Transcomm November 2017

Stem Cells For Drug Dosing and Titration – Personalized Medicine – A New Dimension to the Application

While the early efforts in harnessing the enormous potential of stem cells for treating disease were largely focused on regeneration and the ability to repair damaged tissues in the body, recent advances in this field started driving researchers and clinicians alike to employ stem cells in drug discovery applications, such as novel compound screening, toxicity testing, target identification, disease modeling and personalized medicine development. What makes stem cells such an attractive option for drug discovery studies? The answer is pretty straightforward. Stem cells effectively and faithfully replicate the model of human disease and drug reactions compared to animal models. Using more relevant models of disease for drug discovery while providing financial savings in the long run would also reduce the number of animals required for drug testing.

The effects of physiological changes in patients with ailments like diabetes on pharmacokinetic parameters and the time course of drug response are poorly understood.  Even though dosing or titration considerations exist for certain classes of drugs they are not routinely recommended for patients with severe complications. For the majority of drugs, the issue of dose adjustment and drug titration on the basis of patient specific parameters has not been addressed in detail. The effects of altered body composition on the time course of drug response are also not completely understood. hiPSC-derived cells can serve as a surrogate “patient” to anticipate adverse side effects and calibrate optimal dosing/titration of drugs. Personalized medicine wherein hiPSC-derived motor neurons from patients with amyotrophic lateral sclerosis were tested with drugs to augment the limited treatment options is just one of the very many examples to prove the enormous potential of stem cells in drug discovery and personalized medicine.

In the context of existing drug testing platforms, such as animal studies, human clinical trials, animal iPSCs, and ESCs, hiPSCs provide advantages that can augment the current approaches to drug discovery. Stem cells while useful in predictive low-throughput and unbiased high-throughput drug screening can also help discern the biological mechanisms behind drug-drug interactions, an area currently not very well explored. The various advantages stem cells offer over traditional drug discovery approaches makes them a powerful and versatile instrument for the advancement of safe drug discovery and development.

“Dosing is an integral component in being precise with one’s medicine. It’s estimated that somewhere between 30 and 40 percent of the drugs people take do nothing for them. Yet people rarely consider whether their dose could be wrong.”Dean B. Joseph Guglielmo, PharmD

Nov 1

Pharmacist Janel Boyle, PharmD, PhD, who is developing dosing models tailored for children strongly opines that If you receive the wrong dose or the wrong medication, your results could range from not getting better to feeling worse to even dying. According to the Food and Drug Administration (FDA), more than 700,000 people each year experience serious drug reactions, and more than 117,000 die from them. By contrast, a more precise, individualized dose could boost a drug’s effectiveness against your disease while reducing or eliminating any potential side effects. Using stem cells to calculate the precise dosage and appropriate titration of the drug could one day help circumvent the burgeoning problem of either under or over dosage of drugs.

Understanding the genetics of Drug Induced  Hypersensitivity Reactions using stem cells

Understanding genetic susceptibilities to drug responses (i.e., adverse reactions and efficacy) is critical to the implementation of personalized medicine. Genetic variants have been associated with severe adverse reactions to carbamazepine, a common drug used primarily in the treatment of epilepsy and trigeminal neuralgia. In particular, two HL A-related variants (HL A-B* 1502 in Asian populations and HL A-A* 3101 in Caucasian populations)have been associated with an increased risk of developing Stevens-Johnson (SJS) syndrome and toxic epidermal necrolysis (TEN), two forms of a life threatening skin condition. However, these HLA variants predict only a portion of individuals who will develop these conditions. This suggests that other rare or non-HLA related variants may also play an important role. Scientists at NCTR, in collaboration with scientists at the University of Liverpool (UK) and the Huashan Hospital (China) are performing whole genome sequencing and genetic analysis to identify susceptibilities to carbamazepine-induced SJS or TEN using stem cells. The researchers hope that by identifying additional factors that help to explain variation in patient response, they will be able to better predict in advance who will have an adverse reaction to the drug.

Nov 2

Cayo et al. have established that patient specific iPSC–derived hepatocytes could be used to definitively determine the functional contribution of allelic variation in regulating lipid and cholesterol metabolism and could potentially provide a platform for the identification of novel treatments of CVD. Because hiPSCs can be reprogrammed from easily accessible somatic cell types, such as skin fibroblasts, this raises the possibility of using hiPSCs from GWAS patients as a source of hepatocytes to study the role of specific allelic variants in regulating cholesterol metabolism. In addition, the availability of hepatocytes derived from patients with inborn errors in hepatic metabolism could provide a platform for developing effective drug dosing and titration strategies.

(Click here to Stem cell - Transcell cancer articledownload pdf )
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Transcomm October 2017

Winding the biological clock: A small molecule based approach

“A human body can think thoughts, play a piano, kill germs, remove toxins, make a baby all at once. Once it’s doing that your biological rhythms are actually mirroring the symphony of the universe because you have Circadian rhythms, seasonal rhythms, tidal rhythms you know they mirror everything that is happening in the whole universe”.

