Stem Cell Clinic

Tenaya Therapeutics Has Been An Early Stage Company For Too … – Seeking Alpha

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Tenaya Therapeutics (NASDAQ:TNYA) is an early stage developer of heart disease therapies and a relatively new IPO that I covered briefly 2 years ago. They have a set of interesting platforms - cellular regeneration, gene therapy and precision medicine - that they are using to develop a number of molecules targeting various heart diseases. The pipeline is at an early stage, with just one molecule in the clinic, but heart disease companies are rare, and the company looks like it is doing interesting science. So we will take a look.

Tenaya was established in 2016 with IP from Gladstone Institute and UT Southwestern. The company was able to raise $50mn in a Series A financing that year. In 2019, they raised another $90mn in a series B. 2 years later, they were able to raise another $106mn in a series C financing after they published preclinical data from two programs. That same year, they launched their IPO.

The company, like I mentioned, has three platforms. The Cellular Regeneration platform delivers genes to cardiac cells using viral vectors to regenerate them. Diseases like myocardial infarction, chemotherapy-related toxicity, and viral infection which result in loss of cardiomyocytes can be targeted through this platform. The Gene Therapy platform uses AAV vectors to deliver genes to correct functional defects in heart cells. These defects could be congenital or non-genetic forms. The precision medicine platform uses "human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as proprietary disease models and analysis of human genetics for the identification of new targets, validation of known targets, and high-throughput screening for drug discovery."

The company is very early stage and their pipeline looks thus:

TNYA Pipeline (TNYA website)

At the time of this Corporate Presentation, they had 2 INDs approved and a third in the works. The latest stage product candidate seems to be small molecule HDAC6 inhibitor TN-301 for HFpEF or Heart Failure with preserved Ejection Fraction. This is in a phase 1 trial, however there is no listing in the registry. TN-201 also has a phase 1 trial - ongoing? - however, again there's no listing yet. TN-201 is a gene therapy targeting mutations of the MYBPC3 gene in hypertrophic cardiomyopathy (HCM). The third IND-enabled asset is TN-401, another gene therapy targeting PKP2 gene in Arrhythmogenic right ventricular cardiomyopathy.

These gene therapy assets use the AAV9 vector. AAVs have been in use for over 2 decades, and 6 gene therapies using AAVs have been FDA-approved. More than 5500 patients have been treated across 40 countries. In hundreds of trials, they have demonstrated their safety, and their long lasting transgene expression. Other important positives for AAV vectors are their low immunogenicity and ability to penetrate both dividing and nondividing cells, and so on. Some disadvantages include inability to deliver larger molecules, expensive manufacturing and so on.

As to the various diseases, MYBPC3 HCM has some 115k US patients. This genetic mutation is the most common form of inherited cardiomyopathy. There are no treatments for the underlying genetic mutation although the disease can lead to higher risks of sudden heart failures. Tenaya's treatment produces a functional copy of the MYBPC3 gene to the cardiomyocytes. These transgenes produce the MyBP-C protein which carries out normal heart function.

In preclinical trials, TN-201 demonstrated that despite a 5x increase in RNA versus wild type genes, there was no protein overexpression:

In vivo comparison (Company website)

There was also higher selectivity for the heart than other cells elsewhere in the body. Preclinical data also showed signs of efficacy in mice models. A single dose in mice demonstrated reduced hypertrophy, durable improvement in cardiac function and extended survival. The phase 1b study, informed by this preclinical data, will begin dosing in Q3. It is an open label dose escalation and dose expansion study. Initial data is expected in 2024.

The small molecule HDAC6 inhibitor TN-301 targets HFpEF. HDAC6 inhibition is an area of recent research interest in stopping the progression of this disease. In 2021, data published in Nature from a study of CKD-506 showed improvements in exercise capacity, heart function, and quality of life. Standard treatments for HFpEF have not included this modality previously. Tenaya says that in preclinical studies, TN-301 has shown a differentiated mechanism versus SGLT2 inhibitors, which are part of the arsenal against HFpEF. The company will start a randomized, placebo-controlled phase 1 SAD/MAD study with safety and tolerability as primary endpoints and PK/PD as secondary endpoints. The company says that "Dosing Commenced in Multiple-Ascending Dose Stage of First-In-Human Clinical Trial of TN-301; Data Anticipated in Second Half 2023." I still do not see anything on the registry.

TNYA has a market cap of $180mn and a cash balance of $204mn. In November, the company raised $77mn through a secondary offering. R&D expenses were $25.7 million for the fourth quarter and G&A expenses were $8.8 million. At that rate, they have a cash runway extending into 2025.

