeuronal identity is likely determined or affected by local cues produced within each specific brain region, and potentially by intrinsic gene expression within the glial cells that convert to neurons within each brain subarea.
“It seems highly likely that neuronal identity is determined (or at least affected) by local cues produced within each specific brain region, and potentially by intrinsic gene expression within the glial cells that convert to neurons within each brain subarea.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationAssays thought to rely on hippocampal related behaviors.
“Assays thought to rely on hippocampal related behaviors43–45 were performed two months post ASO delivery to test the functionality of PTB ASO generated new neurons in the dentate gyri of 1.5 year old control or PTB ASO ICV injected mice.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [43] Van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270 (1999). source
- cites [44] Barnes, C. A. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J. Comp. Physiol. Psychol. 93, 74–104 (1979). source
- cites [45] Heyser, C. J. & Chemero, A. Novel object exploration in mice: not all objects are created equal. Behav. Process. 89, 232–238 (2012). source
May combine two claims.
Interpretationown dataGenerating new neurons in the aging brain (especially within the dentate gyrus) can be achieved with a therapeutically feasible approach of ASO-mediated transient reduction in PTB, and a therapeutically feasible pharmacological intervention with ASOs to transiently suppress PTB can facilitate generation of replacement neurons within the aged mammalian nervous system.
“Our findings demonstrate that generating new neurons in the aging brain (especially within the dentate gyrus) can be achieved with a therapeutically feasible approach of ASO-mediated transient reduction in PTB.”
- Also stated in: § Discussion · boosted
“Nevertheless, our findings strongly support that a therapeutically feasible pharmacological intervention with ASOs to transiently suppress PTB can facilitate generation of replacement neurons within the aged mammalian nervous system.”
Quote in the paperSubstantial claim- Rests on an assumption: Production of new neurons can replace those lost in neurodegenerative diseases of aging and thereby provide therapy.
- Also stated in: § Discussion · boosted
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe ASOs used for this study are not clinical candidates.
“The ASOs we used for this study are not clinical candidates.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The use of ASOs to modulate gene expression in human organoids has not previously been reported.
“Recognizing that the use of ASOs to modulate gene expression in human organoids has not previously been reported, we initially added a fluorescently tagged ASO targeting the long non-coding RNA Malat1 to brain organoid culture media and monitored its free uptake and efficacy over time.”
The paper relies on this without support.
Human organoids are a well-established in vitro model of neurodevelopment.
“PTB suppression in the human organoid model, a well-established in vitro model of neurodevelopment, induced 50–100% increase in new neurons.”
The paper relies on this without support.
Production of new neurons can replace those lost in neurodegenerative diseases of aging and thereby provide therapy.
“This discovery may represent a foundational first step for therapy development through production of neurons to replace those lost in neurodegenerative diseases of aging.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Aged-mouse DCX experiment has conflicting ages
MinorThe results describe the two-week DCX observation in 1.2-year-old mice and cite Extended Data Figure 8, but that figure identifies its two-week experiment as using 1.5-year-old mice.
“two weeks following ICV injection with PTB-ASO in 1.2 year old mice, many DCX positive cells were present, while there was a complete absence of DCX positive cells present in any of the age matched, control ASO injected mice (Figure 4e, Extended Data Figure 8).”
“Figure: Extended Data Figure 8: DCX expression levels 2 weeks post-PTB-ASO ICV delivery into 1.5 years old mice.”
Extended Data Figure 1 gives conflicting ASO doses
MinorPanel (a) specifies a 500 μg injection, while panels (b) and (c) specify 500 mg for the same type of injection into 3-month-old mice-a thousand-fold difference.
“3 days post ICV injection of 500 μg PTB or control ASOs into 3-months-old mouse brain”
“3 days and 15 days post ICV injection of 500 mg PTB or control ASOs into 3-month-old mouse brain”
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The 2021 yearbook of Neurorestoratology
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“Maimon et al. (Maimon et al., 2021) confirmed that downregulation of PTB by an antisense oligonucleotide (ASO) significantly reprogrammed astrocytes into neurons in vitro.”