Michio Kaku, the famous physicist and futurist could not have said it any better. Derived from the Latin “circa diem” which translates to “approximately a day”, the word circadian has garnered a lot of attention from researchers and general public alike. The circadian clock simply put is the body’s own time keeping mechanism that is calibrated by the light and dark cycles in a 24-hr period. This biological clock is found in all living things irrespective of the species. Our very first understanding of this rather fascinating and accurate time keeping mechanism came from research carried out on the fruit fly (Drosophila melanogaster). The terms “biological clock” and “circadian rhythms” are oft used interchangeably. Despite the relationship between the two, they are not one and the same. Circadian rhythms are produced and controlled by the said biological clocks and play a rather pivotal role in regulating their timing. Taking cues from the environment and other factors, the genes that control the molecular structure of the biological clocks either turn on or off. The biological clock whilst controlling the circadian rhythms also determine the sleep-wake cycle, regulate the hormone release and help maintain the body temperature and metabolism besides other functions.

bio prof

From Left to Right: Dr. Hall, Dr. Roshbash and Dr. Young were awarded the Nobel prize in Physiology or Medicine, 2017 for their groundbreaking discoveries on the molecular mechanisms controlling the body’s circadian rhythm. Using fruit fly as a model, the three Nobel laureates isolated a gene that controls the daily biological rhythm in sync with the earth’s revolutions.

The health of a human being is largely governed by their habits. Regular sleep and diet play a crucial role in preventing chronic disorders such as obesity, diabetes, depression and seasonal affective disorders. Researchers have already described the negative impact circadian rhythm disruption has on the human health and have identified molecular targets of small-molecule biological clock modulators. Our understanding of the small-molecule modulators needs to deepen for us to be able to decipher the key regulatory elements in the circadian network. The current edition of Transcomm, Prof Javed Iqbal summarizes on the “Pharmacological Modulation of Circadian Rhythm-related Metabolic Disorders using small molecule agonists”. It is a sincere effort to educate the reader on the importance of the circadian rhythms and how certain small molecules can be deployed to combat metabolic disorders linked to perturbations in the biological clock.

prof javed

Prof. Javed Iqbal brings decades of experience across all major areas of the healthcare ecosystem. Prof. Iqbal is a pharmaceutical and biotechnology executive, serial entrepreneur, advisor, an educator, public speaker, investor, and a dynamic leader who has helped many organizations in the last three decades achieve their goals.

Prof. Iqbal is currently the program lead of Human health and wellbeing of Regional committee on Asia and Pacific (RCAP) of International council of Science (ICSU) based at Kuala Lumpur, Malaysia and Founder Chairman of Cosmic Therapeutics, Hyderabad. Prof. Iqbal is also a fellow IUPAC and a member of Indian Prime Minister’s committee on CSIR society and is a member of Department of Science and Technology’s committee on Drugs and Pharmaceuticals and sits on many other institutional advisory boards. Prof Iqbal has been a visiting fellow at several International universities and is currently on the international advisory board of medicinal chemistry journal CHEMMEDCHEM published by Wiley-VCH. Prof Iqbal has contributed significantly to the areas of medicinal chemistry, drug discovery and organic synthesis and has published more than 200 research papers and has filed 135 patents in the area of diabetes, infectious diseases, cancer, process chemistry for API’s and pharmaceutical co-crystals. Two of the drugs discovered by his group at DRL underwent phase I clinical trials in Canada and UK.

Javed Iqbal graduated from Delhi University and worked as a research scientist at Ranbaxy Laboratories, New Delhi. Following his brief industrial stint, he moved to Cambridge University where he worked as an SERC post-doctoral fellow in the research group of Prof Ian Fleming, FRS. He later moved to Oxford University and worked as a research fellow with Prof J. E. Baldwin, FRS. He was a Professor at the Department of Chemistry, Indian Institute of Technology (IIT) Kanpur during 1984-99 and subsequently moved to Dr Reddy’s Laboratories Ltd (DRL), Hyderabad where he served as Distinguished Research Scientist and Global Head, Discovery Chemistry during 2000-07. Prof Iqbal served as a Director of Regional Research Laboratory (CSIR) Trivandrum during 2002 and of Dr Reddy’s Institute of Life Sciences, Hyderabad during 2007-20013.

Introduction: The intrinsic and genetically operated timekeeping system referred to as “circadian clock” is an essential timing system driving daily oscillations of physiology and behavior, including sleep/wake cycles, cell division cycles, metabolism, cardiovascular functions, hormone secretion, and mood balance. Circadian rhythms encompass several ubiquitous biological oscillations over 24-h period that are evolutionarily conserved from cyanobacteria to humans. This periodic rhythm is not a simple response to alternating changes of day and night rather the internal timekeeping system that allows organisms to anticipate environmental changes, thereby optimizing their physiology and behavior at the right time of day. The biological clock also greatly contributes to ensuring that certain biological processes take place in coordination with others. The circadian clock is self-sustainable by an elaborate cooperation of genetic components and most cells in multi-cellular organisms harbor their own cell-autonomous oscillators, which are hierarchically organized into a circadian timing system. At the apex of the mammalian circadian system, the suprachiasmatic nucleus (SCN) in the hypothalamus composed of densely packed neurons generates self-sustaining rhythms by both genetic and neural mechanisms and thus is considered as the central or master clock. The SCN central clock receives the environmental time information (primarily light) to adjust or entrain its phase and then orchestrates other oscillators in extra-SCN brain regions and peripheral tissues to exhibit overt circadian rhythms such as the rest-activity cycle, periodic daily variations in metabolism and body temperature, and the rhythmic secretion of hormones.