According to insider data, the company saw heavy insider buying in recent months. I was especially glad to see insiders buying the secondary in the open market.

Insider transactions (openinsider.com)

The company has heavy institutional and PE/VC presence, with over 90% of the shares.

In the two years since I covered it last, TNYA has put together preclinical data for its assets. However, nothing has gone into the clinic, although the company has been in existence for nearly a decade, with hundreds of millions of dollars in funding available. I am afraid there's nothing to see here until we have the first proof of viability from the company. That should happen in 2024. We will take another look at that time.

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Tenaya Therapeutics Has Been An Early Stage Company For Too ... - Seeking Alpha

Pathology and Astrocytes in Autism | NDT – Dove Medical Press

Introduction

Autism spectrum disorder (ASD) is as a neurodevelopmental disorder that presents with disturbances in social communication and repetitive behaviors.1 One in every 54 children suffers from ASD in the United States with a prevalence 4.3 times higher in males than in females.2 Global prevalence around the world is approximately of 1/100 children varying based on geographic, ethnic, and socioeconomic factors.3 The etiology of ASD is not well understood, however genetic, environmental, and immune factors have been reported to be the cause.4 Many genes linked to ASD have also been associated to other neurodevelopmental disorders, indicating a etiological heterogeneity and genetic pleiotropy in ASD.5 Candidate genes linked to ASD include DISC1, DYX1C1, RELN, AVPR1a, ITGB3, RPL10, and SHANK3, among many others.6 These genes regulate development, metabolism, plasticity, synapsis, and other important functions.7,8 Although numerous genes have been involved in ASD, a genetic diagnosis is not possible in most of the cases because the established genetic causes of ASD account for only a small portion of cases.9 Environmental factors such as hypoxia or trauma at birth, heavy metal exposure, maternal obesity, vitamin D deficiency, and maternal diabetes, have been associated with ASD.10 There is also a significant link between ASD with increase in reactive oxygen species (ROS) and a reduction in antioxidant capacity in the brain of ASD patients. ROS accumulation can directly enhance neuroinflammation and cytokine release.11 Accordingly, immune system impairment with elevated expression of pro-inflammatory cytokines and chemokines and microglia activation have been reported in postmortem ASD brains.12,13 Genetic, environmental, and immune factors are involved in the ASD phenotype, but how exactly is poorly understood.

The pathology of ASD is yet to be determined. However, the anatomy of several brain areas such as cerebellum, amygdala, hippocampus and cerebral cortex have been reported to be affected.1416 Increased brain size and disorganization of white and grey matter have been identified in patients with ASD.17,18 MRI studies showed abnormalities in gyral cortical anatomy, especially in the sylvian fissure, superior temporal sulcus,intraparietal sulcus,and inferior frontal gyrus in ASD patients.19,20 Multiregional dysplasia is present in 92% of ASD cases.21 It has been hypothesized that focal dysplasia in ASD may result from abnormalities in progenitor cell division, and/or migration and maturation of newly generated cells during prenatal brain development.21,22 Cortical dysplasia in ASD could explain high seizure prevalence and sensory disturbance in ASD.23 Mini-columnar abnormalities have also been reported in ASD.24,25 Mini-columns contain oriented arrays of pyramidal cells and GABAergic interneurons that modulate pyramidal cells input and output. Mini-columns are considered the basic functional unit in the neocortex. In ASD, there are more mini-columns but they are smaller in size. There is also less neuropil space resulting in cells more compacted.24,25 The increased number of mini-columns may result from additional division of progenitor cells during prenatal development, while the deficits in peripheral neuropil space may result from lack of inhibitory cells.26 White matter is also affected in ASD. In particular, there is a reduction in the number of long axons that are connected to long distance areas, and an increase in thin axons that communicate neighboring areas. This indicates a disconnection between long distance pathways and short distance over-connection. This is the case for the white matter in the anterior cingulate cortex, an area associated with attention, social interaction and emotion, functions altered in ASD. Moreover, there is also a reduction in axonal myelin thickness in some areas such as the white matter of the orbitofrontal cortex.27

