Transcomm February 2018

Stem cell derived exosomes as a novel therapeutic option for AD

These days, all news in India is only about healthcare: heavy investments in healthcare, new apps for healthcare, new business models for healthcare and finally funding agencies with a mandate to fund basic and translational research coming forward to give away tax payer’s money generously to healthcare startups and established companies, but mental healthcare often remains, paradoxically, forgotten and ignored.

Alzheimer’s disease (AD) is the most common cause of Dementia. AD and other forms of dementia are a growing public health problem among the elderly in developing countries with aging population increasing rapidly. It is estimated that by the year 2020, approximately 70% of the world’s population aged 60 and above will be living in developing countries, with 14.2% in India.

I want the reader to know that AD although was reported in 1907 by Lois Alzheimer who characterized the disease as causing memory loss and cognitive impairment, till today, the disease is neither scientifically nor medically understood reflecting on the recent (2016) drug clinical trial failing (Eli Lilly). Like Cancers, Alzheimer’s disease is also a death sentence to the entire family of the patient and there is no reversal of the condition anytime killing more people than breast and prostate cancers combined.

In Feb’s Transcomm, we have Dr Sasidhar throwing light on the disease, stem cells as therapeutic tools to treat the disease, introducing stem cell derived Exosome Vesicles to treat AD. He practices exosomes research and his statements are straight from the lab data.

The biggest disease today is not AD or Cancers, but rather the feeling of being unwanted..

Wishing good health for everybody,


Sasidhar Manda


Dr. Sasidhar Manda is the Founder of Urvogelbio, Hyderabad, a startup developing exosome-based diagnostics and therapeutics in the area of CNS and oncology diseases. He leads the research division of Apollo Hospital Educational Research foundation (AHERF).


Pathologically, AD is described by accumulated beta-amyloid plaques, neurofibrillary tangles and neuro degeneration. Current AD therapies only offer symptomatic relief and do not cure the disease, though there are a number of marketed drugs approved for AD; this remains a significant area of unmet medical need. Despite substantial impetus in AD research, etiology of AD is unknown. Amyloid plaques and tau fibrils stand as significant molecular pointers of AD. But, existing strategies targeting amyloid or tau are unable to repair regeneration of already damaged neural tissues. There has been increasing demand to harness the potential of stem cells for disease modelling, drug discovery and therapy. Recently, Stem Cell therapy (SC therapy) has emerged as a potential player for neurodegenerative diseases including AD.

Embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and tissue-derived stem cells such as bone marrow (BM) and adipose derived stem cells are the major Stem cell candidates with a potential for AD therapy. Stem Cell therapy is believed to work through the following mechanisms including integration into the existing neural networks of the AD brain, increasing acetyl choline levels to improve cognition and memory, increasing neurotrophic factors to modulate neuroplasticity and neurogenesis and other mechanisms.ESCs are self-renewing, totipotent cells which have the capability to differentiate into neuron progenitor cells (NPCs), and these can result in a therapeutic effect when these cells are transplanted into AD animal models. Significant developments currently taking place in the area of AD research includes-

  • Generation of induced pluripotent stem cells by reprogramming adult somatic cells
  • Generation of iPSC repositories
  • Genomic engineering
  • Lineage differentiation
  • Modulation of endogenous stem cell regeneration and differentiation
  • Development of a three-dimensional organoid system

Safety and ethical concerns of stem cell-based therapies

Safety and ethical concerns of stem cell-based therapies Despite promising results in both pre-clinical (animal models) and clinical (six Phase I and II human clinical studies) stages, Stem cells have safety, manufacturing, ethical, biological and logical concerns for successful translation into a AD drug. These concerns coupled with the failure of almost 99.5 % of clinical trial candidates in AD therapeutic area, have compelled the research community to explore for innovative therapeutic options combining neuroprotective properties and disease modifying capabilities. Exosomes derived from stem cells sources could be ideal alternative candidates, as they have the potential to nullify the concerns raised against stem cells and also function as natural drug delivery vehicles.

Stem cell derived vesicles – The revolutionary discovery of Exosome Vesicles (EVs) has shed new light on the development of disease modifying treatments for AD, owing to their potential in delivering the therapeutics agents to the brain. The ease of using EVs as natural drug delivery vehicles coupled with their ability to harbor molecular cargo as the stem cells make them excellent candidates as novel AD drugs. Mesenchymal Stem Cells (MSCs) have emerged as a significant players and offer a promising treatment for AD as a regenerative option and therapeutic gene delivery. Additionally, adipose tissue derived MSCs host neprilysin, which has an ability to clear Ab plaques.  Initially, the therapeutic efficacy of MSCs was attributed to their migratory capacity and engraftment at the target site, with the development of bio distribution and in vivo studies, it is being agreed among the scientific community that therapeutic efficacy of MSC is attributable to the paracrine effects of MSCs released EVs.