Mechanism of Circadian Rhythm: At the molecular level, the cellular oscillator is similar in both SCN and peripheral tissues, containing interlocked negative feedback loops. In the primary clock feedback loop, heterodimeric transcription factors (CLOCK/BMAL1 and NPAS2/BMAL1) drive expression of the Period1/2 and Cryptochrome1/2 genes. The encoded PER1/2 and CRY1/2 proteins in turn heterodimerize and repress CLOCK/BMAL1 and NPAS2/BMAL1 activity to inhibit their own expression. In addition, a secondary feedback loop consisting of the nuclear hormone receptors (REV–ERBs and RORs) directly regulates Bmal1 gene transcription, thus modulating the transcriptional output of the primary loop. REV-ERBs also have a key role in controlling various circadian outputs by cooperation with a variety of cell type-specific transcriptional regulators. Taken together, these two interlocked feedback loops provide a molecular basis for the self-sustaining circadian oscillations with a period of approximately 24 hours. The post-translational regulatory mechanisms influences the circadian clock as a wide range of auxiliary proteins such as protein kinases, chromatin modifying proteins and RNA-binding proteins are related to the control of protein stability, subcellular trafficking, and transcriptional activity of clock proteins, thereby contributing to fine and precise control of the cellular circadian rhythms. Among these posttranslational regulatory mechanisms, phosphorylation state of the negative limb proteins, PERs and CRYs is key to setting the period because phosphorylation-dependent degradation of PER and CRY proteins is required to terminate the repression phase leading to initiation of a new cycle of transcription.

Therapeutic potential for Circadian Rhythm Related Diseases: Several research studies have shown that a robust circadian timing is prerequisite for human health and disruption of the intrinsic rhythms leads to diverse pathological states. For instance, misalignment of the intrinsic oscillators by shift-work, jetlag (either physical or social) or irregular food intake is strongly associated with various human diseases such as sleep disorders, metabolic syndrome, affective disorders and even tumorigenesis. Phenotypic analyses on mutant mice models with defective clock genes along with human genetic studies also supported the above notion and revealed mechanistic links between disrupted circadian clock and the onsets of these circadian rhythm related diseases. As a result of extensive studies on circadian clock and its functional roles in the last decades, the identification of small molecule chemical compounds capable of modulating circadian clocks either directly or indirectly has become an emerging issue. Recent studies have resulted in discovery of small chemical compounds that can pharmacologically modulate circadian timing system. The discovery of endogenous ligand for REV-ERBs led to identification of compounds which in a rest period impaired locomotor activities and during the subsequent active period significantly affected the circadian expression of core clock genes in the murine hypothalamus, indicating that these compounds sufficiently and selectively enhance REV-ERBs-mediated transcriptional repression in vivo. These small molecules have promising therapeutic potential to modulate the activity of core components of the molecular circadian clock.

Small Molecules Modulators of CRY Proteins and REV-ERBs: A Novel Therapeutic Strategy for Metabolic Syndrome

 The reciprocal links between circadian clock and metabolism is well established. Thus small molecule modifiers of circadian clock have been identified for metabolic disorders as well as circadian misalignment for their therapeutic applications. The therapeutic potential of compound 1 (Figure 1), a CRYs activator/stabilizer on hepatocyte carbohydrate metabolism and diabetes has been demonstrated in mouse hepatocytes studies where CRY proteins are known to regulate fasting hormone-induced transcription of the Pck1 and G6pc genes which are associated with fasting blood glucose concentrations and type-2 diabetes in humans. Thus Compound 1 suppressed glucagon-dependent induction of Pck1 and G6pc genes without affecting their basal expression in cultured mouse primary hepatocytes and repressed glucagon-mediated activation of glucose production, suggesting the potential of 1 to control fasting hormone-induced gluconeogenesis. Two other related molecules 2 and 3 (Figure 1) were also shown to modulate the activities of CRY proteins leading to better metabolic control during circadian cycle. Recent studies have demonstrated a direct binding of compounds 1-3 (Figure 1) with CRY proteins and continuous treatment with them led to significant period lengthening and amplitude reduction of both Bmal1 and Per2 promoter activities in cultured SCN explants and fibroblast cells, implying activation of endogenous CRY proteins. It is shown that compound 1 binds to CRY protein through the FAD-binding pocket, which is known to be recognized by FBXL3 and mediate proteasomal degradation. The co-crystal structure of the compound 1 and CRY2 complex revealed that compound 1 compete with FAD to occupy the FAD binding site and then interferes with the binding of FBXL3 C-terminal to CRY, thereby stabilizing CRY proteins.