The ASD brain also presents with alterations in the number of specific cell types. However, most of the cell types and regions of the brain have not been studied, and some of the data collected do not agree. Alteration in cerebellar cortex including a decrease in size and number of Purkinje cells and abnormality in functional connectivity between the cerebellum and other areas of the brain was reported in postmortem ASD brains. Decrease in Purkinje cells number was more noticeable in posterior lobe (lobule VIIA) of the cerebellum. Accordingly, a reduction in grey matter volume and a smaller vermis lobules VIVII were present in ASD children.28 Children with ASD had a bigger amygdala than typically developing children.29 A study on non-neuronal cell population numbers in the amygdala, reported no changes in number, however there was a strong microglial activation in two of eight ASD brains. In addition, there was a reduced number of a oligodendrocytes in the amygdala of adult ASD cases aged 20 and older.30 In the fusiform gyrus in seven postmortem ASD subjects, there was a decrease in number of neurons in layers III, V and VI, and in the mean perikaryal neuronal volumes in layers V and VI.31 An increase in the pyramidal cell population32,33 and a reduction in oligodendrocyte and astrocyte numbers (Figure 1AB) have also been reported in the prefrontal cortex of ASD postmortem brains.33,34 Also, a reduction in parvalbumin+ chandelier GABAergic interneurons was found in the dorsolateral and ventral prefrontal cortex.17,35,36 Decreased dendrite numbers in the dorsolateral prefrontal cortex and reduced dendrite branching in the CA4 and CA1 have been reported in individuals with ASD.37 Overall, abnormalities in different cell type populations and their morphology may lead to the disturbed neuronal function characteristic of ASD.

Figure 1 (A and B) GFAP+ astrocytes in prefrontal cortical plate (CP) and the white matter (WM) (A) control (CT) and (B) ASD. (A and B) Reconstruction of an average case depicting GFAP+ astrocyte location in the CP and WM. (A) control (CT) and (B). (CF) Astrocytes activation state. (C) Resting astrocyte with few processes and small cell body, (D) mild reactive astrocyte with slightly enhanced staining of glial processes and minor enlargement of cell body, (E) moderate reactive astrocyte with significant increase of cell body size and glial cell ramifications with dark stained processes and (F) severe reactive astrocyte with gemistocytic cell body and degraded processes that present as dark stained puncta.105 Scale bar in A, A, B, B: 500 m; C, D, E, F: 20 m.

Astrocytes are key elements for neuronal metabolic and structural support in the brain. They control ion concentration, modulate neurotransmitter release, maintain the bloodbrain barrier, and regulate blood flow in the nervous system, among many other functions.38 They also have crucial roles in neurodevelopment including in neurogenesis, neuronal migration, and synaptic plasticity.39,40 In addition, with pre- and postsynaptic neurons, perisynaptic astrocytes form tripartite synapses to modulate synaptic transmission.41 Together with microglia, astrocytes are regulators of the inflammatory responses. Innate immune responses are mediated through activation of microglia and astrocytes that produce cytokines, chemokines, and other immune mediators.38,42,43 Astrocyte activation could be either neurotoxic, by accelerating inflammatory responses and tissue damage, or neuroprotective by promoting neuronal survival and tissue repair, though this classification is not clear cut. Pro-inflammatory astrocytes secrete pro-inflammatory factors, such as tumor necrotic factor (TNF) and nitric oxide (NO), whereas neuroprotective astrocytes upregulate neurotrophic factors and thrombospondins to control neuroinflammation. Excessive neuroinflammation with increased reactive astrocytes and pro-inflammatory cytokines has been reported in ASD. Given the role of astrocytes in higher cognitive functions, any alteration in their number, distribution, morphology, and/or function, could lead to major neuronal dysfunction that could contribute to neurodevelopmental disorders such as ASD.44

Glial fibrillary acidic protein (GFAP) is a type III intermediate filament that is mainly expressed in astrocytes. It is also known as a marker for reactive astrocytes (Figure 1CF).42,45 GFAP is reported to be elevated in the cerebrospinal fluid of ASD subjects.46,47 Increased GFAP is correlated with astrogliosis and reactive damage that might result in immune response and further cytokines release.13,48 Data regarding GFAP gene expression in different regions of the ASD brain is controversial. Some studies reported upregulation of GFAP gene expression in the prefrontal cortex and cerebellum,49,50 whereas others reported no significant changes in GFAP gene expression in anterior cingulate cortex and anterior prefrontal cortex in ASD brains.51,52 Rats treated with propionic acid showed increased GFAP gene expression in the hippocampus, and presented ASD-like behaviors including aggressive behavior during adjacent interactions.53 At the protein level, several studies reported an increase in GFAP protein in superior frontal cortex, parietal cortex, cerebellum, and anterior cingulate cortex white matter.13,48,51 There was also an increase in GFAP protein in the cerebellum of postmortem brains whereas vimentin was decreased in both cerebellum and prefrontal cortex.54 In a valproic acid (VPA) animal model of ASD, there was an increase in the number of astrocytes and GFAP in medial prefrontal cortex and primary somatosensory cortex on postnatal day 30.55 In contrast, some other studies showed no change in GFAP protein in anterior cingulate grey matter, amygdala, and anterior and dorsolateral prefrontal white matter of postmortem ASD brains.30,51,56 Other proteins expressed by astrocytes are also changed in ASD. There was decreased amount of aquaporin 4 (AQP4), a water channel protein located in astrocytes, in the medial prefrontal cortex, but an elevation in the primary somatosensory area in the VPA animal model of ASD. AQP4 is mainly responsible for eliminating water from the cerebral parenchyma as well as supporting potassium buffering.55,55 In addition, there was a reduction in AQP4 protein in the cerebellum and an increase of connexin (cnx) 43, a gap junction protein located in astrocytes, in BA9 of postmortem ASD brains.57 Beside buffering ions and neurotransmitters concentration, cnx43 is responsible for regulating cellular growth and cell-cell adhesion. Increased cnx43 expression in ASD subjects could signify enhancement of glial-neuronal communication in frontal lobe that is in charge of executive functions.57