BackgroundInfluentialPtbp1 knockdown failed to induce astrocytes to neurons in vivo
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Neuronal conversion from glia to replenish the lost neurons
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“The new neurons functionally integrated into endogenous circuits and improved behavioral performance in mice (Maimon et al., 2021).”
BackgroundHippocampal neurogenesis and pro‐neurogenic therapies for Alzheimer's disease
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PTBP1 regulates injury responses and sensory pathways in adult peripheral neurons
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“In contrast to overexpression such as NeuroD1 by viral vector, PTB knockdown by shRNA can be achieved with a shorter vector and ASO technique (Maimon et al., 2021), which are more easily applied in the clinic.”
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Therapeutic Potential of PTBP1 Inhibition, If Any, Is Not Attributed to Glia-to-Neuron Conversion
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Dong, W., Liu, S., Li, S., & Wang, Z. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.390965 · Cited by 20 · see citing works
A promise for neuronal repair: reprogramming astrocytes into neurons in vivo
Huang, L., Lai, X., Liang, X., Chen, J., Yang, Y., Xu, W., Qin, Q., Qin, R., Huang, X., Xie, M., et al. (2024) · Bioscience Reports · doi:10.1042/bsr20231717 · Cited by 18 · see citing works
Therapeutic Potential of PTB Inhibition Through Converting Glial Cells to Neurons in the Brain
Fu, X.-D., & Mobley, W. C. (2023) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-083022-113120 · Cited by 16 · see citing works
Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brainPreprint
Hoang, T. V., Kim, D. W., Appel, H., Pannullo, N. A., Leavey, P. J., Ozawa, M., Zheng, S., Yu, M., Peachey, N. S., Kim, J., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.04.462784 · Cited by 17 · see citing works
“Our data contrasts sharply with several recent studies that analyze the effects of Ptbp1 knockdown using ASO, shRNA, and/or CasRx (Zhou et al. 2020; H. Qian et al. 2020; Fu et al. 2020; Maimon et al. 2021), but is in agreement with a recent study the re-examined previous studies reporting astrocyte-to-neuron conversio…”
BackgroundResultInfluentialApplication and prospects of somatic cell reprogramming technology for spinal cord injury treatment
Yang, R., Pan, J., Wang, Y., Xia, P.-H., Tai, M., Jiang, Z., & Chen, G. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.1005399 · Cited by 15 · see citing works
Greșiță, A., Hermann, D., Boboc, I. K., Doeppner, T., Petcu, E., Semida, G. F., & Popa-Wagner, A. (2025) · Translational Stroke Research · doi:10.1007/s12975-025-01331-7 · Cited by 11 · see citing works
“Techniques like CRISPR-CasRx have successfully converted astrocytes into functional neurons in models of visual dysfunction and Parkinson’s disease, demonstrating integration and behavioral improvements in mice [143].”
McDowall, S., Bagda, V., Hodgetts, S. I., Mastaglia, F. L., & Li, D. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00450-9 · Cited by 14 · see citing works
Fukui, Y., Morihara, R., Hu, X., Nakano, Y., Yunoki, T., Takemoto, M., Abe, K., & Yamashita, T. (2024) · Scientific Reports · doi:10.1038/s41598-024-71212-w · Cited by 13 · see citing works
“The novel object recognition test (NORT) was performed to test recognition memory, which is thought to be linked to hippocampal damage 14 .”
InfluentialContardo, M., Gioia, R. D., Gagliardi, D., Comi, G. P., Ottoboni, L., Nizzardo, M., & Corti, S. P. (2022) · Biomedicines · doi:10.3390/biomedicines10020399 · Cited by 13 · see citing works
“Nonetheless, how aging can impact the feasibility of glia-to-neuron reprogramming is still largely unknown, although the Cleveland group paper [14] demonstrated that PTB reduction benefits glia-to-neuron conversion in aged mouse brains as well.”
BackgroundInfluentialPost-transcriptional mechanisms controlling neurogenesis and direct neuronal reprogramming
Papadimitriou, E., & Thomaidou, D. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.390976 · Cited by 13 · see citing works
“…cerebrospinal fluid of aged mice resulted in the conversion of radial glial-like cells and other glial fibrillary acidic protein (GFAP)-expressing glial cells into new neurons in the cortex and the dentate gyrus and led to their functional integration in endogenous circuits (Maimon et al., 2021).”