CRY modulators

Apart from the CRYs activator, pharmacological ligands for the circadian nuclear receptors REV-ERB were also shown to modulate body metabolism in vivo.  The metabolic effects of REV-ERB agonists 4 and 5 (Figure 1) were studied in mice models and chronic treatment with these agonists resulted in weight loss and reduced fat mass with increased energy expenditure. Notably, the modulation of REV-ERBs activity by agonist 4 and 5 altered daily expression of several genes related to glucose and lipid metabolism. Treatment with 4 and 5 also decreased lipogenesis and cholesterol/bile acid synthesis in the liver, increased lipid and glucose oxidation in the skeletal muscle, and decreased triglyceride synthesis. Notably, REV-ERB agonists were also effective in a high fat diet-induced obesity model as chronic treatment with compounds 4 and 5 significantly decreased plasma glucose, triglycerides, total cholesterol, non-esterified fatty acids and leptin, leading to a severe reduction in body weight and adiposity in the rodent model of obesity.

It conclusion, the pharmacological activation of CRYs or REV-ERBs may provide a novel therapeutic strategy to treat circadian-rhythm related disorder like obesity, metabolic and cardiovascular diseases in near future.

(Click here to Stem cell - Transcell cancer articledownload pdf )

Transcomm September 2017

Stem Cells For Therapeutic Nihilism

Therapeutic nihilism refers to the “skepticism regarding the worth of therapeutic agents especially in a particular disease”. The view that the era of modern medicine began with the introduction of the sulfonamides is supported by a standard textbook of pharmacology that refers to the years 1908-35 as being characterized by “therapeutic nihilism”. The failure of several promising drugs in the clinical trial stages led to a sense of therapeutic nihilism in big pharma about the prospects of using chemical and biologics as effective treatment modalities. Cell based therapies represent a “third wave” of therapeutics following in the wake of the “small molecule” and “biologicals” approaches. In recent years, the proof-of-concept studies using stem cell-based approaches in transgenic animal models, clinical trials in patients provide new hope to develop stem cell-based therapies for the effective treatment of various diseases that were hitherto classified under therapeutic nihilism.

Stem cells Therapeutic Nihilism

While there remains “hope” that stem cell based therapies will be effective in treating various diseases, there is also an excess of “hype”. Whenever the term “stem cells” surfaces, it often incites unrealistic expectations among patients, their caregivers and families, and the press. In this age of social media, patients and their families become easy targets for easier exploitation by many a shady group claiming to be providing the service with no credible research backing. Often times, patient desperation and hyping of stem cells has led to “stem cell tourism” where patients and families often travel overseas spending thousands of dollars for expensive treatments. The patients and their families are ill-informed about the risk of seeking treatment from unscrupulous operators. We at Transcell, strongly believe in the adage “patient first” and strive unrelentingly to uphold the highest standards in stem cell harvesting, culturing, clinical handling and cryopreserving for the intended applications. In the current issue of Transcomm, our aim is to educate the general public and clinicians alike about the regenerative and reparative capabilities of stem cells and how they can in the near future be a source of optimism in therapeutic nihilism.

Multiple sclerosis (MS) is an autoimmune disease which leads to demyelination that is disruption of the myelin sheath insulating nerve cells in the spinal cord and brain. Depending upon the area where there is loss of neurons, this condition can lead to paralysis, loss of vision, vertigo, muscle spasticity, painful involuntary muscle contractions etc. In a randomized study patients diagnosed with relapsing-remitting (RR) MS underwent an autologous Peripheral blood stem cell transplant (PBSCT) and this treatment was compared with FDA approved standard of care (i.e. natalizumab). The stem cells transplanted did show the ability to immunomodulate, it reduced the amount of Th1 and Th17 cells and normalized the amount of Treg cells and ensured a longer period of remission as opposed to the patients receiving the standard treatment. In another similar 3 year study patients with relapsing-remitting (RR) multiple sclerosis (MS) who had  previously received standard treatment and showed no improvement received  high-dose immunosuppressive therapy (HDIT) along with autologous hematopoietic cell transplant (HCT) and showed improved neurological function, disease functional scores and quality of life.

Multiple Sclerosis

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Cerebral palsy is used to describe a set of neurological disorders which leads to loss or impairment of muscle movement. It appears early in childhood and it leads to muscle weakness, tremors and stiffness. In 2015 a report was published where in 40 patients were administered with autologous bone marrow mononuclear cells and 6 months post treatment 95% of the group should a definitive improvement in locomotory functions. On comparing the pre- and postscans, it was observed that the metabolism in areas such as frontal, temporal, parietal, basal ganglia, thalamus, and cerebellum had increased. There was a significant association observed between the symptomatic improvements and cell therapy, thus confirming that these cells were capable of reducing the degree of impairment and did potentially improve the quality of life. In another study stem cells from umbilical cord blood (UCB) along with recombinant human erythropoietin was used to treat children with cerebral palsy. The erythropoietin was used to improve the efficacy of the cord blood stem cells and also for its neurotrophic ability. Six months post treatment, a clear improvement was observed in the motor and cognitive function of the patients accompanied by structural and metabolic changes in the brain.

