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Historic Overview of Genetic Engineering Technologies for Human Gene …

Posted: March 28, 2024 at 2:40 am

Abstract

The concepts of gene therapy were initially introduced during the 1960s. Since the early 1990s, more than 1900 clinical trials have been conducted for the treatment of genetic diseases and cancers mainly using viral vectors. Although a variety of methods have also been performed for the treatment of malignant gliomas, it has been difficult to target invasive glioma cells. To overcome this problem, immortalized neural stem cell (NSC) and a nonlytic, amphotropic retroviral replicating vector (RRV) have attracted attention for gene delivery to invasive glioma. Recently, genome editing technology targeting insertions at site-specific locations has advanced; in particular, the clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/Cas9) has been developed. Since 2015, more than 30 clinical trials have been conducted using genome editing technologies, and the results have shown the potential to achieve positive patient outcomes. Gene therapy using CRISPR technologies for the treatment of a wide range of diseases is expected to continuously advance well into the future.

Keywords: gene therapy, genome editing, ZFN, TALEN, CRISPR/Cas9

Gene therapy is a therapeutic strategy using genetic engineering techniques to treat various diseases.1,2) In the early 1960s, gene therapy first progressed with the development of recombinant DNA (rDNA) technology,1) and was further developed using various genetic engineering tools, such as viral vectors.35) More than 1900 clinical trials have been conducted with gene therapeutic approaches since the early 1990s. In these procedures, DNA is randomly inserted into the host genome using conventional genetic engineering tools. In the 2000s, genome editing tootls, including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the recently established clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/Cas9) technologies, were developed, which induce genome modifications at specific target sites.5) Genome editing tools are efficient for intentional genetic engineering, which has led to the development of novel treatment strategies for a wide range of diseases, such as genetic diseases and cancers. Therefore, gene therapy has again became a major focus of medical research. However, because gene therapy involves changing the genetic background, it raises important ethical concerns. In this article, we review the brief history of gene therapy and the development of genetic engineering technologies.

In 1968, the initial proof-of-concept of virus- mediated gene transfer was made by Rogers et al.6) who showed that foreign genetic material could be transferred into cells by viruses. In the first human gene therapy experiment, Shope papilloma virus was transduced into two patients with genetic arginase deficiency, because Rogers et al. hypothesized that the Shope papilloma virus genome contained a gene that encodes arginase. However, this gene therapy produced little improvement in the arginase levels in the patients.7) Sequencing of the Shope papilloma virus genome revealed that the virus genome did not contain an arginase gene.7)

This experiment prompted public concerns about the risks and ethical issues of gene therapy. In 1972, Friedman et al.8) proposed ethical standards for the clinical application of gene therapy to prevent premature application in human. However, in 1980, genetic engineering was unethically performed in patients with thalassemia without the approval of the institutional review board.9) The patients bone marrow cells were harvested and returned into their bone marrow after transduction with the plasmid DNA containing an integrated b-globin gene.9) This treatment showed no effects, and the experiments were regarded as morally dubious. The gene therapy report of the President's Commission in the United States, Splicing Life, emphasized the distinction between somatic and germline genome editing in humans, and between medical treatment and non-medical enhancement.10) An altered gene inserted into sperm or egg cells (germ cells) would lead to changes not only in the individual receiving the treatment but also in their future offspring. Interventions aimed at enhancing normal people also are problematic because they might lead to attempts to make perfect human beings.

In 1980, only nonviral methods, such as microinjection and calcium-phosphate precipitation, were used for gene delivery. Nonviral methods showed some advantages compared with viral methods, such as large-scale production and low host immunogenicity. However, nonviral methods yielded lower levels of transfection and gene expression, resulting in limited therapeutic efficacy.11) In 1989, the rDNA Advisory Committee of the National Institutes of Health proposed the first guidelines for the clinical trials of gene therapy. In 1990, retroviral infection, which is highly dependent on host cell cycle status, was first performed for the transduction of the neomycin resistance marker gene into tumor-infiltrating lymphocytes that were obtained from patients with metastatic melanoma.3,4) Then, the lymphocytes were cultured in vitro and returned to the patients bodies.3,4) The first Food and Drug Administration (FDA)- approved gene therapy using a retroviral vector was performed by Anderson et al. in 1990; the adenosine deaminase (ADA) gene was transduced into the white blood cells of a patient with ADA deficiency, resulting in temporary improvements in her immunity.2,12)

