Neurotherapeutics

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no definitive disease-modifying therapies available, underscoring the urgent need to identify novel druggable targets. The G protein-coupled receptor GPR17 is a critical regulator of oligodendrocyte maturation and has emerged as a candidate target in ALS, yet its relevance to human disease and therapeutic potential remain unclear. Here, we demonstrate that pathological GPR17 upregulation defines a conserved, pathologically immature oligodendroglial state in human ALS that can be pharmacologically leveraged to restore myelin integrity and improve functional outcome in vivo. Publicly available transcriptomics datasets and histological analysis revealed an increased abundance of GPR17-expressing immature oligodendrocytes in post-mortem human spinal cord tissue from ALS cases compared with non-neurological controls. Moreover, sustained activation of GPR17 with a selective agonist was able to induce GPR17 internalization in heterologous expression systems. In line with this mechanism, treatment with the same agonist promoted the differentiation of primary oligodendrocyte precursor cells derived from SOD1G93A mice. Translating these findings in vivo, chronic treatment with a brain-penetrant GPR17 agonist derived from the same pharmacological class significantly extended survival, delayed body weight loss, and improved motor performance in female SOD1G93A mice, whereas male mice showed no therapeutic benefit. These effects were associated with restored oligodendrocyte maturation, preserved myelin integrity, motor neuron survival, and attenuated reactive gliosis in the spinal cord of female SOD1G93A mice, while milder effects were observed in males. Together, these findings establish oligodendroglial GPR17 as a conserved and pharmacologically actionable target in ALS and show that sustained in vivo GPR17 agonism can reprogram altered oligodendroglial states and slow disease progression in a sex-dependent manner.

Spinocerebellar ataxia type 3 (SCA3) is most common subtype of autosomal dominant spinocerebellar ataxia worldwide and the most prevalent CAG expansion disorder in the east Asian population, but disease-modifying therapies remain unavailable. SCA3 is caused by the accumulation of polyglutamine- (polyQ-) expanded mutant ataxin-3 (mAtxn3), while the wild-type ataxin-3 (wtAtxn3) plays an important cellular role. Thus, allele-selective clearance of mAtxn3 without affecting wtAtxn3 is highly desired for SCA3 treatment. To achieve this goal, we tested previously reported compounds that have been shown to selectively degrade the Huntingtons disease causing mutant HTT protein by tethering the expanded polyQ to the autophagosome protein LC3. Here, we demonstrated that two of these compounds, AN2 and GW5074, selectively reduced both soluble and aggregated mAtxn3 with expanded polyQ (84Q), but not wtAtxn3, in both cellular and mouse models of SCA3. Mechanistically, both compounds lowered mAtxn3 by enhancing its autophagic degradation without obvious activation of global autophagy. At the molecular level, both compounds increased mAtxn3-LC3 interaction and colocalization to enhance the allele-selectively autophagic degradation of mAtxn3. Phenotypically, both compounds rescued cell viability and ATP content of SCA3 cellular models. In SCA3 patient pluripotent stem cells (iPSCs) derived cortical neurons, both compounds allele-selectively reduced mAtxn3 and partially rescued neurite shortening. Importantly, in a well-established SCA3 transgenic mouse model (MJD84.2), intracerebroventricular, intraperitoneal, and oral administration allele-selectively reduced mAtxn3 in multiple brain regions and rescued motor function deficits. Oral dosing achieved nanomolar cerebellar exposure and showed no overt liver, kidney, or glial toxicity over 28 days. Analyses of 1303 Chinese patients with SCA3 and ATXN3 constructs of different polyglutamine lengths further supported the compounds polyQ length-dependent activity with relative sparing of normal-length ataxin-3. Together, these findings provide preclinical proof of concept that utilizing orally available small molecule compounds to allele-selectively enhance mAtxn3 autophagic degradation for SCA3 treatment. One-sentence summarySmall-molecule autophagosome-tethering compounds selectively lower mutant ataxin-3 through an LC3- and autophagy-dependent mechanism and improve disease-related phenotypes in preclinical models of SCA3.