13Alzheimer’s is a chronic neurodegenerative disorder which primarily leads to dysfunction in behavior, memory and ones thinking ability. Dr. Duk L. Na from Samsung Medical Center. Korea has completed a Phase I trial where in the safety and the efficacy of Neurostem®-AD (human umbilical cord blood derived mesenchymal stem cells) was evaluated. Human umbilical cord blood derived mesenchymal stem cells were selected due to their regenerative ability, paracrine effect on the microenvironment and immunomodulatory characteristics. Very recently the Ageless Regenerative Institute, USA has begun a phase II multi-center study trial to check the safety and effects of autologous adipose-derived stromal cells in patients with Alzheimer’s disease.

Autism is a complex lifelong neurodevelopmental spectrum disorder, it hampers the ability of the person to function or interact with other people. It affects every individual in a unique way and to a unique degree. In 2013 a phase I/II trial was conducted where in a group of autistic children were infused with a combination of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs). 1Around 37 individuals were registered for this phase and the Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist (ABC) were adopted to assess the treatment. Post treatment, statistically significant differences were observed in the CARS, ABC scores and a considerable amount of behavioral changes were also observed too. In this study, the combination of CBMNCs and UCMSCs showed larger therapeutic effect than just the treatment with CBMNCs. Another group organized a Phase II trial wherein bone marrow mononuclear cells (BMMNCs) were transplanted in a group of patients out of which 91% showed an improved disorder score and a marked difference with statistical significance between the pre and post scores with very few cases of adverse events.

Diabetes mellitus is a metabolic disorder, which occurs when there is prolonged high blood sugar levels either due to insufficient insulin production or when the surrounding cells of the body are unresponsive to insulin. A study was conducted where in a group of people who had previously been treated for diabetes, and were still dependent on a high dose of insulin were selected for a stem cell transplant. Autologous bone marrow-derived stem cells were transfused in the individuals twice in 12 weeks. Post treatment, 82% of the individuals observed a reduction in their insulin requirement. ABMSCT did result in a significant decrease in the insulin dose requirement along with an improvement in the stimulated C-peptide levels.

(Click here to Stem cell - Transcell cancer articledownload pdf 

 

Transcomm August 2017

Stem cells as Cyclosporin

Transplantation is the act of transferring an organ, tissue, or cell from one body to another. Cell transplant (referred to hereby as stem cell transplant) is a process which involves either replacing diseased or ineffective tissue with healthy new stem cells.  The two most common types of stem cell transplants are autologous or allogenic transplants. Both transplantation procedures are a common treatment option for treating cancers such as Leukemia, Lymphoma and Multiple Myeloma. Similarly, the field of organ transplantation has made remarkable progress in a short period of time. Transplantation has evolved to become the treatment of choice for end-stage organ failures resulting from almost any of a wide variety of causes. Transplantation of the kidney, liver, pancreas, intestine, heart, and lungs has now become common practice in all parts of the world. Broadly speaking, organ transplants are divided into three categories based on the similarity between the donor and the recipient: 1-Autotransplants, wherein transfer of tissue or organs is done from one part of an individual to another part of the same individual. This kind of transplantation does not require immune suppression. They are the most common type of transplants and include skin grafts and vein grafts for bypasses. 2-Allotransplants: involves transfer of cells/tissue/organs from one individual to a different individual of the same species—the most common scenario for most solid organ transplants performed today. Immunosuppression is required for allograft recipients to prevent rejection. 3-Xenotransplants: involve transfer across species barriers. Currently, xenotransplants are largely relegated to the laboratory, given the complex, potent immunologic barriers to success.

One of the biggest problems associated with allogenic organ transplantation is Graft-versus-host disease or GVHD as it is commonly referred to. In bone marrow and other transplants, T cells in the allografts reconstitute T-cell immunity in the recipient. Unfortunately, these T cells recognize the recipient as ‘non-self’ and employ a wide range of immune mechanisms to attack recipient tissues in a process known as graft-versus-host disease (GVHD).  More than 25,000 allogeneic transplantations are performed annually. Given current trends, the number of transplants from unrelated donors is expected to double within the next five years, significantly increasing the population of patients with GVHD. Yet the major complication, i.e GVHD, remains lethal and limits the use of this important medical strategy. Long-term immunosuppressants are usually the treatment regimen for chronic GVHD. Prolonged usage of immunosuppressants would lead to other complications such as Fungal, bacterial, and viral infections leading to complete immunity collapse followed by death.