A recombinant adenoviral (AV) vector was developed after advances in the use of the retroviral vector. In 1999, a clinical trial was performed for ornithine transcarbamylase (OTC) deficiency. A ubiquitous DNA AV vector (Ad5) containing the OTC gene was delivered into the patient. Four days after administration, the patient died from multiple organ failure that was caused by a cytokine storm.13,14) In 1999, of the 20 patients enrolled in two trials for severe combined immunodeficiency (SCID)-X1, T-cell leukemia was observed in five patients at 25.5 years after the treatment. Hematopoietic stem cells with a conventional, amphotropic, murine leukemia virus-based vector and a gibbon-ape leukemia virus-pseudotyped retrovirus were used for gene transduction in those trials.15,16) Although four patients fully recovered after the treatment, one patient died15,16) because oncogene activation was mediated by viral insertion.15,16)

Viral vectors continued to be crucial components in the manufacture of cell and gene therapy. Adeno- associated viral (AAV) vectors were applied for many genetic diseases including Lebers Congenital Amaurosis (LCA), and reverse lipoprotein lipase deficiency (LPLD). In 2008, remarkable success was reported for LCA type II in phase I/II clinical trials.17) LCA is a rare hereditary retinal degeneration disorder caused by mutations in the RPE65 gene (Retinoid Isomerohydrolase RPE65), which is highly expressed in the retinal pigment epithelium and encodes retinoid isomerase.17) These trials confirm that RPE65 could be delivered into retinal pigment epithelial cells using recombinant AAV2/2 vectors, resulting in clinical benefits without adverse events.17) Recently, the FDA approved voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics, Philadelphia, PA, USA) for patients with LCA type II. Alipogene tiparvovec Glybera (uniQure, Lexington, MA, USA) is the first gene-therapy-based drug to reverse LPLD to be approved in Europe in 2012. The AAV1 vector delivers an intact LPL gene to the muscle cells.18) To date, more than 200 clinical trials have been performed using AAV vectors for several genetic diseases, including spinal muscular atrophy,19) retinal dystrophy,20) and hemophilia.21)

Retrovirus is still one of the mainstays of gene therapeutic approaches. Strimvelis (GlaxoSmithKline, London, UK) is an FDA-approved drug consisting of an autologous CD34 (+)-enriched cell population that includes a gammaretrovirus containing the ADA gene that was used as the first ex-vivo stem cell gene therapy in patients with SCID because of ADA deficiency.22) Subsequently, retroviral vectors were often used for other genetic diseases, including X-SCID.23)

Lentivirus belongs to a family of viruses that are responsible for diseases, such as aquired immunodeficiency syndrome caused by the human immunodeficiency virus (HIV) that causes infection by inserting DNA into the genome of their host cells.24) The lentivirus can infect non-dividing cells; therefore, it has a wider range of potential applications. Successful treatment of the patients with X-linked adrenoleukodystrophy was demonstrated using a lentiviral vector with the deficient peroxisomal adenosine triphosphatebinding cassette D1.25) Despite the use of a lentiviral vector with an internal viral long terminal repeat, no oncogene activation was observed.25)

A timeline showing the history of scientific progress in gene therapy is highlighted in .

History of gene therapy

A variety of studies were performed to apply gene therapy to malignant tumors. The concept of gene therapy for tumors is different from that for genetic diseases, in which new genes are added to a patient's cells to replace missing or malfunctioning genes. In malignant tumors, the breakthrough in gene therapeutic strategy involved designing suicide gene therapy,26) which was first applied for malignant glioma in 1992.26,27) The first clinical study was performed on 15 patients with malignant gliomas by Ram et al (phase I/II).27) Stereotactic intratumoral injections of murine fibroblasts producing a replication-deficient retrovirus vector with a suicide gene (herpes simplex virus-thymidine kinase [HSV-TK]) achieved anti-tumor activity in four patients through bystander killing effects.27) Subsequently, various types of therapeutic genes have been used to treat malignant glioma. Suicide genes (cytosine deaminase [CD]), genes for immunomodulatory cytokines (interferon [IFN]-, interleukin [IL]-12, granulocyte- macrophage colony-stimulating factor [GM-CSF]), and genes for reprogramming (p53, and phosphatase and tensin homolog deleted from chromosome [PTEN]) have been applied to the treatment of malignant glioma using viral vectors.28,29)