Despite a wealth of preclinical studies establishing neuroprotective and neurorestorative properties of glial cell-line-derived neurotrophic factor (GDNF) in animal models of Parkinsons disease (PD), clinical trials utilizing direct intracranial infusion of GDNF protein, or adeno-associated virus (AAV)-mediated GDNF gene transfer has not achieved the desired efficacy, largely due to challenges in delivery methods. Given GDNFs strong potential for neuroprotection, alternative strategies to elevate its expression by beyond invasive injection or genetic manipulation remain a promising therapeutic avenue for PD. We previously reported that prokineticin signaling provides a compensatory protective response against dopaminergic neuronal degeneration in cell and animal models of PD. Herein, we report a novel finding that PK2 regulates GDNF gene expression in astrocytes, suggesting that PK2 signaling can be harnessed for neuroprotection in PD. Treatment of cultured astrocytes with the PK2 protein, PK2 gene overexpression or prokineticin receptor 1 (PKR1) agonist IS20 significantly induced the GDNF gene expression and the protein secretion, resulting in enhanced dopaminergic cell survival in cell culture models of PD. Importantly, systemic administration of IS20 through intraperitoneal or intranasal routes elevated GDNF levels in the mouse brain, including the nigrostriatal system. Furthermore, IS20 treatment conferred significant neuroprotective effects in both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and MitoPark transgenic mouse models of PD. Collectively, our translational findings suggest that pharmacological modulation PK2 signaling may unlock the full clinical benefit of GDNF, offering a novel and non-invasive therapeutic strategy for Parkinsons disease.

BackgroundParkinsons disease (PD) is the second common neurodegenerative disorder, driven by the loss of dopaminergic neurons and pathological -synuclein protein accumulation. Currently, there is no disease-modifying therapy that can halt PD progression. Our previous study uncovered a critical pathogenic feed-forward loop between amyloid precursor protein (APP) and leucine-rich repeat kinase 2 (LRRK2), in which the two proteins mutually enhance each others expression, ultimately leading to mitochondrial dysfunction and neurotoxicity. Targeting this vicious cycle represents a promising therapeutic strategy for PD. MethodsTo discover novel inhibitors targeting this axis, we performed high-throughput screening of an FDA-approved drug library using a fluorescence-based biosensor system. We identified Mitoxantrone hydrochloride (MH), an antineoplastic agent, as a lead compound that inhibits both APP and LRRK2 expression. Its efficacy was validated in cellular models, including patient induced pluripotent stem cell (iPSC)-derived dopaminergic neurons and human peripheral blood mononuclear cells (PBMCs). Motor behavioural and safety assessments were subsequently conducted in PD mouse models. ResultsWe demonstrated that MH suppresses both APP and LRRK2 expression in various cell types in a dosage-dependent manner. In addition, MH also inhibits phosphorylation of LRRK2 and its downstream substrate Rab10. We further showed MH inhibits LRRK2 activity through direct binding to its kinase domain. Critically, MH treatment rescued dopaminergic neuron loss and reversed motor deficits in both 6-Hydroxydopamine (6-OHDA)-induced and LRRK2G2019S genetic PD mouse models. Moreover, we found that oral administration of MH is therapeutically effective, providing superior neuroprotection and behavioral recovery without detectable cardiotoxicity or gastrointestinal damage. ConclusionsOur findings demonstrate MH as a compelling, repurposable therapeutic candidate capable of disrupting a core pathogenic mechanism in PD.