In this current issue of Transcomm, we would like to educate the common public and doctors about the advantages of considering a special type of stem cells called mesenchymal stem cells (MSCs) as immunosuppressant for treating GVHD and associated post-transplant complications. We are positive that the reader would appreciate the beauty of these stem cells in circumventing such grave disease complications as GVHD in organ or cell transplantations. Another reason to store your loved one’s stem cells.

In a recent clinical trial, children suffering with Grade II-IV acute Graft vs Host disease (aGVHD) were recruited. They were not responding to standard treatment such as steroids or other immunosuppressive agents. Soas an alternate treatment, remestemcel-L (Prochymal) an off the shelf source of Human Mesenchymal stem cells, which is essentially an allogenic transplantation was employed. Most of the children enrolled had multiple organs such as the skin, liver, gastrointestinal system affected by GVHD. The patients were given eight infusions of two million MSC cells periodically; post which the patients were monitored. The infusions were successful with no post procedure complications and when compared to the control group, the average survival rate of all the patients increased. This study has paved the way for using (Prochymal) stem cells for treating aGVHD.

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In another similar study (November, 2015), a clinical trial was conducted using mesenchymal stem cells (MSCs; JR-031) for steroid-refractory grade II or III acute graft-versus-host disease (aGVHD). After receiving extremely positive results in the phase I/II of the study, the study was taken further to phase II/III study where in the stem cells were used to treat steroid-refractory grade III or IV GVHD. Close to 25 patients were enrolled for this phase of the study. Four weeks post MSC infusions, no adverse effects were observed in the patients and they started responding positively to the treatment. Towards the end of 24 weeks, 48% of the patients showed an evident increase in the survival rate indicating a complete response to the treatment.

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In the year 2007 Christian Medical College, Vellore, India had begun a single center non randomized, non-blinded Phase I/II clinical trial wherein they want to check the role of mesenchymal stem cells (MSC) in the management of steroid refractory graft versus host disease (GVHD) following an allogeneic stem cell transplant. Patients who developed grade II or IV GVHD following an allogeneic bone marrow stem cell transplant were enrolled. Results are yet to be published.

In another study, bone marrow derived MSCs were used to treat refractory acute graft-versus-host disease (aGVHD) incurred after allogeneic hematopoietic stem cell transplantation. This group followed the immunomodulatory effects of the MSCs used for the treatment very closely. Close to 50 patients enrolled for this study and a dose of million cells were given weekly to each patient till a complete response was observed for about 8 weeks. 75% of the group responded positively to the treatment and the severity of the disease drastically lowered in the group receiving the MSC treatment. The amount of T- lymphocytes and the levels of     T-regulatory cells had increased in patients receiving the MSC transplantation compared to pre-treatment levels of the patients and the control group. This was an indication that the MSCs infused could successfully reduce the severity of the disease in patients with  aGVHD  while also slowing down the incidence of chronic GVHD and this could be achieved because the immunomodulatory and immunoregulatory characteristic of MSCs which helped in improving thymus function and also increase the amount and activity of T-regulatory cells.

 

Transcomm July– 2017

Stem cells in personalizing implants

Mesenchymal stem cells (MSCs) are multipotent stromal stem cells that can be harvested from many different sources and differentiated into a variety of cell types. The effectiveness of MSCs based therapies is dependent on a gamut of factors which include differentiating state of the MSCs at the site of application, vehicle used and the nature/extent of injury. Tissue engineering and regenerative medicine, coupled with genetic engineering and gene therapy are revolutionizing the way cell therapy is performed these days. While several studies from different research groups have shown encouraging results wherein MSCs were used to develop personalized implants, the exact mechanism behind MSC mediated therapy is work in progress.

Scientists across the world are trying to answer the question of how stem cells aid in the repair process and what could be done to speed up the process of wound healing/repair. As is the case with many other novel therapies, stem cell based implants and their potential applications as an alternative to conventional implants with limited and inert efficacy is exploratory in nature. Despite the negative press about stem cell based therapies, scientists and clinicians across the world are reporting success stories wherein stem cells were able to replace or support the conventional treatment modalities, especially in the field of implantology. With the ever increasing demand for implants and enhancing wound healing procedures, stem cells could be playing a vital role in trying to meet these demands. With the current issue of Transcomm, our sincere effort is to educate the audience about the benefits of stem cells in implantology and to encourage stem cell storage as a very important short term investment that can have long term implications on their loved ones’ quality of life.

Implants and their limitations in application

A 36 year old male patient was detected with a primary tumor in his distal trachea and main bronchi, recurrent and cancerous and of inoperable size. He was previously treated with debulking surgery and radiation therapy, but constant recurrence of the cancerous tissue forced the doctors to adopt a cell based therapy. After the tumour was resected, the airway was substituted with a tailored bioartificial nanocomposite containing autologous bone-marrow mononuclear cells. 5 months post transplantation, the patient is tumour free and asymptomatic. Postoperatively, mobilization of peripheral mesenchymal stromal cells was detected, along with up-regulation of receptors, non- apoptotic genes and regeneration-associated plasma factors which showed the signs of ECM remodeling, cell mediated wound healing, neovascularisation of the graft. This study confirmed the potential of tailor made bioartificial scaffolds with cells to replace complex airway defects.

