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Yang, K.; Liu, Y.; Zhang, M. Targets on Astrocytes for the Treatment of ALS. Encyclopedia. Available online: https://encyclopedia.pub/entry/55081 (accessed on 16 April 2024).
Yang K, Liu Y, Zhang M. Targets on Astrocytes for the Treatment of ALS. Encyclopedia. Available at: https://encyclopedia.pub/entry/55081. Accessed April 16, 2024.
Yang, Kangqin, Yang Liu, Min Zhang. "Targets on Astrocytes for the Treatment of ALS" Encyclopedia, https://encyclopedia.pub/entry/55081 (accessed April 16, 2024).
Yang, K., Liu, Y., & Zhang, M. (2024, February 16). Targets on Astrocytes for the Treatment of ALS. In Encyclopedia. https://encyclopedia.pub/entry/55081
Yang, Kangqin, et al. "Targets on Astrocytes for the Treatment of ALS." Encyclopedia. Web. 16 February, 2024.
Targets on Astrocytes for the Treatment of ALS
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Astrocytes, the most numerous and giant glial cells in the central nervous system (CNS), possess the unique ability to divide and proliferate throughout life. The cytosol of astrocytes exhibits a distinctive star-shaped morphology, housing a critical structural component known as the glial filament. Comprised of glial fibrillary acidic protein (GFAP), this intermediate filament is essential to the cytoskeleton and serves as a standard marker for astrocytes. Importantly, it is not entirely exclusive to astrocytes but also labels neural stem cells. Apart from organizing the blood–brain barrier (BBB) and supporting, sequestering, and isolating neurons, these cells perform a multitude of vital biological functions. These include the metabolism, synthesis, and secretion of neurotrophic factors, regulation of neurotransmitters and calcium homeostasis, maintenance of mitochondrial function, participation in nervous system and circuit development, and regulation of the immune status of the CNS. However, these functions are partially or wholly lost in reactive astrocytes. Amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by the degeneration of upper and lower motor neurons (MNs), with an average survival of 3–5 years.
reactive astrocytes amyotrophic lateral sclerosis pathogenesis astrocyte-targeting strategies

1. Introduction

At present, the available treatment options and their therapeutic effects for amyotrophic lateral sclerosis (ALS) are minimal. As previously mentioned, astrocytes play an essential role in the pathogenesis and disease progression of ALS. To date, riluzole remains the sole drug that targets astrocytes [1]. Therefore, there is an urgent imperative to identify novel potential therapeutic targets for astrocytes.

2. Glial-Cell-Line-Derived Neurotrophic Factor

The neurotrophic factor glial-cell-line-derived neurotrophic factor (GDNF), secreted by astrocytes, plays a crucial role in neuronal survival and synaptic promotion. However, the function of reactive astrocytes is impaired in ALS models and patients, resulting in motor neuron death. Consequently, delivering central nervous system (CNS) GDNF or transplanting healthy astrocytes may potentially improve motor function in ALS patients [2][3].
A combination of stem cell and gene therapy was employed in a phase I/IIa clinical trial led by Dr Clive Svendsen’s team [2]. Neural progenitor cells, which were genetically engineered to express GDNF protein, were transplanted into the dorsal and ventral horns of the lumbar segment of the spinal cord in ALS patients. These cells were then transformed into supportive glial cells. The neural precursor cells can give rise to new supporting glial cells, releasing the protective protein GDNF, collectively aiding in preserving motor neurons [2]. This “double whammy” approach concurrently employs the generated new glial cells and GDNF protein to support the survival of dying motor neurons in the face of the disease.
The limited half-life of GDNF in plasma, its inability to directly cross the blood–brain barrier during subcutaneous administration, and its poor penetration into the brain and spinal cord during intrathecal injection trials render it challenging to achieve a therapeutic effect using these approaches. Consequently, in this trial [2], the stem cell product CNS10-NPC-GDNF was safely delivered into the dorsal and ventral horns of the lumbar segment of the spinal cord in ALS patients using a novel in-house-developed injection device. After a single transplant via this innovative method, neural progenitor cells survived up to 42 months and continued to generate new glial cells and GDNF proteins. The results indicated that the rate of leg strength decline was slower on the treated side than on the untreated side, although this difference was not statistically significant. Furthermore, this cell transplantation did not cause substantial adverse effects on muscle strength in the treated leg compared to the untreated side. However, in some patients, many of these cells reached sensory areas in the spinal cord, potentially leading to pain [2]. Overall, this clinical trial demonstrated the safety of this approach, but further assessments of efficacy are required. The team is also currently utilizing these GDNF-secreting stem cells in another ALS clinical trial (https://clinicaltrials.gov/ct2/show/NCT05306457, accessed on 3 November 2023) by transplanting them into the “hand-knob” area of the motor cortex of patients with ALS. Ongoing progress in the efficacy and safety of stem cell combined gene therapy for ALS patients should be expected.