BackgroundLiu, Y., Ren, J. M., Zhang, W., Ding, L., Ma, R., Zhang, M., Zheng, S., Liang, R., & Zheng, S. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122707 · Cited by 12 · see citing works
Post-transcriptional regulation of the transcriptional apparatus in neuronal development
Nazim, M. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1483901 · Cited by 11 · see citing works
Astrocytes, a Promising Opportunity to Control the Progress of Parkinson’s Disease
Sánchez, A., Moráles, I., Rodriguez‐Sabate, C., Solé-Sabater, M., & Rodrı́guez, M. (2021) · Biomedicines · doi:10.3390/biomedicines9101341 · Cited by 12 · see citing works
Dennison, R., Usuga, E., Chen, H., Paul, J. Z., Arbelaez, C. A., & Teng, Y. D. (2023) · Cells · doi:10.3390/cells12040618 · Cited by 11 · see citing works
“Dentate gyrus, aged GFAPCreERT2CAG-loxstop-lox-tdTomato mice (1 year), M + F [33] ASO-PTBP1 CSF injection 5 (2 mpi) Granule cell layer neurons”
BackgroundSpatially Precise Genetic Engineering at the Electrode‐Tissue Interface
Xu, K., Yang, Y., Ding, J., Wang, J., Fang, Y. Z., & Tian, H. (2024) · Advanced Materials · doi:10.1002/adma.202401327 · Cited by 9 · see citing works
Can pluripotent/multipotent stem cells reverse Parkinson’s disease progression?
Wu, Y., Meng, X., Cheng, W., Yan, Z., Li, K., Wang, J., Jiang, T., Zhou, F., Wong, K., Zhong, C., et al. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1210447 · Cited by 9 · see citing works
Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury
Liu, J., Xin, X., Sun, J., Fan, Y., Zhou, X. C., Gong, W., Yang, M., Li, Z., Wang, Y., Yang, Y., et al. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.380907 · Cited by 8 · see citing works
Woods, C. R., Makia, M. S., Lewis, T. R., Crane, R., Zeibak, S., Yu, P., Kakakhel, M., Castillo, C. M., Arshavsky, V. Y., Naash, M. I., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48846-5 · Cited by 7 · see citing works
“The control ASO has been previously employed as a control in various contexts: to suppress polypyrimidine tract binding protein 1 in neurons 72 , to increase microglial phagocytosis 73 , to deliver to the cornea 74 , to alleviate hepatic fi brosis 75 , in fi nding a protective factor in Dravet…”
Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease
Lukiw, W. J. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.875957 · Cited by 7 · see citing works
“In a related approach and targeting the polypyrimidine tract binding protein 1 (PTBP1) using a stabilized ∼20 nt antisense oligonucleotide containing 2-methoxyethyl (MOE)-modified nucleotides, and delivered by a single injection into the CSF, it was shown that the new neurons generated functionally integrated into end…”
BackgroundMethodJiang, Y.-K., Dong, F.-Y., Dong, Y.-B., Zhu, X., Pan, L.-H., Hu, L., Xu, L., Xu, X.-F., Xu, L.-M., & Zhang, X. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2023.1139737 · Cited by 6 · see citing works
“Compared with other approaches, ASO strategy could overcome the potential risks posed by permanent downregulation of PTBP1 as it can be paused (Maimon et al., 2021; Contardo et al., 2022).”
BackgroundRewiring Brain Recovery: Astrocyte–Neuron Metabolic Cooperation in Stroke
Lu, W., Jiang, Z., & Wen, J. (2026) · Antioxidants and Redox Signaling · doi:10.1177/15230864251411183 · Cited by 5 · see citing works
“Local transient injection of antisense oligonucleotides that directly target PTBP1 mRNA in the substantia nigra likewise reprograms astrocytes to dopaminergic neurons in mice (Maimon et al., 2021).”