Data regarding the number of astrocytes in the brain with ASD are scarce (Table 1). We previously reported a decrease in the number of astrocytes, labeled with GFAP and S100, and a mild activation in GFAP+ astrocytes in the prefrontal areas BA9, BA46, and BA47 of postmortem ASD brains compared to control individuals.34 Figure 1 depicts representative images of astrocytes labeled with GFAP antibody and their location in control and ASD prefrontal cortex and astrocytes in different stages of activation. In another study from our laboratory, using Nissl staining, we showed a generalized reduction in astrocytes number with an increase in the neuronal population in layer II in the same areas.33 A reduced number of astrocytes could result from a reduced production and/or increased cell death. Increased overall glial cell densities, including astrocytes, oligodendrocytes and microglial cells, in layer II of olfactory cortex was reported, that may correlate with sensory deficits including damaged olfactory identification observed in patients with ASD. This increased glial cell density was correlated positively with the scores for restricted and repetitive behavior domain in the autism diagnostic interview revised (ADI-R) questionnaire.58 Using clustering nuclear profiles, genetic studies showed upregulated protoplasmic astrocyte gene expression in the prefrontal cortex and anterior cingulate cortex of postmortem ASD brains.59 In addition, upregulation of a gene set that was enriched in astrocytes and microglia was observed in frontal and temporal cortex of 251 postmortem samples from 48 ASD cases and 49 control subjects.60 These data contrast with anatomical studies demonstrating a decreased number of astrocytes in the prefrontal cortex. This may be because anatomical landmarks were not taking into account and the number of astrocytes was quantified using homogenated tissue.

Table 1 Summarizing Astrocyte Abnormalities in ASD Human Studies

Astrocytes play a critical role in neurotransmitter homeostasis, and in regulating the excitation/inhibition balance that is disturbed in the ASD cortex. Disturbance in astrocyte calcium signaling through inositol 1,4,5-trisphosphate 6 receptor 2 (IP3R2), that regulates neurotransmitter release, leads to ASD-like behaviors including repetitive behaviors and abnormal social interaction in mice.6163 Also, elevated level of glutamine synthetase (GS), an adenosine triphosphate-dependent enzyme that maintains glutamate levels located in astrocytes, was reported in the plasma of ASD patients.64 Increased mRNA expression of excitatory amino acid transporter 1 (EAAT1), located in astrocytes and responsible for glutamate uptake, and glutamate receptor AMPA 1, were found in the cerebellum of postmortem ASD brains. However, the density of AMPA glutamate receptor protein was decreased in the cerebellum. These findings reveal abnormalities in glutamatergic system in ASD.50 Some other studies reported a correlation between the glutamate transporter single gene polymorphism and the severity of anxiety and repetitive behaviors in ASD children.65 Furthermore, excessive electrical activity resulting from an abnormal glutamatergic function has been reported in ASD patients that can lead to pathologic behaviors.66 In VPA animal model of ASD, there was a decrease of 40% in glutamate transporter 1 (GLT1) at P15, but an increase of 92% in GLT1 with an increase of 160% in glutamate uptake at P120. The amount of glutathhione (GSH) was also increased 27% at P120 suggesting a disturbance in astrocytic glutamate clearance from the synaptic cleft in an animal model of ASD.67

Some report ASD as a hypo-glutamatergic disorder because of the symptoms produced by glutamate antagonists in ASD.68 Accordingly, a hypo-glutamatergic animal model displayed behavioral phenotypes that overlapped with the features observed in ASD69, indicating an alteration in the glutamatergic function in ASD.