Recently, a nonlytic, amphotropic retroviral replicating vector (RRV) and immortalized human neural stem cell (NSC) line were used for gene delivery to invasive glioma.3032) In 2012, a nonlytic, amphotropic RRV called Toca 511 was developed for the delivery of a suicide gene (CD) to tumors.32) A tumor-selective Toca 511 combined with a prodrug (Toca FC) was evaluated in patients with recurrent high-grade glioma in phase I clinical trial.30) The complete response rate was 11.3% in 53 patients.30) In addition, the sub-analysis of this clinical trial revealed that the objective response was 21.7% in the 23-patient phase III eligible subgroup.33) However, in the recent phase III trial, treatment with Toca 511 and Toca FC did not improve overall survival compared with standard therapy in patients with recurrent high-grade glioma. A further combinational treatment strategy using programmed cell-death ligand 1 (PD-L1) checkpoint blockade delivered by TOCA-511 was evaluated in experimental models, which may lead to future clinical application.34) Since 2010, intracranial administration of allogeneic NSCs containing CD gene (HB1.F3. CD) has been performed by a team at City of Hope. Autopsy specimens indicate the HB1.F3. CD migrates toward invaded tumor areas, suggesting a high tumor-trophic migratory capacity of NSCs.31) No severe toxicities were observed in the trial. Generally, it is difficult to obtain NSCs derived from human embryonic or fetal tissue. The use of human embryos for research on embryonic stem cells is ethically controversial because it involves the destruction of human embryos, and the use of fetal tissue associated with abortion also raises ethical considerations.35) Recently, the tumor-trophic migratory activity of NSCs derived from human-induced pluripotent stem cells (hiPSCs) was shown using organotypic brain slice culture.36) Moreover, hiPSC-derived NSCs with the HSV-TK suicide gene system demonstrated considerable therapeutic potential for the treatment of experimental glioma models.36) Furthermore, iPSCs have the ability to overcome ethical and practical issues of NSCs in clinical application.

Genetic engineering technologies using viral vectors to randomly insert therapeutic genes into a host genome raised concerns about insertional mutagenesis and oncogene activation. Therefore, new technology to intentionally insert genes at site-specific locations was needed. Genome editing is a genetic engineering method that uses nucleases or molecular scissors to intentionally introduce alterations into the genome of living organisms.6) As of 2015, three types of engineered nucleases have been used: ZFNs, TALENs, and CRISPR/Cas ().6)

Characteristics of genome editing technologies

ZFNs are fusions of the nonspecific DNA cleavage domain of the Fok I restriction endonuclease and zinc-finger proteins that lead to DNA double-strand breaks (DSBs). Zinc-finger domains recognize a trinucleotide DNA sequence (). However, design and selection of zinc-finber arrays is difficult and time-consuming.37)

Genome editing tools. Three types of genome editing tools including ZFNs, TALENs, and CRISPR/Cas9 are shown. ZFNs are hybrid proteins using zinc-finger arrays and the catalytic domain of FokI endonuclease. TALENs are hybrid proteins containing the TAL effector backbone and the catalytic domain of FokI endonuclease. The CRISPR/Cas9 system is composed of Cas9 endonuclease and sgRNA. Cas9: CRISPR-associated-9, CRISPR: clustered regularly interspaced palindromic repeats, sgRNA: single-guide RNA, TALENs: transcription activator-like effector nucleases, ZFNs: zinc-finger nucleases.

TALENs are fusions of the Fok I cleavage domain and DNA-binding domains derived from TALE proteins. TALEs have multiple 3335 amino acid repeat domains that recognizes a single base pair, leading to the targeted DSBs, similar to ZFNs ().38)

The CRISPR/Cas9 system consists of Cas9 nuclease and two RNAs (CRISPR RNA [crRNA] and trans- activating CRISPR RNA [tracrRNA]).39) The crRNA/tracrRNA complex (gRNA) induces the Cas9 nuclease and cleaves DNA upstream of a protospacer-adjacent motif (PAM, 5-NGG-3 for S. pyogenes) ().40) Currently, Cas9 from S. pyogenes (SpCas9) is the most popular tool for genome editing.40)