3. AstroRx®

AstroRx®, an allogeneic cell-based product derived from human embryonic stem cells, is generated under cGMP conditions in Kadimastem’s GMP facility via standard procedures and assessed according to stringent criteria by external qualified certified GLP laboratory (Hylabs laboratories, Jerusalem, Israel) [3]. It exhibits functional, healthy astrocyte effects, such as clearing excessive glutamate, reducing oxidative stress, secreting various neuroprotective factors, and acting as an immunomodulator. In a phase I/IIa clinical trial involving intrathecally injected human astrocytes (AstroRx®), the rate of ALSFRS-R worsening within the first three months post-treatment was significantly reduced, accompanied by fewer adverse events, regardless of whether subjects received high or low doses of healthy astrocytes. These positive results warrant further exploration of repeated intrathecal administration of AstroRx®, such as every three months [3].
Regarding the two emerging clinical trials mentioned above, each has its merits and drawbacks. After a single treatment with stem cells combined with gene therapy, neural progenitor cells can survive for extended periods, differentiate into new glial cells, continuously produce GDNF proteins, and directly act on a specific group of neurons. In contrast, direct intrathecal injection of astrocytes has a shorter duration of action and may necessitate injections every three months. Most importantly, the ability of healthy astrocytes to perform their normal function in the CNS within an inflammatory environment remains unclear. Meanwhile, there are existing challenges associated with stem cell transplantation, including immune rejection, abnormal hyperplasia, ethical concerns, etc. In terms of efficacy, intrathecal injection of astrocytes has been preliminarily validated in phase I/IIa clinical trials. However, the effect of stem cells combined with gene therapy remains uncertain in current clinical trials. Overall, these research advancements are promising and deserve further investigation.

4. Cx43

In recent years, foundational research has unearthed additional potential astrocyte targets. Cx43, an essential astrocyte connectivity protein, together with its hemichannels, facilitates communication between astrocytes within the central nervous system [4]. Increased expression of Cx43 has been observed in animal models of ALS, the cerebrospinal fluid of ALS patients, and postmortem samples, indicating its toxicity towards neurons [5]. In vitro experiments such as co-culturing and blocking Cx43 and its hemichannels corroborate this. In vivo experiments have revealed that the removal of Cx43, specifically from astrocytes in SOD1G93A mice, resulted in a spatial (in the cervical and lumbar spinal cords) and temporal (at the pre-symptomatic, symptomatic, and end stages) deceleration of disease progression, as well as protection for motor neurons, and an increase in survival rate [5]. Tonabersat, a drug candidate capable of blocking Cx43 hemichannels and crossing the blood–brain barrier [6], has been shown to provide neuroprotection by reducing neuronal death when co-cultured with human induced pluripotent stem-cell-derived astrocytes (hiPSC-A) derived from both familial and sporadic ALS patients using control motor neurons (hiPSC-MNs) [6]. Administration of tonabersat intraperitoneally at 10 mg/kg once daily to SOD1G93A mice exhibited potential for enhancing motor function [5]. Notably, the expression of Cx43 in astrocytes remains unaltered by tonabersat, whereas the expression of GFAP and Iba-1 significantly decreased [5]. The drug has also been investigated in the context of migraine and epilepsy [6]. In conclusion, the targeted blockade of astrocyte Cx43 and the integration of tonabersat into ALS clinical trials are worth considering.