Mitochondria are critical for sustaining the high energy demands of neuronal activity and their dysregulation is a hallmark of neurodegeneration. Targeting pathways of neurotrophic signaling is a well-established therapeutic strategy to enhance mitochondrial function and mitigate neurodegeneration. The VPS10p domain receptor, SorCS2, has recently emerged as a receptor with neurotrophic signaling capabilities. Here, we design and develop novel SorCS2-derived macrocyclic peptides mimicking receptor activation in vivo. We show that SorCS2-peptides enhance both neurotrophic support and boost metabolism by activating CREB and AMPK in a CAMKK2-dependent manner. This leads to upregulation of the key transcription factors PGC1 and TFEB and consequentially mitochondrial biogenesis. Furthermore, we show that the lipidated SorCS2 macrocycle, TT-P34, rescues motor behavioral deficits and preserves synaptic and mitochondrial signatures in the zQ175 mouse model of Huntingtons Disease. In addition, treating a MPTP-induced mouse model of Parkinsons Disease leads to amelioration of behavioral deficits and reduction of dopaminergic loss. Finally, we demonstrate that TT-P34 crosses the blood-brain barrier in non-human primates, and estimate human therapeutic dosing by pharmacodynamic modelling. Together, our findings support the use of TT-P34 as a novel disease-modifying therapy targeting SorCS2-receptor signaling to prevent neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by rapid progression and high mortality. With genetic mutations, particularly in the SOD1 gene, playing a significant role in ALS pathogenesis, targeted therapies have become a primary focus. This study introduces RD-12500 (RAG-17), a novel siRNA-ACO (Accessory Oligonucleotide) conjugate designed to address the challenges of delivering duplex RNAs to the central nervous system (CNS). RD-12500 exhibits remarkable in vitro stability and target specificity with minimal immunostimulation. In vivo studies demonstrate its extensive CNS biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation. Notably, RD-12500 significantly reduces cerebrospinal fluid (CSF) SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys. Most notably, our study breaks new ground by demonstrating the effectiveness of RD-12500 in late-stage treatment scenarios. In SOD1G93A ALS mice, post-onset administration of RD-12500 significantly delayed disease progression, improved motor function, and extended survival, marking a significant advancement over other treatments which are typically initiated pre-symptomatically in the same model mice. These findings suggest RD-12500s potential to provide therapeutic benefits not only to pre-symptomatic but also to post-symptomatic and late-stage SOD1-ALS patients.

NOS1AP is a genetically validated driver of tau pathology in Alzheimer's disease (AD), yet the NOS1AP-tau interaction itself has remained pharmacologically untargeted. We report CAPTOR-1, a first-in-class small molecule that disrupts this interaction by binding a pocket in the N-terminal region of NOS1AP (residues 1-126). A drug-resistant NOS1AP Y16A/F42A variant that retained tau binding but exhibited a 78-fold reduction in CAPTOR-1 affinity provides genetic evidence supporting an on-target mechanism. In human iPSC-derived neurons, CAPTOR-1 dose-dependently reduces endogenous NOS1AP-tau association, tau seeding activity, and pathogenic tau phosphorylation, phenocopying genetic NOS1AP knockdown; these effects extend to neurons from patients with sporadic AD. Orally dosed CAPTOR-1 crosses the blood-brain barrier and engages NOS1AP in brain dose-dependently. Chronic oral dosing rescues pathology, synaptic function, and memory in a tauopathy model (PS19) and an amyloidosis model (APP/PS1), sparing wild-type littermates in both. This work establishes pharmacological disruption of the NOS1AP-tau interaction as a viable, disease-modifying strategy for AD and positions CAPTOR-1 as a biomarker-ready chemical probe (pTau217, neurofilament light) for translational studies.

Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of -2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.