Several studies have demonstrated the off-target effects of Cas9/gRNA complexes.41) It is important to select unique target sites without closely homologous sequences, resulting in minimum off-target effects.42) Additionally, other CRISPR/Cas9 gene editing tools were developed to mitigate off-target effects, including gRNA modifications (slightly truncated gRNAs with shorter regions of target complementarity <20 nucleotides)43) and SpCas9 variants, such as Cas9 paired nickases (a Cas9 nickase mutant or dimeric Cas9 proteins combined with pairs of gRNAs).44) The type I CRISPR-mediated distinct DNA cleavage (CRISPR/Cas3 system) was developed recently in Japan to decrease the risk of off-target effets. Cas3 triggered long-range deletions upstream of the PAM (5'-ARG).45)

A confirmatory screening of off-target effects is necessary for ensuring the safe application of genome editing technologies.46) Although off-target mutations in the genome, including the noncoding region, can be evaluated using whole genome sequencing, this method is expensive and time-consuming. With the development of unbiased genome-wide cell-based methods, GUIDE-seq (genome-wide, unbiased identification of DSBs enabled by sequencing)47) and BLESS (direct in situ breaks labeling, enrichment on streptavidin; next-generation sequencing)48) were developed to detect off-target cleavage sites, and these methods do not require high sequencing read counts.

HIV-resistant T cells were established by ZFN- mediated disruption of the C-C chemokine receptor (CCR) 5 coreceptor for HIV-I, which is being evaluated as an ex- vivo modification in early-stage clinical trials.49,50) Disruption of CCR5 using ZFNs was the first-in-human application of a genome editing tool. Regarding hematologic disorders, since 2016, clinical trials have attempted the knock-in of the factor IX gene using AAV/ZFN-mediated genome editing approach for patients with hemophilia B.51)

In addition to these promising ongoing clinical trials for genetic diseases, CRISPR/Cas9 and TALEN technologies have improved the effect of cancer immunotherapy using genome-engineered T cells. Engineered T cells express synthetic receptors (chimeric antigen receptors, CARs) that can recognize epitopes on tumor cells. The FDA approved two CD19-targeting CAR-T-cell products for B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma.52,53) Engineered CARs target many other antigens of blood cancers, including CD30 in Hodgkin's lymphoma as well as CD33, CD123, and FLT3 of acute myeloid leukemia.54) Recent research has shown that Cas9-mediated PD-1 disruption in the CAR-T cells improved the anti-tumor effect observed in in- vitro and in- vivo experimental models, leading to the performance of a clinical trial.55,56) All other ongoing clinical trials using genome-editing technologies are highlighted in .

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Stem cells: a comprehensive review of origins and emerging clinical …

Posted: March 19, 2024 at 2:38 am

Orthop Rev (Pavia). 2022; 14(3): 37498.

1Department of Anesthesiology, Mount Sinai Medical Center

1Department of Anesthesiology, Mount Sinai Medical Center

2 LSU Health Science Center Shreveport School of Medicine, Shreveport, LA

3 University of Arizona College of Medicine-Phoenix, Phoenix, AZ

3 University of Arizona College of Medicine-Phoenix, Phoenix, AZ

4Department of Emergency Medicine, University of Central Florida

5Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport

5Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport

5Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport

6Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Innovative Pain and Wellness, Creighton University School of Medicine

5Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport

1Department of Anesthesiology, Mount Sinai Medical Center

2 LSU Health Science Center Shreveport School of Medicine, Shreveport, LA

3 University of Arizona College of Medicine-Phoenix, Phoenix, AZ

4Department of Emergency Medicine, University of Central Florida

5Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport

6Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Innovative Pain and Wellness, Creighton University School of Medicine

Corresponding author: Salomon Poliwoda MD; Telephone: 7862716678; email: salomon.pb@gmail.com