5. EphrinB2

Expression of ephrinB2, a transmembrane signaling molecule, is significantly elevated in astrocytes within the spinal cord of SOD1G93A mice and ALS patients [7][8]. Delivery of viral-mediated shRNA to astrocytes in the cervical segment of the spinal cord selectively represses ephrinB2 expression, thereby mitigating motor neuron loss and preserving respiratory function by sustaining motor neuron innervation of the diaphragm [8]. This research suggests that the upregulation of ephrinB2 is both a transcellular signaling mechanism for astrocyte pathogenicity in ALS and a promising therapeutic target.

6. NAD+, Nrf2, and SIRT6

Preliminary findings suggest that NAD+, Nrf2, and SIRT6 synthesized by astrocytes confer neuroprotection against ALS, with SIRT6 playing a pivotal role. An increase in NAD+ availability is known to enhance resistance to oxidative stress and reduce mitochondrial ROS production in various cell types and disease models [9]. Nrf2 activation is critical for regulating antioxidant defenses and protecting neighboring neurons in co-culture and in vivo settings [10][11]. Furthermore, elevating total NAD+ levels in astrocytes activates Nrf2 and SIRT6 in these cells, while SIRT6 overexpression further activates Nrf2. Decreased expression of NAD+, Nrf2, and SIRT6 has been observed in the spinal cords of ALS patients. In animal models of ALS, NAD+ depletion does not affect survival, but administering biologically active NAD+ precursors significantly improves motor performance and extends survival [12]. In addition, upregulating Nrf2 in astrocytes has been demonstrated to promote neuronal survival in in vitro co-culture studies [13] and in an ALS mouse model [14]. However, silencing SIRT6 expression in an in vitro cell culture model did not prevent astrocyte neurotoxicity towards motor neurons, even with pre-supplementation of NAD+ precursors [15]. Thus, SIRT6 plays a crucial role in this neuroprotective effect. Overall, enhancing SIRT6 and Nrf2 activity and administering NAD+ precursors that abolish the neurotoxic phenotype of astrocytes expressing the ALS-associated mutation SOD1 are potential therapy approaches [16][17][18].

7. Mechanistic Target of Rapamycin Kinase 

The mechanistic target of rapamycin kinase (MTOR) is a regulator of numerous extracellular and intracellular signals that participate in cellular metabolism, growth, proliferation, survival, and macro-autophagy/autophagy [19]. Activation of the MTOR pathway has been demonstrated to be elevated in SOD1G93A mutant hiPSC-derived astrocytes, resulting in the suppression of macro-autophagy/autophagy, aberrant cell proliferation, and an increased reactivity of the astrocytes [20]. Concurrently, MTOR pathway activation is correlated with post-transcriptional upregulation of the insulin-like growth factor 1 receptor (IGF1R). Therefore, inhibition of the IGF1R-MTOR pathway decreases cell proliferation and the reactivity of mutant SOD1G93A astrocytes, thereby mitigating their toxicity towards motor neurons. These findings suggest that modulation of the IGF1R-MTOR pathway in astrocytes may represent a plausible therapeutic target for ALS [20].