Astrocytes also participate in gamma-aminobutyric acid (GABA) clearance. Some studies have shown a relationship between astrocyte abnormalities and the GABAergic system dysfunction in ASD. Wang et al showed a reduction in astrocyte-derived ATP that impaired GABAergic system and lead to ASD-like behaviors in the PFC of the IP3R2 mutant mice. ATP can modulate GABAergic synaptic transmission via P2X2 receptors located at the GABAergic interneuron terminals.63 In an in vitro study, cultured astrocytes exposed to VPA showed impairment in GABAergic inhibitory synapses but the excitatory synapses remained unchanged. This indicates that VPA can alter E/I balance in neural network by affecting the astrocyte-neuron interaction, highlighting the impact of astrocyte dysfunction in ASD pathology.70 Overall, there is evidence that astrocyte regulating of both glutamate and GABA neurotransmitters is altered in the ASD brain.

Neuroinflammation plays a main role in ASD pathology and many studies reported activation of astrocytes in postmortem ASD brains.13,71,72 Reactive astrocytes are the major source of releasing cytokines. The macrophage chemoattractant protein (MCP-1), that is in charge of monocyte/macrophage recruitment to the areas of inflammation, and pro-inflammatory cytokine interleukin-6 (IL-6), are altered in cortical and subcortical white matter in ASD.13 The expression of the translocator protein 18 kDa (TSPO), that is a marker for brain inflammation, and the amount of activated microglia in the frontal cortex and cerebellum are increased in reactive astrocytes in ASD.73 Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine that has been reported to be elevated in the brain and blood of ASD cases.13,74 CCL2 is produced by astrocytes and microglia in the brain and is necessary for proliferation, migration and activation of microglia and astrocytes.75,76 Elevated level of CCL2 could also increase bloodbrain barrier (BBB) permeability and allow more T-lymphocytes to enter the brain during neuroinflammation.77 Multifocal perivascular lymphocytic cuffs are associated with astrocytes blebs that represents a cytotoxic reaction to lymphocyte attack, suggesting a dysregulation in cellular immunity that could damage astrocytes in ASD brains.78 Although many studies reported immune system dysfunction in ASD, it is not clear whether it is a cause or a consequence of the pathology.72

Astrocytes perform a critical role in synaptic formation, maturation, function, and elimination. An alteration in astrocyte structure and function alters neuronal activity.79 Astrocytes secrete platelet responsive protein (TSP) that works through its neuronal receptor calcium channel subunit 2-1, to control excitatory synaptogenesis.80 The synaptic signaling protein Rho GTPase Ras-related C3 Botulinum toxin substrate 1 (RAC1), is downstream of the TSP-2-1 pathway and has an important role in regulating synaptic and spinal growth.81 Disturbed RAC1 signaling is strongly associated with ASD and epilepsy pathology.82,83 The fact that astrocytes control the TSP-2-1-RAC1 pathway, is an example of the role of astrocytes on synaptic formation in ASD.84 Astrocytes secrete cytokines, such as transforming growth factor 1 (TGF-1) to regulate synaptogenesis. TGF-1 enhances phosphorylation of calcium/calmodulin dependent protein kinase II (CaMK II), downstream of NMDA receptors, to induce the formation of inhibitory synapses.85 TGF-1, with the NMDA coactivator D-serine, encourages the formation of excitatory synapses through NMDA receptor-dependent mechanisms.86 Supporting a role of TGF-1 in the formation of inhibitory synapses suggest that a relationship between the TGF-1 dysfunction and inhibitory synapse disturbance in ASD.87 Hevin is another protein secreted by astrocytes that is essential for maintaining synaptogenesis. Hevin bridges the presynaptic protein Neurexin-1 (NRX1) and postsynaptic Neuroligin-1B (NL1B) to assemble excitatory synapses.88 Mutations in Hevin, Neurexins and Neuroligins are strongly related to ASD pathology suggesting a critical role of these proteins in normal brain development.89

Astrocyte abnormalities have also been reported in other neurodevelopmental disorders, such as schizophrenia (SZ), bipolar disorder (BD) and major depressive disorder (MDD). A reduction in astrocyte densities was present in some brain areas of postmortem brains with SZ including cingulate and motor cortex, medial and ventrolateral regions of the nucleus accumbens, basal nuclei and substantia nigra.90 In an electron microscopic morphometric study of astrocytes in hippocampal CA3 region of 19 SZ cases, mitochondrial volume fraction and area density was negatively correlated with the duration of disease. However, the volume fraction of lipofuscin granules was positively associated with the duration of illness suggesting progressive astrocyte dysfunction due to the mitochondrial deficit.91 An increased expression of GFAP mRNA with astrogliosis was also observed in SZ patients with neuroinflammation.92 Furthermore, in animal studies of SZ, transgenic mice that expressed a mutant form of the disrupted in schizophrenia 1 (DISC1) gene in astrocytes, showed behavioral abnormalities related to SZ supporting the role of astrocytes in SZ pathology.93,94