BACKGROUND: Myofascial Pain Syndrome (MPS) is a common musculoskeletal pain condition associated with myofascial trigger points that has been reported to occur in 30-93% of patients who present with musculoskeletal pain. The current pharmacologic treatments (such as nonsteroidal anti-inflammatory drugs [NSAIDs], muscle relaxants, and tricyclic antidepressants) are only partially effective and have side effects. Shilajit, a mineral-organic exudate from the Himalayas, has antioxidant, anti-inflammatory, mitochondrial bioenergetic, and central analgesic effects and has not previously been examined as an analgesic in any musculoskeletal pain condition. METHODS: This was an exploratory pilot clinical trial with open-label design in a single arm for an 18-month period at All India Institute of Medical Sciences (AIIMS), Rishikesh, India. Patients aged 18 to 65 years with clinically diagnosed MPS (Simons et al. 1999 criteria) and a baseline visual analog scale (VAS) score >4 were enrolled. Native Himalayan Shilajit 250 mg daily was administered as add-on therapy for 49 days. The main outcome was the percentage of participants with more than or equal to 30% VAS reduction at Day 49. The intensity of pain, the dose of analgesics consumed, and the number of trigger points were evaluated at five time points (Day 0, 12, 24, 36, 49). Throughout, adverse events were monitored. RESULTS: Of 80 enrolled participants, 76 (95.0%) completed the per-protocol analysis. Mean age was 41.25 (SD 9.05) years; 52.6% were male. A total of 56 of 76 participants (73.7%; 95% CI: 62.1-82.8%) achieved the primary endpoint. Mean VAS score declined from 6.63 (SD 1.08) at baseline to 3.63 (SD 1.72) at Day 49 (mean reduction 45.3%; Friedman Chi-square= 278.5, p<0.001). The first signs of pain reduction were seen at Day 24. The number of analgesic doses consumed decreased by 75.5% during the study period (chi-square = 126.1, p<0.001). There was a significant reduction in trigger point count from baseline to Day 49 (p=0.031) of 23.4%. One Grade 2 adverse event (gastrointestinal irritation, Day 28, resolved within 24 hours, no drug discontinuation) occurred; no serious adverse events were reported. Trial registration: CTRI/2025/06/088636. The study was not funded by any external sources. CONCLUSIONS: Native Himalayan Shilajit 250 mg/day for 49 days was associated with clinically and statistically significant reductions in pain intensity, analgesic consumption, and trigger-point burden in patients with MPS, with a favorable safety profile. These findings warrant confirmation in a larger, randomized, placebo-controlled trial.

Rett syndrome is an X-linked neurodevelopmental disorder resulting from mutations in the MeCP2 gene, leading to intellectual disability, impaired motor coordination, decreased sociability, and seizures. Central to the underlying pathophysiology are deficits in synaptic inhibition, which are mediated by hyperpolarizing GABAAR currents. These events develop postnatally and are dependent upon increased neuronal Cl- extrusion mediated by SLC12A5 (KCC2). Therefore, we tested whether its activation modifies the disease phenotypes evident in female MeCP2+/- mice, using OV350, a direct activator of KCC2. OV350 rapidly induced a sustained reduction in EEG power, accompanied by a decrease in the severity of epileptic discharges. Increased motor coordination, sociability, and spatial memory were also observed. Deficits in KCC2 phosphorylation were also seen in MeCP2+/- mice, consistent with reductions in its activity that were also ameliorated by OV350. Thus, KCC2 activation may be efficacious in limiting the impact of Rett syndrome and other neurodevelopmental disorders.

Chronic cluster headache (CCH) is an excruciating disorder of unknown pathophysiology, but hypothalamic dysfunction has been implicated. CCH is difficult to treat but on a case-basis, the psychedelic compound psilocybin is said to have beneficial effects. In this first-ever clinical trial (NCT04280055), we evaluate in a small open-label study of CCH patients the feasibility and prophylactic effect of three low-to-moderate doses of psilocybin as well as effects on hypothalamic functional connectivity (FC), using functional magnetic resonance imaging. The treatment was well-tolerated and without serious adverse reactions. Attack frequency was on average reduced by 30% from baseline to follow-up (PFWER=0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with relative reduction in attack frequency, implicating this neural pathway in treatment response. Further clinical studies are warranted to confirm the safety and prophylactic efficacy of psilocybin for CCH and hypothalamic involvement in treatment response.