MSC-EVs possess several advantages compared to other vehicles of treatment. Firstly, EVs can be used as natural vehicles for therapeutic delivery of a variety of disease-modifying molecules to the brain due to their ability to cross the blood brain barrier. Secondly, they can be instilled as nasal spray for instance, ensuring easy administration of drugs, so that they could directly reach the brain through the olfactory route. Thus, EVs loaded with drugs, and can serve to stop/reverse and assist the revival of neurons which remains as the major road block and the reason for failure of several AD therapies. Altogether, MSC-EVs can be envisaged as the therapeutic intervention with potential to reverse/cure AD, while majority of the existing drugs offer mere symptomatic relief to slow down its progression.

Rationale for use of MSC -EV therapy for AD

In a healthy subject, Aβ is produced and maintained at a certain level owing to the balance achieved by its degradation system in the body. However, if Aβ accumulates excessively due to complex factors including genetic factors and abnormal lipid metabolism AD sets in. Neprilysin (CD10, hereinafter called NEP), a type II transmembrane metalloendopeptidase aids in the decomposition of Aβ. In AD patients, the activity NEP is reduced and as such therapeutic strategies supplementing the reduced NEP are considered effective. Human adipose derived MSCs which are enriched with NEP can be employed to both reduce and promote the clearance of Ab levels in the brain. Further, genetically modified MSCs can be conceived as an advanced model to enhance the therapeutic effect of EVs.

Advantages of Using Stem Cell-Derived Exosomes over Stem Cells for Therapeutic Purposes

Exosomes may provide a way to increase the possibilities of a cell cargo to reach other places in the body and, due to their small size; they expand the “interacting surface of a cell” in relation to its volume. There are several considerations about the advantages/risks of exosomes versus stem cell therapy. Among the risks of cell therapy with stem cells are negative tumor modulation, malignant transformation, and obstruction of small vessels. Some of the advantages of EV therapy are low immunogenicity, no vascular obstructive effect and permeability through BBB. A brief outline of development of stem cell exosomes is potrayed in the picture to the left. Three important aspects need to be established for conducting first-in-man trials. Quality aspects, Clinical and non-clinical requirements of the exosome formulations need to be established for registering exosomes as drug.

“Store your mesenchymal stem cells today with TRANSCELL BIOLIFE, the only biobank facilitating personalized medicine in India”.

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


Transcomm January 2018

Sleep deprivation and its effects on precious functional stem cells

Sleep is that golden chain that ties health and our bodies together

-Thomas Dekker

Stem cells are mother cells that have the potential to become any type of cell in the body. One of the main characteristics of stem cells is their ability to self-renew or multiply while maintaining the potential to develop into other types of cells. Stem cells can become cells of the blood, heart, bones, skin, muscles, brain etc. There are different sources of stem cells but all types of stem cells have the similar capacity to develop into multiple types of cells. Scientists first studied the potential of stem cells in mouse embryos over two decades ago. Over years of research they discovered the properties of these stem cells in 1998. A stem cell transplant is a procedure that replaces defective or damaged cells in patients with healthy stem cells. Stem cell transplants commonly are used to treat leukemia and lymphoma, cancers that affect the blood and lymphatic system palliatively. They also can help patients recover from or better tolerate cancer treatment. In addition, these stem cell transplants are practiced to treat hereditary blood disorders, such as sickle cell anemia, and autoimmune diseases, such as multiple sclerosis. Many of the factors affecting the success of stem cell transplantations are still unknown. While stem cell transplantation is a standard therapeutic procedure for various malignant and non-malignant diseases, the impact of sleep on hematopoietic (blood) cell (HSCs) transplantation appears to be of common man’s interest. Circadian rhythms provide temporal organization to molecular, cellular, and biochemical processes and they may therefore be synchronizing HSCs functions with sleep. A relationship of this nature between sleep and the function of HSCs can be especially important, as more than 100 million people around the world, including potential bone marrow donors, suffer from disorders of sleep and wakefulness. As sleep is a complex phenomenon, it is difficult to determine the factors that mediate the effects of sleep on the reconstitution potential of the stem cells. Sleep affects almost every physiological and behavioral system (metabolism, heart rate, endocrine system, immune system, etc.). It is therefore unlikely that a single factor mediates all the effects of sleep on the stem cells’ viability, regenerative and reparative potential. In the current issue of Transcomm, we try to shed light on the effects of sleep or lack thereof on stem cells and their properties. We are sure the reader while appreciating the various uses of stem cells in modern medicine would realize the importance of incorporating ample amount of sleep in their daily life to maintain their overall health and wellbeing.