Li, S.-T., Wan, Y., Chen, L., & Ding, Y. P. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114817 · Cited by 5 · see citing works
Re-Activation of Neurogenic Niches in Aging BrainPreprint
Maimon, R., Chillón-Marinas, C., Vazquez‐Sanchez, S., Kern, C., Jenie, I., Malukhina, K., Moore, S. R., Cui, J., Goginashvili, A., Moghadami, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.27.575940 · Cited by 5 · see citing works
Self-citationAnalysis of the senescence secretome during zebrafish retina regeneration
Konar, G. J., Vallone, K. T., Nguyen, T. D., & Patton, J. G. (2025) · Frontiers in Aging · doi:10.3389/fragi.2025.1569422 · Cited by 5 · see citing works
Zhou, Y., Zhang, K., Wang, F., Chen, J., Chen, S., Wu, M., Lai, M., Zhang, Y., & Zhou, W. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1174341 · Cited by 3 · see citing works
“By knocking down this protein, transformation of astrocytes into functional neurons can be realized within a few weeks to a month (Qian et al., 2020; Zhou et al., 2020; Maimon et al., 2021).”
BackgroundLi, Q., Zhang, W., Qiao, X.-Y., Liu, C., Dao, J.-J., Qiao, C.-M., Cui, C., Shen, Y., & Zhao, W. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.12360 · Cited by 2 · see citing works
Direct Neural Reprogramming in situ: Existing Approaches and Their Optimization
Dokukin, N. V., Chudakova, D. A., Shkap, M. O., Kovalchuk, A. M., Kibirsky, P. D., & Baklaushev, V. P. (2025) · Biochemistry (Moscow) · doi:10.1134/s000629792460426x · Cited by 2 · see citing works
“Although the knockdown of PTBP1 induced efficient transformation of some types of glial cells into functional neurons [61, 62], genetic labeling of cell lines, scRNA-seq, and electroretinogram analysis showed that selective induction of heterozygous or homozygous loss-of-function PTBP1 mutants in…”
Liu, B.-Y., Chen, X.-D., Liu, H.-L., Wang, S.-W., Song, Q. Y., Cheng, H., Li, S., Wang, H.-Y., Lu, X.-M., & Yong-tang, W. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01629-4 · Cited by 3 · see citing works
“Previous studies demonstrate that PTBP1 knockdown (KD) alone suf fi ciently induces mature cells transdifferentiating into functional neurons, revealing its therapeutic potential for neurodegenerative diseases 15 – 17 .”
Konar, G. J., Lingan, A. L., Vallone, K. T., Nguyen, T. D., Flickinger, Z., & Patton, J. G. (2025) · Experimental Eye Research · doi:10.1016/j.exer.2025.110420 · Cited by 2 · see citing works
“Despite the controversy, multiple studies support the finding that knockdown of PTB induces gene expression changes by mechanisms that remain unclear but which are consistent with neuronal differentiation (Maimon et al., 2021; Makeyev et al., 2007; Xue et al., 2013).”
PTBP1 depletion in mature astrocytes reveals distinct splicing alterations without neuronal featuresPreprint
Zhang, M., Kubota, N., Nikom, D., Arient, A., & Zheng, S. (2025) · eLife · doi:10.7554/elife.107683.3 · Cited by 1 · see citing works
“Maimon et al. used intrace-rebroventricular (ICV) delivery of anti-Ptbp1 ASO to generate new neurons in aged wild-type mouse hippocampus and improve cognitive measures ( Maimon et al., 2021 ).”