The pathology of Parkinsons disease is defined by -synuclein (-syn) aggregation into neuronal Lewy bodies, which may lead to chronic neuroinflammation and dopaminergic neurodegeneration. Misfolded -syn activates Toll-like receptor signaling in microglia, leading to downstream activation of NF-{kappa}B and subsequent release of pro-inflammatory cytokines. These cytokines recruit pro-inflammatory myeloid cells from circulation, thereby amplifying neuroinflammation. Thus, reducing microglial activation and myeloid cell infiltration has the potential to reduce neuroinflammation and PD pathology. Here, we investigated a targeted immunomodulatory strategy using LA1, a novel, small-molecule agonist of CD11b, a {beta}2 integrin receptor highly and selectively expressed on myeloid cells and microglia. CD11b has key roles in cell adhesion, migration, and phagocytosis. Previous work has demonstrated that CD11b agonism via LA1 transiently enhances integrin-mediated adhesion that limits immune cell transmigration and tissue infiltration. CD11b agonism also suppresses TLR-driven inflammatory signaling and myeloid cell activation. To evaluate its efficacy in vivo, we utilized pre-clinical Parkinsons disease model by stereotaxically delivering AAV2-SYN to induce -synuclein overexpression in the murine midbrain. Mice were treated with oral LA1 for four or eight weeks and analyzed. LA1 treatment significantly reduced microglial activation and decreased brain infiltration of peripheral immune cells, thereby attenuating -synuclein-induced neuroinflammation. These findings suggest that CD11b agonism may offer a dual-action therapeutic approach in Parkinsons disease by dampening pro-inflammatory responses by central and peripheral myeloid cells.

Background: Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating neurodegenerative lysosomal storage disorder caused by alpha-N-acetylglucosaminidase (NAGLU) deficiency. There is currently no approved therapy. We report the 3-month outcomes of a novel intracerebroventricular (ICV) gene therapy in a child with MPS IIIB. Methods: In an open-label, single-center, investigator-initiated trial (ChiCTR2600121466), a single dose of RDGT-101 (2.0E14; vg of an AAV9 vector encoding human NAGLU) was administered via ICV infusion. Primary outcomes were safety and tolerability. Secondary outcomes included serum NAGLU activity, urinary heparan sulfate (HS) excretion, and neurocognitive function. Exploratory analyses included hematological parameters. Results: The patient achieved serum NAGLU activity (17.06 nmol/mL/hour) approaching that of healthy controls (17.75 {+/-} 1.37 nmol/mL/hour) by Month 3, accompanied by a 58.4% reduction in urinary HS. Clinically, previously severe hand and toe contractures resolved, allowing for full extension. Neurocognitive improvements were observed, including clear articulation, logical conversation, and sustained eye contact. Hematological analyses revealed normalized red blood cell indices and improved iron utilization. No dose-limiting toxicities, serious adverse events, or clinically significant laboratory abnormalities were observed. Conclusions: A single ICV infusion of RDGT-101 was safe and well-tolerated in this patient with MPS IIIB. Early biochemical correction was accompanied by marked improvements in somatic, neurocognitive, and hematological parameters. These findings support further investigation of ICV AAV9 gene therapy for MPS IIIB.

Many patients with painful diabetic neuropathy (PDN) do not achieve meaningful pain relief with standard of care. MEDI7352 is a unique bispecific fusion protein targeting two key mediators of pain, TNF and NGF (at relatively low levels of suppression). We report a randomized, double-blind, placebo-controlled, Phase-2a study (NCT03755934/EudraCT-2018-002523-42) assessing efficacy and safety of MEDI7352 in patients aged [&ge;]18 years with inadequately controlled PDN. Patients remained on background standard-of-care treatment and were randomized to placebo (n=54) or MEDI7352 intravenously (5g/kg [n=6], 150g/kg [n=16], 450g/kg [n=36]). Primary endpoint was change in pain scores from baseline to Week 12 vs placebo on a numeric rating scale (NRS). Key secondary outcomes included change in pain scores from baseline at visits prior to Week 12 and responder rates. Of 112 patients randomized, 107 received [&ge;]1 dose study medication; mean age (standard deviation [SD]) in the modified-intent-to-treat population was 60.5 (9.34) years; 62.6% males, 37.4% females. With MEDI7352 450g/kg, change from baseline in pain scores at Week 12 vs placebo was: -1.39 [95% CI: -2.19 to -0.58], p=0.0009; at Week 12, mean (SD) pain scores decreased vs baseline by -2.70 (2.08); 66.7% of patients experienced decreased pain by [&ge;]30% (p=0.0311 vs. placebo); 42.4% experienced decrease [&ge;]50% (p=0.0029). MEDI7352 safety was similar to placebo; no adjudicated Rapidly Progressing Osteoarthritis (RPOA) type-1 or RPOA type-2 events were observed in any group. MEDI7352 achieved statistically significant and clinically meaningful pain reduction in patients with PDN vs placebo and provides an opportunity to change the paradigm for challenging-to-treat pain.