Future is shaped by your dreams while your health is shaped by your healthy stem cells!

So, stop wasting your time and go to sleep….

Sleep deprivation affects stem cells, reducing transplant efficiency

Sleep deprivating effect on stem cell transplantation

Although the research was done in mice, the findings have possible implications for bone marrow transplants, more properly called hematopoietic stem cell transplants, in humans. Drowsy mice make poor stem cell donors, according to a new study by researchers at the Stanford University School of Medicine.  A sleep deficit of just four hours affects by as much as 50 percent the ability of stem cells of the blood and immune system to migrate to the proper spots in the bone marrow of recipient mice and churn out the cell types necessary to reconstitute a damaged immune system, the researchers found. Rolls, who is now an assistant professor at the Israel Institute of Technology, shares lead authorship of the study, which was published Oct. 14, 2015 in Nature Communications.

Sleep deprivating effect on stem cell transplantation 2

Hematopoietic stem cells, also known as blood stem cells, are responsible for giving rise to the cells of our blood and immune system and are the key “ingredient” in bone marrow transplants, a cellular therapy that was pioneered over 50 years ago. The transplantation of bone marrow or hematopoietic stem cells is now routinely used to treat patients with blood cancers such as leukemia or lymphoma and disorders of the immune system. According to the American Society for Blood and Marrow Transplantation, approximately 24,000 patients world-wide are annually transplanted with donor blood stem cells. There are many critical steps in a bone marrow or stem cell transplant between a donor and recipient (known as an allogenic transplant):

Bone marrow or stem cells from an immunologically matched donor are harvested. The recipient’s immune system is “conditioned” to receive the donor cells.Transplanted donor stem cells migrate to the bone marrow – the vascular space inside the bone and home to hematopoietic stem cells.

Donor stem cells engraft in the recipient bone marrow and begin to proliferate to generate the cells that enter the circulation and help restore the patient’s blood and immune system. Even a partial failure in one of these steps can threaten the success of the transplant. It turns out that sleep may also be a critical factor in transplant success. A team of scientists from California and Israel used mice to test the effect of sleep on stem cell transplantation. When mice were sleep-deprived, the ability of their stem cells to restore the blood and immune system of a recipient mouse was dramatically decreased. Not only were there fewer transplanted cells found in the circulation, but there were also fewer donor cells in the bone marrow of transplanted mice. How does sleep deprivation affect hematopoietic stem cell function? Part of the answer appears to be that the “sleepy cells” were functionally impaired (sound familiar?). Hematopoietic stem cells from the sleep-deprived mice were shown to have genetic changes that inhibited their migration. When these genetic changes were experimentally corrected, the “sleepy cells” were able to migrate normally thus demonstrating that the genetic changes were important for stem cell migration. Growth hormone may be another part of the answer. Known to be regulated by sleep, growth hormone was linked to the same genetic changes seen in the “sleepy” stem cells thus suggesting that growth hormone was the link between the lack of sleep and the genetic changes. We all know from our own experience that sleep is important, but how it affects cell function is a fundamental question and the subject of ongoing scientific inquiry. This research adds an important new and underappreciated dimension to stem cell research and their clinical use.

“Store your precious stem cells today for the intended applications with Biolife, a biobank facilitating personalized medicine”.

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

Transcomm December 2017

Personalised Medicine in Dentistry: Current Status and Future Possibilities

The medical profession recognised the importance of genomic information and has embraced and applied this concept in understanding the etiology of the disease and treating and preventing it. However, the dental profession has yet to accept and take advantage of this new technology. Genomics, which focuses on the interactions between all the genes in the genome and with environmental factors has the potential to revolutionise our understanding of oral health and disease. The application of genomics in the dental clinical setting and as useful aid for clinical decision making, requires an analysis of each individual patient’s unique clinical, genetic, genomic, behavioural, and environmental information. The use of this information and application of the technology may enable early identification of disease and provide better prognosis and more effective treatment options for a variety of oral diseases. Oral diseases such as dental caries, periodontitis, orthodontics (e.g. malocclusion) and oral cancer are some of the well-researched diseases in the field of genetics and genomics.