Advances in Astrocyte Research on Neuronal Death and Regeneration
Yuan, C. N., Cao, W.-X. N., Liu, M.-R. N., Wu, H. N., Cui, L.-Y. N., & Liu, Y.-J. N. (2025) · Journal of Integrative Neuroscience · doi:10.31083/jin42985 · Cited by 1 · see citing works
PTBP1: A master regulator of neural development and transdifferentiation—promise and pitfalls
Liu, Y., Huang, Y., Wang, Y., Mao, M., & Huang, M. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.153948 · Cited by 1 · see citing works
Generating neurons in the adult brain
Crunkhorn, S. (2021) · Nature Reviews Drug Discovery · doi:10.1038/d41573-021-00103-w
Fukui, Y., Morihara, R., Hu, X., Nakano, Y., Yunoki, T., Takemoto, M., Abe, K., & Yamashita, T. (2023) · Research Square · doi:10.21203/rs.3.rs-2611669/v1
Base editing of Ptbp1 in neurons alleviates symptoms in a mouse model for Parkinson’s diseasePreprint
Böck, D., Wilhelm, M., Mumenthaler, J., Carpanese, D. F., d‘Aquin, S., Cremonesi, A., Rassi, A., Häberle, J., Patriarchi, T., & Schwank, G. (2024) · eLife · doi:10.7554/elife.97180.1
PTBP1 Depletion in Mature Astrocytes Reveals Distinct Splicing Alterations Without Neuronal FeaturesPreprint
Zhang, M., Kubota, N., Nikom, D., Arient, A., & Zheng, S. (2025) · eLife · doi:10.7554/elife.107683.1
Ptbp1 knockdown induces conversion of rat spinal cord astrocytes into neuron like cells
Hu, X., Han, S., Li, Z., Li, Y., & Gao, J. (2025) · Scientific Reports · doi:10.1038/s41598-025-19720-1
PTBP1 Depletion in Mature Astrocytes Reveals Distinct Splicing Alterations Without Neuronal FeaturesPreprint
Zhang, M., Kubota, N., Nikom, D., Arient, A., & Zheng, S. (2025) · eLife · doi:10.7554/elife.107683.2
Direct glia-to-neuron conversion mitigates hippocampal damage in a vascular dementia mouse model
Ota-Elliott, R. S., Fukui, Y., Hu, X., Bian, Y., Sun, H., An, H., Liu, H., Morihara, R., Ishiura, H., & Yamashita, T. (2026) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x261441070
“19,21,22 Alternatively, migration from the periventricular and parenchymal regions 23 cannot be excluded.”
Liu, S., Li, Q., Qi, B., Guan, Y., Liu, B., Li, X., & Chen, Z. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102309
Modeling Alzheimer’s disease with brain organoids: mechanisms, applications, and future directions
Zhao, Q., Li, S., Ju, Y., Kong, X., & Liu, X. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1791272
“Advances in region-specific transcription factors, G1-phase synchronization, and antisense oligonucleotide (ASO)-mediated PTB suppression are improving the precision and scalability of direct reprogramming (Maimon et al., 2021; Kraskovskaya et al., 2023).”
Harnessing Neurogenic Potential of Glial Cell Types as an Emerging Strategy for Treating Epilepsy
Chesnokova, E., Kotova, I., Reznikova, A., Balaban, P. M., & Bal, N. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27209147
- Authors
- Maimon, R., Chillon-Marinas, C., Snethlage, C. E., Singhal, S. M., McAlonis-Downes, M., Ling, K., Rigo, F., Bennett, C. F., Da Cruz, S., Hnasko, T. S., Muotri, A. R., & Cleveland, D. W.
- Affiliations
- University of California San Diego (US)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Cleveland, Don W.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2021-06-03
- Volume
- 24
- Issue
- 8
- Pages
- 1089-1099
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC8338913
- OpenAlex
- W3164571028
- Semantic Scholar
- df57156c39b19fde3ef389afc385138399691665
- Cited by
- 62
- References
- 71
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 12 · 2023: 17 · 2022: 12 · 2021: 4
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Lirias (acceptedVersion)
- PubMed Central (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX003759)
- National Institute of Mental Health (R01MH108528, R01MH109885, R01MH100175)
- National Institute of Neurological Disorders and Stroke (R01 NS105969, R01 NS027036, P30NS047101, R37NS027036)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- adult neurogenesis, antisense oligonucleotides, PTBP1, dentate gyrus, hippocampus, neuronal maturation, memory enhancement, neurodegenerative disease treatment, brain aging
- MeSH terms
- Animals, Neurons, Oligonucleotides, Antisense, Dentate Gyrus, Polypyrimidine Tract-Binding Protein, Mice, Neurogenesis, Ependymoglial Cells, Cellular Reprogramming
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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