Background: Huntington's disease (HD) is an inherited neurodegenerative disorder primarily associated with motor and psychiatric manifestations. No disease-modifying treatment currently exists, with vesicular monoamine transporter type-2 inhibitors (VMAT2i's) being the only FDA-approved therapy for motor features in HD. Previous studies evaluated the antichorea effects of VMAT2i's but did not address its effects on non-choreiform features. Objectives: This study aimed to characterize the effect of VMAT2i's on hyperkinetic, hypokinetic and total hypokinetic subscores of the UHDRS motor assessment in patients with motor-manifest HD from the Enroll-HD research platform. Methods: Data from 622 participants were analyzed. Linear mixed effects models were constructed to compare the rates of change of choreiform and non-choreiform motor scores before and after the initiation of a VMAT2i. We calculated and plotted the direction, magnitude and significance of VMAT2i administration on the rates of change of motor subscores. A similar analysis was performed investigating the effect of antipsychotic medications on motor subscales in HD. Results: VMAT2i's reversed progression of hyperkinesis but significantly increased the rates of change in the hypokinetic and total hypokinetic subscores. Antipsychotics also displayed efficacy in reversing progression of chorea but did not significantly influence progression of hypokinesis. Conclusions: The initiation of VMAT2i's was associated with an improvement in hyperkinesis but was associated with worsening of other motor features of HD. Hypokinesis increases progressively in HD and is correlated with functional impairment and global decline. Therefore, the use of VMAT2i's to treat motor features in HD should be a nuanced decision, considering its multipronged impact.

Background and ObjectiveGM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are rare, inherited neurodegenerative disorders with no available symptomatic or disease modifying treatments. This clinical trial aimed to investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms of pediatric ([&ge;] 6 years) and adult patients with GM2 gangliosidosis. Methods\We conducted an 8-center, multi-national, open-label, rater-blinded Phase IIb study (IB1001-201). Patients with a genetically confirmed diagnosis of GM2 gangliosidosis were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients [&ge;]13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar rating scales (namely Scale for the Assessment and Rating of Ataxia), clinical global impression, and quality of life assessments. Results30 patients aged 6 to 55 years with a confirmed diagnosis of GM2 gangliosidosis (Tay-Sachs or Sandhoffs disease) were enrolled. 29 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.044), as well as secondary endpoints. No treatment-related serious adverse events occurred. ConclusionsThis study showed NALL led to a statistically significant improvement in symptoms, functioning, and quality of life in patients with GM2 gangliosidosis. It is a safe, well-tolerated, easily administered oral therapy, therefore offering a favorable risk/benefit profile for this serious, debilitating disorder. NALL is a new therapeutic option for the treatment of this rare disease that has no other approved therapies worldwide. Classification of EvidenceThis study provides Class IV evidence NALL is safe, well-tolerated, and improves neurological symptoms and quality of life in patients with GM2 gangliosidosis. Trial Registration InformationThe trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.