Stem cells are types of cells that have unique ability to self-renew and to differentiate into more than one cell lineage. They are considered building blocks of tissues and organs. Over recent decades, they have been studied and utilized for repair and regenerative medicine. One way to classify these cells is based on their differentiation capacity. Totipotent stem cells can give rise to any cell of an embryo but also to extra-embryonic tissue as well. Pluripotent stem cells are limited to any of the three embryonic germ layers; however, they cannot differentiate into extra-embryonic tissue. Multipotent stem cells can only differentiate into one germ line tissue. Oligopotent and unipotent stem cells are seen in adult organ tissues that have committed to a cell lineage. Another way to differentiate these cells is based on their origins. Stem cells can be extracted from different sources, including bone marrow, amniotic cells, adipose tissue, umbilical cord, and placental tissue. Stem cells began their role in modern regenerative medicine in the 1950s with the first bone marrow transplantation occurring in 1956. Stem cell therapies are at present indicated for a range of clinical conditions beyond traditional origins to treat genetic blood diseases and have seen substantial success. In this regard, emerging use for stem cells is their potential to treat pain states and neurodegenerative diseases such as Parkinsons and Alzheimers disease. Stem cells offer hope in neurodegeneration to replace neurons damaged during certain disease states. This review compares stem cells arising from these different sources of origin and include clinical roles for stem cells in modern medical practice.

Keywords: Stem cells, regenerative medicine, bone marrow, umbilical cord, placental tissue

Stem cells are a unique population of cells present in all stages of life that possess the ability to self-renew and differentiate into multiple cell lineages. These cells are key mediators in the development of neonates and in restorative processes after injury or disease as they are the source from which specific cell types within differentiated tissues and organs are derived.1 Within the neonate stage of life stem cells serve to differentiate and proliferate into the multitude of cell types and lineages required for continuing development, while in adults their primary role is regenerative and restorative in nature.2 Stem cells have unique properties that set them apart from terminally differentiated cells allowing for their specific physiological roles. The ability of stem cells to differentiate into multiple cell types is termed potency, and stem cells can be classified by their potential for differentiation as well as by their origin. Totipotent or omnipotent stem cells can form embryonic tissues and can differentiate into all cell lineages required for an adult. Pluripotent stem cells can differentiate into all three germ layers while multipotent stem cells may only differentiate into one kind of germ line tissue. Oligopotent and unipotent stem cells are the type seen in adult organ tissues that have committed to a cell lineage and can only diversify into cell types within that lineage.1 Embryonic stem cells are derived from the inner cell mass of a blastocysts and are totipotent. The range of their use is typically restricted due to legal and ethical factors and for this reason mesenchymal stem cells are typically preferred. Mesenchymal stem cells can be isolated from a variety of both neonate and adult tissues but still maintain the ability to differentiate into multiple cell types allowing for their clinical and research utilization without the ethical issues associated with embryonic stem cells.3

Another key feature of stem cells is their ability to self-renew and proliferate providing a continuous supply of progeny to replace aging or damaged cells. During the developmental phase this proliferation allows for the growth necessary to mature into an adult. After the developmental phase has concluded, this continued proliferation allows for healing and restoration on a cellular level after tissue or organ injury has taken place.2 These physiological and developmental characteristics make stem cells an integral part in the field of regenerative medicine due to their ability to generate entire tissues and organs from just a handful of progenitor cells.

Stem cells began their role in modern regenerative medicine in the 1950s with the first bone marrow transplantation occurring in 1956. This breakthrough shed light on the potential treatments possible in the future with further development and refinement of clinical techniques and paved the way for the stem cell therapies that are now available.4,5 Stem cell therapies are now indicated for a range of clinical conditions beyond traditional origins to treat genetic blood diseases and have seen substantial success where other treatments have fallen short. One emerging use for stem cells is their potential to treat paint states and neurodegenerative diseases such as Parkinsons and Alzheimers disease. Stem cells offer the hope in the setting of neurodegeneration to replace the neurons damaged during the pathogenesis of certain diseases, a goal not achievable utilizing current technologies and methods.6

Organ bioengineering is yet another a rapidly developing and exciting new application for stem cells with both clinical and research implications.7 Immunosuppression free organ transplants are now a possibility with the advancement organ manufacturing utilizing the patients own cells.8 This along with the potential for eliminating organ donor waiting lists is an enticing prospect, but many technological developments are necessary before this technology can be implemented in clinical settings on a wide scale. Research has already benefitted greatly from this field because organ like tissues can be grown in lab settings to model disease progression. This offers the potential to develop new treatments while determining their efficacy on a cellular level without risk to patients.9,10

Currently one of the most prolific clinical uses of stem cells in the field of regenerative medicine is to treat inherited blood diseases. Within these diseases a genetic defect or defects prevents the proper function of cells derived from the hematopoietic stem cell lineage. Treatment includes implantation of genetically normal cells from a healthy donor to serve as a lifelong self-renewing source of normally functioning blood cells. However these treatments are limited by the availability of suitable donors.11