Stem cell Implants Transcell

In a sinus augmentation procedure, the optimal bone formation takes approximately 6-9 months post-surgery, despite using standard grafting materials along with an autogenous bone graft. Therefore for a faster recovery process and bone formation, sinus-augmentation procedure was conducted with an allograft cellular bone matrix (ACBM), containing native mesenchymal stem cells and osteoprogenitors. Post-surgery, there was an improvement in the amount of vital bone content along with an increase in the average healing period which was now within the range of about 3.7-4 months. The high percentage of vital bone content, along with the relatively short healing phase, emphasize the importance of usage of stem cells for implant placement and restoration when considering a cellular implant method.

A 48-year old patient presented with a partial edentulous lower jaw wished for a surgical intervention or implant supported fix for the situation. A stem cell based subepithelial connective tissue graft along with allogenic human bone segments was used in his. The sterile allograft bone product/block which carried the stem cells was derived from human donor bone, which had very high regenerative and osteoconductive properties. These bone blocks were attached to a spongy bone base and were held in place by osteosynthesis screws using a 3D copying machine. Subepithelial connective tissue graft (SCTG), the source of mesenchymal stem cells has been derived from the region between 2nd premolar – 2nd molar. The SCTG graft successfully got incorporated into the recipient site.

partial edentulous lower jaw

Stem cell therapy can play a pivotal role in the treatment of craniofacial bone defects. In a study stem cells and progenitor cells were isolated from the bone marrow, also known as tissue repair cells. 24 patients who required facial/jawbone reconstruction procedures participated in this trial .The patients received stem cell based therapy along with oral implants functionally loaded with tooth restorations along with the control group which received guided bone regeneration (GBR).  The patients of both the groups were observed 1 year post therapy. While not showing any adverse effects, stem cell therapy assisted in accelerated alveolar bone regeneration, thereby reducing the need for secondary bone graft.

craniofacial bone defects

In a study involving four patients with large bone diaphysis defects, a novel tissue engineering approach was used where in stem cells were isolated from the patient’s bone marrow and cultured to get the desired numbers and then seeded onto porous hydroxyapatite (HA) ceramic scaffolds. This scaffold was drawn to match individual patients bone deficit in terms of size and shape.  During surgery, the 3D construct-ceramic scaffolds containing the cells were placed in the area containing the bone defect. The patients who took part in this study were closely monitored for a year post surgery and showed no signs of infections or complications. The last follow up was done 6 to 7 years post-surgery with no complications and the implants remained integrated with no fractures, proving the long term reliability of stem cell therapy.

In vitro Profiling of Indian Patients Head & Neck Tumor Derived Spheres

Head and Neck (H&N) cancers are malignant types contributing to one-third of all cancer types in India. The actual burden of this cancer type in India is much greater than reported and reflected through the existing literature. South-East Asia is documented to face steep increase of over 75% in the number of cancer deaths in 2020 as compared to 2000. Also, on the logic of Indian population becoming nearly twice that of the world in the past 15 years, increase in cancer burden with the same proportion is anticipated.

Read more: In vitro Profiling of Indian Patients Head & Neck Tumor Derived Spheres: Transcell cancer article – Cancer Clinical Research Reports Stem cell - Transcell cancer article

Transcomm June– 2017

Stem cells vs Druggable molecules in modern science

Stem cells remain a hot topic in academia and industry alike, and with the potential to cause a paradigm shift where many believe in their ability to differentiate into a variety of valuable cell types to use for treating diseases. Stem cells have in the past and continue to capture the imagination of biologists, tissue engineers, pharmaceutical company scientists, and indeed the general public, largely because of the prospects, it seems to offer of manipulating cell fate to treat disorders for which there is no other effective therapy/management. The initial focus was on diseases like type I diabetes and Parkinson’s disease (PD), in which attempts had already been made to treat patients with donor cells. But it was quickly realized that the use of embryonic stem cells may pose a problem owing to their behavior. This triggered a race to utilize adult stem cells as products that are safe for use in treating certain conditions.

In the current issue of Transcomm, we will be focusing on how human pluripotent stem cells in culture could be used as therapeutic agents as opposed to small molecules/biologics for treating various medical conditions. We derive our motivation from the widespread recognition that the drug discovery process in practice in most pharmaceutical companies is inefficient, at best, and, in the past decade or so, has been struggling to meet the need for new druggable formulations. This coupled with many famous cases wherein already marketed drugs have been found either ineffective or shown to have unanticipated side effects is what drives us to advocate the use of stem cells in treating various conditions with clinical evidence, where conventional drugs have failed to show any or little effects. Cult Transcell strongly believes that the reader while appreciating the effectiveness of stem cells in treating various conditions would consider storing their loved ones’ stem cells for the future. A small investment in your loved ones’ future now would definitely go a long way.of stem cells. All the stakeholders here at Transcell strongly believe in the power of these super cells and constantly strive towards educating the general public about the same.