Amyotrophic Lateral Sclerosis is the most common motor neuron disease. It is incurable and, at the time of this study, only two treatments with a limited therapeutical effect are available: riluzole and edavarone (not in Europe). These treatments have been shown to delay the progression of the disease by a maximum of 10%. We recently showed that glycolic acid (GA) and D-lactate (DL) are able to revert some of the phenotypes observed in iPSC-derived neurons from FUS- and SOD-1-ALS patients in vitro. Here we show that the administration of GA and DL is able to delay the progression of the disease in SOD1-G93A mice and protect spinal motor neurons against neuronal death. Interestingly, GA and DL were also able to attenuate the lethality in the TBPH silencing strain (iTBPHpkk(108354)) in Drosophila, showing a conserved role between species. Based on these results, we performed two experimental treatments in ALS patients carrying a disease-causing mutation in FUS and SOD-1 respectively. As GA and DL have been shown to be toxic (kidney stones, altered hepatic metabolism) and even lethal above certain doses in humans, we developed and used a specific formulation containing L-alanine to avoid these side effects. Our results show that, together with L-alanine as supportive treatment, GA and DL were well tolerated by the patients. Although promising, well designed and placebo-controlled clinical trials need to be performed in order to confirm the good tolerability and the therapeutic effects in ALS patients.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in MECP2 and characterized by impaired neuronal maturation and synaptic dysfunction. Positive allosteric modulators of AMPA receptors (AMPAR-PAMs) have shown therapeutic promise in RTT models, but the determinants of treatment responsiveness remain unclear. Here, we evaluated the clinically advanced AMPAR-PAM CX1632 in Mecp2-null male and Mecp2-heterozygous female mice across developmental stages and treatment regimens. Therapeutic efficacy was strongly influenced by developmental stage, disease severity, and treatment schedule. Brief neonatal treatment produced long-lasting improvements in survival, disease progression, motor function, and cognition, whereas later intervention was markedly less effective in symptomatic null mice but remained beneficial in less severely affected heterozygous females. Repeated intermittent administration further enhanced selected benefits. Mechanistically, early CX1632 treatment induced sustained activation of neuronal and synaptic gene programs, restored synaptic organization and neuronal activity, and rescued AMPA receptor-mediated transmission weeks after drug withdrawal. These findings identify disease stage as a key determinant of responsiveness to AMPA receptor potentiation and support developmentally informed therapeutic strategies for MECP2-related disorders.

The subgenual anterior cingulate cortex (sgACC) is a key node in treatment-resistant depression (TRD), but precise non-invasive neuromodulation of this target is challenging. Preclinical studies of non-ablative stereotactic radiosurgery (SRS) have shown neuromodulatory ("radiomodulation") effects. In this single-center, double-masked, randomized, dose-seeking pilot trial, nine adults with TRD were randomly assigned to bilateral sgACC radiomodulation at a dose of either 15, 20, or 25 Gy per hemispheric target. Primary endpoints were safety and feasibility; the efficacy endpoint was week-4 change in the Montgomery-Asberg Depression Rating Scale (MADRS). Both primary endpoints were met: the only treatment-related adverse event was transient grade 1 dizziness, with no structural MRI abnormality through week 12. Mean MADRS fell from 33.0 to 17.0 (48.5% reduction); 67% responded and 44% remitted, with benefit sustained to week 12. Resting-state fMRI revealed regional connectivity changes correlating with clinical improvement, with tractography showing streamline counts differing by response status. These first-in-human findings support a larger randomized controlled trial of sgACC radiomodulation for TRD. ClinicalTrial.gov registration: NCT07274917.

TBR1 haploinsufficiency causes a neurodevelopmental disorder associated with intellectual disability and autistic features, but the therapeutic potential of postnatal gene replacement remains incompletely defined. Here, we evaluated adeno associated virus (AAV) mediated human TBR1 replacement in Tbr1 haploinsufficient mice. A single retroorbital injection of AAV.PHP.eB expressing human TBR1 under the human synapsin promoter was administered at postnatal day 3 at a dose of 2 E11 vector genomes. Compared with control vector treated mutants, treated mice exhibited increased TBR1 protein abundance and TBR1, CTIP2, and parvalbumin positive cell counts in selected brain regions. Treatment improved sociability, social transmission of food preference, and buried food seeking. Electroencephalographic (EEG) recordings showed attenuation of elevated relative theta power and improved theta suppression and gamma enhancement during social interaction. However, anterior commissure abnormalities persisted, correction of other EEG abnormalities was incomplete, and sleep wake proportions showed no significant treatment improvement. These findings demonstrate that neonatal TBR1 replacement improves selected behavioral and electrophysiological outcomes despite persistent anatomical abnormalities. These findings support further development of gene replacement for TBR1 haploinsufficiency and highlight EEG measures as candidate biomarkers for monitoring treatment response.