References

  1. Jaiswal, M.K. Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs. Med. Res. Rev. 2019, 39, 733–748.
  2. Baloh, R.H.; Johnson, J.P.; Avalos, P.; Allred, P.; Svendsen, S.; Gowing, G.; Roxas, K.; Wu, A.; Donahue, B.; Osborne, S.; et al. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: A phase 1/2a trial. Nat. Med. 2022, 28, 1813–1822.
  3. Gotkine, M.; Caraco, Y.; Lerner, Y.; Blotnick, S.; Wanounou, M.; Slutsky, S.G.; Chebath, J.; Kuperstein, G.; Estrin, E.; Ben-Hur, T.; et al. Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: Phase I/IIa clinical trial results. J. Transl. Med. 2023, 21, 122.
  4. Xing, L.; Yang, T.; Cui, S.; Chen, G. Connexin Hemichannels in Astrocytes: Role in CNS Disorders. Front. Mol. Neurosci. 2019, 12, 23.
  5. Almad, A.A.; Taga, A.; Joseph, J.; Gross, S.K.; Welsh, C.; Patankar, A.; Richard, J.P.; Rust, K.; Pokharel, A.; Plott, C.; et al. Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS. Proc. Natl. Acad. Sci. USA 2022, 119, e2107391119.
  6. Damodaram, S.; Thalakoti, S.; Freeman, S.E.; Garrett, F.G.; Durham, P.L. Tonabersat inhibits trigeminal ganglion neuronal-satellite glial cell signaling. Headache 2009, 49, 5–20.
  7. Pasquale, E.B. Eph-ephrin bidirectional signaling in physiology and disease. Cell 2008, 133, 38–52.
  8. Urban, M.W.; Charsar, B.A.; Heinsinger, N.M.; Markandaiah, S.S.; Sprimont, L.; Zhou, W.; Brown, E.V.; Henderson, N.T.; Thomas, S.J.; Ghosh, B.; et al. EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS. eLife 2024, 12, RP89298.
  9. Harlan, B.A.; Pehar, M.; Sharma, D.R.; Beeson, G.; Beeson, C.C.; Vargas, M.R. Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1). J. Biol. Chem. 2016, 291, 10836–10846.
  10. Baxter, P.S.; Hardingham, G.E. Adaptive regulation of the brain’s antioxidant defences by neurons and astrocytes. Free Radic. Biol. Med. 2016, 100, 147–152.
  11. Vargas, M.R.; Johnson, J.A. The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev. Mol. Med. 2009, 11, e17.
  12. Harlan, B.A.; Killoy, K.M.; Pehar, M.; Liu, L.; Auwerx, J.; Vargas, M.R. Evaluation of the NAD+ biosynthetic pathway in ALS patients and effect of modulating NAD+ levels in hSOD1-linked ALS mouse models. Exp. Neurol. 2020, 327, 113219.
  13. Vargas, M.R.; Pehar, M.; Cassina, P.; Martínez-Palma, L.; Thompson, J.A.; Beckman, J.S.; Barbeito, L. Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: Consequences for motor neuron survival. J. Biol. Chem. 2005, 280, 25571–25579.
  14. Vargas, M.R.; Johnson, D.A.; Sirkis, D.W.; Messing, A.; Johnson, J.A. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 2008, 28, 13574–13581.
  15. Harlan, B.A.; Pehar, M.; Killoy, K.M.; Vargas, M.R. Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1. FASEB J. 2019, 33, 7084–7091.
  16. De la Rubia, J.E.; Drehmer, E.; Platero, J.L.; Benlloch, M.; Caplliure-Llopis, J.; Villaron-Casales, C.; de Bernardo, N.; AlarcÓn, J.; Fuente, C.; Carrera, S.; et al. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: A randomized, double-blind, placebo-controlled human pilot study. Amyotroph Lateral Scler. Frontotemporal. Degener. 2019, 20, 115–122.
  17. Fels, J.A.; Casalena, G.; Konrad, C.; Holmes, H.E.; Dellinger, R.W.; Manfredi, G. Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301. Hum. Mol. Genet. 2022, 31, 3458–3477.
  18. Obrador, E.; Salvador, R.; Marchio, P.; López-Blanch, R.; Jihad-Jebbar, A.; Rivera, P.; Vallés, S.L.; Banacloche, S.; Alcácer, J.; Colomer, N.; et al. Nicotinamide Riboside and Pterostilbene Cooperatively Delay Motor Neuron Failure in ALS SOD1(G93A) Mice. Mol. Neurobiol. 2021, 58, 1345–1371.
  19. Laplante, M.; Sabatini, D.M. mTOR signaling at a glance. J. Cell Sci. 2009, 122, 3589–3594.
  20. Granatiero, V.; Sayles, N.M.; Savino, A.M.; Konrad, C.; Kharas, M.G.; Kawamata, H.; Manfredi, G. Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1(G93A) astrocytes. Autophagy 2021, 17, 4029–4042.
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