In BD, astrocytic density was also reduced supporting astrocyte dysfunction in regulating glutamate homeostasis, calcium signaling, circadian rhythms and metabolism. Beneficial therapeutical effects of many BD drugs such as lithium, valproic acid (VPA) and carbamazepine (CBZ) are partly due to their positive actions on astrocytes by affecting the gene expression in astrocytes and regulating astroglia homeostatic pathways.95,96 There is also an elevation reported in the expression profile of cortical astrocytes in the postmortem BD subjects generated from eight different cohorts of subjects.97 In an in vitro study, astrocytes derived from induced pluripotent stem cells (iPSCs) generated from BD individuals showed alteration in transcriptome and a decrease in neuronal activity when they were co-cultured with neuronal cells. BD astrocytes also increased IL-6 secretion in the blood of BD patients highlighting the role of astrocytes in inflammatory signaling in BD pathology.98

A reduction in the astrocyte density in various regions of the brain including the prefrontal cortex, cingulate cortex and amygdala is an important feature in MDD pathology.99101 Golgi staining showed astrocytic hypertrophy in cell bodies and processes in the white matter of cingulate cortex of depressed patients that died by suicide. The presence of hypertrophic astrocytes could reflect local inflammation supporting the neuro-inflammatory hypothesis in depressed patients.102 In addition, the protein and mRNA level of pro-inflammatory cytokines secreted by reactive astrocytes were increased in the prefrontal cortex of suicide victims.103 However, other astrocytic proteins and markers such as GFAP, AQP4, cnx43, cnx30, glutamate transporters, and glutamine synthetase were reduced in MDD.104

Astrocytes play an important role in neurodevelopment and neuronal function in the brain, including higher cognitive functions. Available data indicates that astrocyte number is decreased in the cerebral cortex, while their state of activation and GFAP expression is increased in the ASD brain. This dysfunction and other astrocytic alterations may contribute to the ASD pathology. More research is needed to help our understanding of the mechanisms involved in astrocytic-related pathophysiology in ASD, and to introduce astrocytes as one of the promising targets for ASD treatment. Future research should answer questions as if the decreased in astrocyte number found in cortex occurs in other brain areas, if there are areas where astrocytic activation is more pronounced that others, what is the role of astrocytes on development, plasticity, and inflammation, and what other astrocytic functions are altered in ASD.

The authors report no conflicts of interest in this work.

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Pathology and Astrocytes in Autism | NDT - Dove Medical Press

Google’s Ray Kurzweil says humans will be immortal by 2045 – Daily Mail

Would you like to live forever? Well, some experts say you might.

Last week, a formerGoogleengineer said he believes that humans will achieve immortality within the next eight years.

Ray Kurzweil - who has an 86 per cent success rate with his predictions - thinks that advances in technology will quickly lead to age-reversing 'nanobots'.

While it sounds far-fetched, scientists have been looking for years into ways we can regenerate our cells, or upload our minds to a computer.

MailOnline takes a look at the strangest ways humanity could attain eternal life.

Electronic immortality

Electronic immortality - Preserving brain after death and uploading the mind to a computer.

Freezing the brain - Cryogenically freezing the brain until technology advances to allow it to be brought back to life.

Cell rejuvenation- Rejuvenating ageing or damaged cells in the body by injecting them with stem cells.

Reanimating the brain- Pumping the brain with artificial blood to keep it alive.

The idea of uploading your mind to a computer has been theorised for many years now, but it has mostly remained the stuff of science fiction.

Nectome, a US-based startup, is trying to change that by devising a way to preserve the human brain so that its memories can be uploaded to the cloud.

The firm has figured out a way to preserve the human brain in microscopic detail using a 'high-tech embalming process,' according to the MIT Technology Review.

It uses a chemical solution that can keep the body intact for hundreds or thousands of years as a statue of frozen glass.

'You can think of what we do as a fancy form of embalming that preserves not just the outer details but the inner details,' said Robert McIntyre, Nectome's cofounder.

Speaking to prospective customers, Nectome positions its service as: 'What if we told you we could back up your mind?'

But the key to being able to recreate a person's consciousness involves accessing the organ's 'connectome.'

A connectome is the complex web of neural connections in the brain, often referred to as the brain's wiring system.

Nectome, which has been referred to as a 'preserve-your-brain-and-upload-it' company, has figured out a way to embalm the connectome as well.

However, in order for the technology to work, participants have to be willing to be euthanized, which led to it losing a contract with theMassachusetts Institute of Technology (MIT) in 2018.