Case studies:
Stem cell transplantation in people with relapsing and progressive MS

In Northwestern University over the course of about 10 years, 123 people with relapsing-remitting Multiple sclerosis (MS) and 28 with secondary-progressive Multiple sclerosis received a stem cell based treatment, wherein they received a non-myeloblative hematopoietic stem cell transplantation. Their immune system was suppressed, but not completely depleted before the HSC transplantation. Out of the total number of patients the 145 available for follow up showed remarkable improvements in terms of their disability score in comparison with their pretreatment score. The score improved by one point or more. Relapses and MRI-detected disease activity were also significantly reduced. Unfortunately people with secondary-progressive MS didn’t show any improvement on their disability scores, proving the need for stem cell intervention at the earlier stages of the disease.Stemcells multiple sclerosis

 

The Association for Research in Vision and Ophthalmology (ARVO) reported about a patient suffering from ad­vanced wet age-related macular degeneration (AMD) and who was not responding to standard treatments and so underwent stem cell transplantation. A small piece of skin from the patient’s arm was collected and modified into induced pluripotent stem cells (iPSC), these iPSCs were then transformed into retinal cells, which were trans­planted into the patient’s eye. The transplanted cells survived without any adverse events for over a year and an improvement in vision was observed.

induced pluripotent stem cells

A study was carried out where in twenty-five patients suffering from grade III and grade IV steroid-refractory acute graft-versus-host disease were transfused with Bone marrow-derived mesenchymal stem cells along with no additional immunosuppressant. Remarkably, 4 weeks post MSC infusion, almost 60 % of the patients responded to the treatment and showed an absolute decrease in the disease progression while the average survival rate increased drastically. There were no adverse effects observed with the treatment, further reinforcing the potential of using stem cell as a possible cure.

A 68-year-old patient suffering from severe heart failure – left ventricular ejection fraction (LVEF) was treated with help of transplanted embryonic stem cells transformed into cardiac progenitor cells. The Isl-1+ SSEA- 1+ cells were embedded into a fibrin scaffold which was surgically delivered into the patient via a coronary artery bypass which was performed in a non-infarcted area. After 3 months, the patient is symptomatically improved; the disease condition progressed from NYHA functional Class III to NYHA functional Class I and no new complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events was observed. This study demonstrates the potential of generating a clinical-grade population of human ESC-derived cardiac progenitors.

Stem cells progenitor cell-loaded fibrin patch

Intraoperative view of the progenitor cell-loaded fibrin patch that has been slid into the pocket between an autologous pericardial flap and the epicardial surface of the infarct area

In another case study, stem cell therapy was carried out for HIV positive patients .The human immunodeficiency virus (HIV) is a lentivirus that causes HIV infection and over time acquired immunodeficiency syndrome (AIDS). A study was carried out wherein HIV positive patients underwent allogenic hematopoietic stem cell transplantation in order to reduce the HIV -1 reservoir. The hematopoietic stem cell transplantation led to a loss of detectable HIV-1 from blood and gut tissue and thus reduction of the HIV-1 reservoir and also for a brief period of time antiretroviral-free HIV-1 remission was recorded, along with the reduction in the intensity of the symptoms.

The world’s 1st stem cell treatment for Parkinson’s disease: A ground-breaking study, was undertaken by researchers in the year 2016 at The Royal Melbourne Hospital (RMH) in Australia, where in as a part of Phase I clinical trial, neural stem cells derived from unfertilized eggs were inserted into the brains of 12 patients with moderate to severe Parkinson’s. This phase was to standardize the dosage of neural stem cells required per surgery. The 1st surgery was performed successfully in a 64 year old Parkinson’s patient. The hope is that the neural cells will transform into dopaminergic neurons and boost the level of dopamine. These studies will be carried out throughout 2017 and the definitive results will be obtained by 2019.

A Clinic in Europe, the Swiss Medica Clinic, which treats diseases such as diabetes, liver cirrhosis, osteoarthritis, Lyme disease, Chron’s disease etc has had a successful case report with a patient suffering from Autism. The patient, Yu Wanhuai during the first 3 years of his life was developing quite normally, But by the age of 4 the disease onset led to a series of behavioral changes; for example the patient started being antisocial, had a ritualistic behavior and soon was diagnosed with Autism. The patient was injected with his own adipose-derived mesenchymal stem cells and the symptoms have reported to gradually reduce over time. The child seems less restricted and more open to interaction, is open to socializing and making new friends.

Technically, the FDA calls stem cells “biologics”, but the FDA regulates stem cell products with the goal of ensuring safety and efficacy much the same as traditionally defined chemical “drugs”. Unlike conventional drug regimens wherein a patient is treated with chemical drugs often with undesirable side effects, stem cell based therapies are free from any undesired side effects mainly due to their biological origin. Moreover, stem cells have been reported not to raise any observable immune response which makes them all the more desirable as “biological drugs” for the treatment of various ailments.