The medical profession recognised the importance of genomic information and has embraced and applied this concept in understanding the etiology of the disease and treating and preventing it. However, the dental profession has yet to accept and take advantage of this new technology. Genomics, which focuses on the interactions between all the genes in the genome and with environmental factors has the potential to revolutionise our understanding of oral health and disease. The application of genomics in the dental clinical setting and as useful aid for clinical decision making, requires an analysis of each individual patient’s unique clinical, genetic, genomic, behavioural, and environmental information. The use of this information and application of the technology may enable early identification of disease and provide better prognosis and more effective treatment options for a variety of oral diseases. Oral diseases such as dental caries, periodontitis, orthodontics (e.g. malocclusion) and oral cancer are some of the well-researched diseases in the field of genetics and genomics.

As the field of genomics grows in terms of the increase in its applicability and feasibility, so will the knowledge of the genomic basis for oral diseases, which will then enable dentists to apply this technology in the diagnosis, prognosis, and treatment of various oral diseases. There is a potential for genomic technologies to transform oral health care practice, which in the future may result in a paradigm shift, from a reactive, treatment-based clinical approach to a more proactive, personalised-based preventive approach. The National Institute of Dental and Craniofacial Research (NIDCR)-supported National Practice-based Research Network (PBRN), in the USA is one example of an organisation that acts as a catalyst to link practicing dentists and researchers/scientists, to adopt new tools and technologies in the field of personalised medicine and/or oral health care.

However, personalised oral health care is not without its challenges, in both the developed and developing countries context. There are issues related to awareness and acceptance in the general public in terms of the risks and benefits of genome sequencing. In addition, there are a number of socio-ethical, legal, and professional barriers and scientific and technological know-how. The developing countries context provides additional challenges in addition to the above barriers mentioned, in terms of the feasibility, appropriateness and meaningfulness of personalised oral health care.

One of the strategies for the dental profession to overcome some of these barriers is to foster an environment of dialogue, engagement and education around personalised oral health care with the various stakeholders, including the policy makers, dental clinicians, researchers/scientists, dental educators and the general public. Personalised oral health care is here to stay and will rapidly evolve in the coming decades. It is therefore imperative for various stakeholders to engage and collaborate to provide the best possible oral health outcomes for the public in general.


Dr Sandeep Moola BDS MHSM (Hons) MPhil PhD

Research Fellow, University of Adelaide, Adelaide


Dental Pulp Mesenchymal Stem Cells In And For Personalized Dentistry


In Restorative Dentistry, the protection of the dentin-pulp complex consists of the application of one or more layers of specific materials (varnishes, calcium hydroxide-based products, glass ionomer cements (GICs) and adhesive systems) between the restorative material and dental tissue, to avoid additional damage of pulp tissue caused by operative procedures, toxicity of restorative materials and bacteria penetration due to microleakage. GICs, invented and originally described by Wilson and Kent, are consisted of basic glass powder (calcium or strontium aluminofluorosilicate) and a water-soluble acidic polymer, such as polyacrylic acid.

Responses to GICs differ among cell types, and thus, it is of great importance to thoroughly investigate the influence of these restorative materials on pulp stem cells that are source for dental tissue regeneration invivo.

Human dental pulp stem cells are mesenchymal stem cells and are established platforms to qualify the GICs in the labs, to be used in Restorative Dentistry routinely. 

Silver nanoparticles: Evaluation of DNA damage, toxicity and functional impairment in human mesenchymal stem cells

Silver nanoparticles (AgNPs) have been extensively studied for their antimicrobial properties, which provide an extensive applicability in dentistry.Due to a distinct lack of information on hazardous properties of AgNPs in human cells, their applications is not regulated in most of the indications. Human mesenchymal stem cells have been shown as established platforms to evaluate AgNP concentrations to be used in nanocomposites; implant coatings; pre-formulation with antimicrobial activity against cariogenic pathogens, periodontal biofilm, fungal pathogens and endodontic bacteria; and other applications such as treatment of oral cancer and local anesthesia not to induce DNA damage, cell death and functional impairment but present the powerful antimicrobial property.



Genomics of Tooth Derived Mesenchymal Stem Cells4

Human Tooth derived Mesenchymal Stem Cells, their methods of isolation, culture expansion in the labs, large scale productions along with complete omics of genes expressed in the healthy human body is very well established science now after their discovery in 2003. The use of these stem cells is beyond their Regenerative Medicinal applications and gaining popularity in Personalized Dentistry, Palliative Medicine, Precision Medicine.

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

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 )

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.

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