The prestigious institution claimed the technology is in its infancy and there is no guarantee that they can recreate consciousness.

Despite the setback, that same year, a prominent futurist predicted that 'electronic immortality' would be available to humans by 2050.

Dr Ian Pearsonsaid that human intelligence, memory or senses could be connected to external technology.

Rather than creating a backed up copy of your mind, most of your intelligence would simply be running from a place outside of your physical brain.

In a blog post, he wrote: One day, your body dies and with it your brain stops,' he wrote in a blog post.

'But no big problem, because 99 per cent of your mind is still fine, running happily on IT, in the clouds.

Assuming you saved enough and prepared well, you connect to an android to use as your body from now on, attend your funeral, and then carry on as before, still you, just with a younger, highly upgraded body.

He adds that this type of immortality has dangers too, as itwould require the use of a purchased or rented android and cloud space ultimately owned by a tech company.

These companies could thus enslave workers after their deaths, by maintaining ownership of the mind for their own benefit down the line.

Maybe the cloud company could replicate your mind and make variations to address a wide range of markets, the futurist wrote.

Maybe they can use your mind as the UX on a new range of home-help robots. Each instance of you thinks they were once you, each thinks they are now enslaved to work for free for a tech company.

Cryogenics is the art of freezing bodies by preserving a dead body with liquid nitrogen.

Currently, it can only legally happen when someone has just been declared dead.

The freezing process must begin as soon as the patient dies in order to prevent brain damage, with facilities currently available in Russia and the US.

In the procedure, the body is cooled in an ice bath to gradually reduce its temperature bit by bit.

Experts then drain the blood and replace it with an anti freeze fluid to stop harmful ice crystals forming in the body.

Freezing the brain

Some companies offer the opportunity for people to have their brains frozen after they die,in the hope they can be brought back to life in the future.

One of these is Russiancryonics firm KrioRus, which currently has 91 human 'patients'stored at -320.8F (-196C) with the aim of protecting them against deterioration.

This is cold enough to stop all cellular function and preserve a body's state until defrost

This is so that they can potentially be revived in the future when science advances enough to cure any illness they may have had, including death itself, says KrioRus.

Their brains, or full bodies, are all currently floating in large vats of liquid nitrogen and housed in a corrugated metal shed outside Moscow.

It costs at least$28,000 (22,500) to be cryogenically preserved with this company.

It claims the service gives people left behind by dead relatives a 'peace of mind' and hope they will see them again.

They also freeze pets, and currently store 58 dogs, cats, birds, hamsters, rabbits and a chinchilla.

But, the head of the Russian Academy of Sciences's Pseudoscience Commission, Evgeny Alexandrov, described cryonics as 'an exclusively commercial undertaking that does not have any scientific basis', in comments to the Izvestia newspaper.

It is 'a fantasy speculating on people's hopes of resurrection from the dead and dreams of eternal life', the newspaper quoted him as saying.

Valeriya Udalova, KrioRus's director, had her dog frozen when it died in 2008, she says it helps people deal with loss.

She said it is likely that humankind will develop the technology to revive dead people in the future, but that there is 'no guarantee of such technology'.

This is by far the only company offering such a service, and there are thought to at least 500 bodies frozen in this way worldwide.

Another prominent company is the Alcor Life Extension Foundation in Arizona, USA, which had 199 patients as of October 2022.

There, full bodies are stored in large cylindrical chambers alongside three other full bodies. Brains can be stored in shelves, with five fitting into a slot for one body.

After a person dies, doctors must work fast to preserve the body and get it into storage.

Comparing the process to organ harvesting, Max More, CEO of Alcor, said in a 2020 interview that the first step was draining the body of its blood and liquids.

They then pump it full of an antifreeze-like substance. This is to prevent cells from becoming crystallised and damaged during the freezing process.

People who invest in these services are often desperate to reunite with family in the future.

The youngest known Alcor patient is a two-year-old Thai girl who died of brain cancer. Her family hopes to reunite with her down the line.

But cryogenic freezing also attracts the rich and eccentric. Bitcoin pioneer Hal Finney chose to have his body cryopreserved after he died from complications related to ALS in 2014.

There are serious ethical and moral concerns about the practice which has been touted for decades but remains a pipe dream.

The high prices of this preservation can often drain a person's estate, and will often consume a massive portion of their life-insurance payout - which could have instead benefited their family down the line.

Mr More admitted during an interview in February 2020 that his firm does not know when technology needed to wake up their patients will exist.

However, he is hopeful that this technology will exist and cited recent success in stem-cell research and lab-made organ growth as starting to pave the way forward.

