Tamir Ben-Hur’s research while affiliated with Hebrew University of Jerusalem and other places

Background Fulminant idiopathic intracranial hypertension (fIIH) is a severe condition which causes rapid visual loss. Conventional fIIH management involves surgical interventions, but their effectiveness and safety remain uncertain. The use of temporary continuous CSF drainage (CD) for fIIH has not been fully explored in the adult population. We present the results of CD treatment in severe IIH cases. Method IIH Patients treated with CD were compared to control groups of extreme CSF opening pressure (> 45 cm H2O) and random IIH patients (> 25 cm H2O). Results Eighteen female patients underwent CD treatment. Indications for CD treatment were acute visual deterioration or development of a VI nerve palsy and severe papilledema (despite acetazolamide treatment). All patients stabilized after CD treatment. Four patients had acute complications that fully resolved. Visual acuity (VA) in fIIH patients was significantly reduced prior to treatment (mean 6/15 ± 6/19 vs. 6/7.5 ± 6/30, p < 0.01). CD treatment resulted in marked long‐term improvement in VA (mean 6/7.5 ± 6/19 vs. 6/7 ± 6/38, p = 0.12 and 6/7 ± 6/48, p = 0.05). Compared to the extreme CSF opening pressure group, female sex, obesity, and TVO's were more common in the CD group. Compared to the general IIH group, female sex, obesity, endocrinopathy, and CSF opening pressure were higher in the CD group. Conclusion IIH patients with very high CSF opening pressure and the presence of obesity and endocrinopathy may be at higher risk to develop fIIH. CD treatment is an extremely effective and safe treatment option for severe cases of IIH.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide. Emerging research has challenged the conventional notion of a direct correlation between amyloid deposition and neurodegeneration in AD. Recent studies have suggested that amyloid and Tau deposition act as a central nervous system (CNS) innate immune driver event, inducing chronic microglial activation that increases the susceptibility of the AD brain to the neurotoxicity of infectious insults. Although modifiable risk factors account for up to 50% of AD risk, the mechanisms by which they interact with the core process of misfolded protein deposition and neuroinflammation in AD are unclear and require further investigation. This update introduces a novel perspective, suggesting that modifiable risk factors act as external insults that, akin to infectious agents, cause neurodegeneration by inducing recurrent acute neurotoxic microglial activation. This pathological damage occurs in AD pathology-primed regions, creating a “hit and run” mechanism that leaves no discernible pathological trace of the external insult. This model, highlighting microglia as a pivotal player in risk factor-mediated neurodegeneration, offers a new point of view on the complex associations of modifiable risk factors and proteinopathy in AD pathogenesis, which may act in parallel to the thoroughly studied amyloid-driven Tau pathology, and strengthens the therapeutic rationale of combining immune modulation with tight control of risk factor-driven insults.

The impact of high-intensity interval training (HIIT) on the central nervous system (CNS) in autoimmune neuroinflammation is not known. The aim of this study was to determine the direct effects of HIIT on the CNS and development of experimental autoimmune encephalomyelitis (EAE). Healthy mice were subjected to HIIT by treadmill running and the proteolipid protein (PLP) transfer EAE model was utilized. To examine neuroprotection, PLP-reactive lymph-node cells (LNCs) were transferred to HIIT and sedentary (SED) mice. To examine immunomodulation, PLP-reactive LNCs from HIIT and SED donor mice were transferred to naïve recipients and analyzed in vitro. HIIT in recipient mice did not affect the development of EAE following exposure to PLP-reactive LNCs. HIIT mice exhibited enhanced migration of systemic autoimmune cells into the CNS and increased demyelination. In contrast, EAE severity in recipient mice injected with PLP-reactive LNCs from HIIT donor mice was significantly diminished. The latter positive effect was associated with decreased migration of autoimmune cells into the CNS and inhibition of very late antigen (VLA)-4 expression in LNCs. Thus, the beneficial effect of HIIT on EAE development is attributed solely to systemic immunomodulatory effects, likely because of systemic inhibition of autoreactive cell migration and reduced VLA-4 integrin expression.

Remyelination failure is considered a major obstacle in treating chronic‐progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin‐forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non‐specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic‐progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph‐node cells. It also significantly impaired the immune‐modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro‐regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro‐myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro‐regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi‐systematic therapeutic approach, which cannot be achieved through a single molecule‐based therapy.

Background Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. Methods We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 10⁶ AstroRx® cells and 5 patients with 250 × 10⁶ cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). Results A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 10⁶ AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from − 0.88/month pre-treatment to − 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 10⁶ AstroRx® arm, the ALSFRS-R slope decreased from − 1.43/month to − 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. Conclusions Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 10⁶ or 250 × 10⁶ cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. Trial Registration: NCT03482050.

Background: AstroRx is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. We previously showed that AstroRx protects neurons in ALS animal models by multiple mechanisms, including clearance of toxic compounds (e.g. glutamate), reduction of oxidative stress, immunomodulation, and secretion of various neuroprotective factors. We hypothesized that transplantation of AstroRx can compensate for the malfunction of astrocytes in ALS patients in a clinical setting. Methods: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of AstroRx transplantation in patients with ALS. Five patients were injected intrathecally with a single dose of 100x10⁶ AstroRx cells and 5 patients with 250x10⁶ cells (low and high dose, respectively). Safety and efficacy assessments were recorded during a period of 3-months pre-treatment (run-in) and 12-months post-treatment (follow-up). Results: A single administration of AstroRx at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx cells were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate and resolved. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100x10⁶ AstroRx arm, the ALSFRS-R rate of deterioration was attenuated from -0.88/month pre-treatment to -0.30/month in the first 3 months post-treatment (p=0.039). In the 250x10⁶ AstroRx arm, the ALSFRS-R slope from -1.43/mo to -0.78/mo (p=0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No significant difference in the rate of ALSFRS-R deterioration was observed beyond 3 months after treatment. No significant change was found in hand-held dynamometry (HHD), grip strength (JAMAR), ALSAQ-40, or serum biomarkers. Conclusions: Overall, these findings suggest that a single IT administration of AstroRx to ALS patients at a dose of 100x10⁶ or 250x10⁶ cells is safe. A signal of beneficial clinical effect was observed for the first 3 months post cell injection. These results support further investigation of repeated IT administrations of AstroRx. Trial Registration: NCT03482050