Dr Michael Hendricks, a biologist at Canada's McGill University, wrote in 2015 that what makes a person's personality, sense of self, decision making and day-to-day mood are small connections between nerve cells.

But current technology has no way of perfectly storing these cells across the body, and changes to them would fundamentally change who a person is.

Cell rejuvenation

Many scientific breakthroughs have been made with regards to stem cell injections, which have been found to be able to rejuvenate cells.

Stem cells are unique because they can differentiate into different types of cells in the body, such as muscle, bone or nerve cells.

When injected into the body, they can integrate with damaged tissues and help to repair and regenerate them.

In 2016, stem cell injectionsreversed the scar tissuein a trial of 11 seriously ill patients who had suffered heart attacks, reducing scarring by 40 per cent.

Similarly, in 2019,Cambridge University researchersregenerated lost heart muscle and blood vessels in rats with damaged hearts after transplanting stem cells from a human heart.

Stem cells are found everywhere in the body, especially the bone marrow, standing ready to morph into the 200-odd types of cell that make up humans to repair damage.

But their numbers fall as we age, leaving older adults lacking the same regenerative capabilities as their younger peers.

Some creatures, like flatworms and hydras, have stem cells throughout their lives so are always able to regenerate lost body parts.

Dr Steven Cohen, who owns wellness clinics in California andLondon, says that stem cell therapy could be the key to extending the human life expectancy to up to 150.

Last month, he said his technology, which involves injecting people with exosomes, small vesicles that are naturally produced by stem cells, is just five years away.

The hope is that the exosomes - bursting with essential proteins, lipids, nucleic acids and others - will flow into organs and help to 'de-age' them, allowing someone to live longer.

A paper published last year found that more exosomes in the body boosted brain function, while another from the same year suggested they could reduce frailty and help someone live longer.

Other scientists have suggested people could one day live to the age of 200and are exploring technology like pills to flush out 'zombie cells' and ways to tweak DNA to extend someone's lifespan.

These cells stop dividing like others but start to spew a cocktail of harmful chemicals, damaging and degrading those around them.

Pills that flush these out are already in human trials with scientists saying they could hit the market in as little as 10 years.

A 2016 study from theSalk Institute in California claimed that the key tohalting or reversing ageing may lie in cellular reprogramming.

This is a process in which the expression of four genes, known as the Yamanaka factors, is induced, allowing scientists to convert any adult cell into induced pluripotent stem cells (iPSCs).

Like embryonic stem cells, which are derived from early-stage embryos, iPSCs are capable of dividing indefinitely and becoming any cell type present in our body.

The researchers found that when cellular reprogramming was induced in mice, their cells looked and acted younger.

Reanimating the brain

A technology that was developed to help scientists study brains in three dimensionscould also provide the key to eternal life.

In 2019, scientists at Yale Universityrestored the circulation and cellular activity in a pig's brainfour hours after its death by pumping it withoxygen-rich artificial blood.

Neuroscientist and lead author Dr Nenad Sestan said it is possible the brains could have been kept alive indefinitely and that additional steps could be taken to restore awareness, according to the Massachusetts Institute of Technology'sTechnology Review.

But he added that his team chose not to attempt either because 'this is uncharted territory.'

Chemicals added to prevent swelling during the procedure would likely prohibit consciousness indefinitely.

This means it may not be possible for the team to resuscitate brains that can still 'think' using their current methods.

The experiment's success provided a new way of studying the structure and function of the intact large mammalian brain.

'Previously, we have only been able to study cells in the large mammalian brain under static or largely two-dimensional conditions utilising small tissue samples outside of their native environment, said co-first author Stefano Daniele.

'For the first time, we are able to investigate the large brain in three dimensions, which increases our ability to study complex cellular interactions and connectivity.'

The team hoped these future 3D brain studies could help doctors find ways to salvage brain function in stroke patients, or test novel therapies.

But scientists also said it may one day allow humans to become immortal by hooking up our minds to artificial systems after our natural bodies have perished.

Nottingham Trent ethics and philosophy lecturer Benjamin Curtis said that this maylead to humans being locked in an eternal 'living hell' and enduring a 'fate worse than death.

'Even if your conscious brain were kept alive after your body had died, you would have to spend the foreseeable future as a disembodied brain in a bucket, locked away inside your own mind without access to the sense that allow us to experience and interact with the world,' Curtis told The Conversation.

'In the best case scenario you would be spending your life with only your own thoughts for company.'

Brain and memory preservation has been explored at length by futurists, scientists and science fiction junkies alike.

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Google's Ray Kurzweil says humans will be immortal by 2045 - Daily Mail