Stem cells can be derived from multiple sources including adult tissues or neonatal tissues such as the umbilical cord or placenta. Embryonic stem cells have been utilized in the past for research, but ethical concerns have led to them being replaced largely by stem cells derived from other origins.12 Common tissues from which adult oligopotent and unipotent stem cells are isolated include bone marrow, adipose tissue, and trabecular bone.13 Bone marrow has traditionally been the most common site from which to extract non neonatal derived stem cells but involves an invasive and painful procedure. Peripheral blood progenitor cells have been utilized to avoid harvesting cells from bone marrow. However, this technique has issues and risks of its own and was initially a less potent source of stem cells. It is also now known that stem cells differ in their proliferative and differentiation potential based on their origin. Cells sourced from umbilical Whartons jelly and adipose tissue were found to proliferate significantly more quickly than cells sourced from bone marrow and placental sources.14,15

A rapidly advancing source of stem cells known as induced pluripotent stem cells (iPSCs) are now being utilized clinically as well. These iPSCs are derived from somatic cells that have been reprogrammed back to a pluripotent state utilizing reprogramming factors and require less invasive techniques to harvest in comparison to traditional sources.16,17 Once returned to a pluripotent state, the cells then undergo a process called directed differentiation in which they are converted into desired cell types. Directed differentiation is achieved by mimicking microenvironments and extracellular signals in vitro in a manner that produces predictable cell types.18 In the future, this technique could provide a novel form of personalized gene therapy in which oligopotent or unipotent cells are procured from tissue, reprogrammed back to a less differentiated state, and then reintroduced into a different location within the patient. Work is also being done to combine this technique with modern gene editing methods to provide an entirely new subset of therapies.19 This method of transplantation would greatly reduce the chance for rejection and does not require a suitable donor, as the cells are sourced from the patient being treated.20,21

Stem cells are required by self-renewing tissues to replace damaged and aging cells because of normal biological processes. Both myeloid and lymphoid lineage cells derived from hematopoietic stem cells are relatively short-lived cell types and require a continuous source of newly differentiated replacement cells.22 Hematopoietic stem cells (HSCs) are those that reside within the bone marrow and provide a source for the multiple types of blood cells required for normal physiological and immunological functions. These cells inhabit a physiological niche which allows them to undergo the process of asymmetric division. When stem cells divide asymmetrically the progeny of the division includes one identical daughter cell but also results in the production of a differentiated daughter cell. Differentiation of these daughter cell into specialized cell types is guided by certain microenvironments, extrinsic cues, and growth factors that the cell comes in contact with.23,24 This mechanism allows for bone marrow stem cell numbers to stay relatively constant despite sustained proliferation and differentiation of progeny taking place.22,25,26

HSCs are the most studied class of adult tissue derived stem cells and their clinical potential was recognized early in the history of regenerative medicine. At the beginning of the 1960s, HSCs were isolated from bone marrow and therapeutic models in mice induced with leukemia were developed in order to show the efficacy of bone marrow derived stem cell treatments. Success in these experiments led to further refinement of techniques and by the 1970s and 80s clinical stem cell transplants were a regular occurrence and began to make the impact on blood diseases that we continue to see today.27,28

Bone marrow has historically been the predominant harvesting site for stem cell collection due to its accessibility, early identification as a source, and lengthy research history. Isolating stem cell from bone marrow involves an invasive and painful surgical procedure and does come with a risk hospitalization or other complications. Patients also report increased post procedural pain and pre-procedural anxiety when compared with other harvesting techniques.29,30 Bone marrow however has proved to be a denser source of cells than other harvesting methods yielding 18 times more cells than peripheral blood progenitor cell harvesting techniques initially. As technology and methods improved however, it was found that treating patients with a cytokine treatment prior to peripheral blood progenitor cell harvesting mobilized many of the desired cells into the blood stream and drastically increased the efficacy of this technique, making it clinically viable.3133 In a double blinded randomized study 40 patients underwent bone marrow and peripheral blood progenitor cell collections and the yield of useable harvested cells were compared. It was found that blood progenitor cell collection yielded significantly more useable stem cells and patients were able to undergo the collection procedure more frequently when compared to the bone marrow harvesting method.32 This, coupled with the invasiveness and risks associated with harvesting stem cells from bone marrow have increased peripheral blood progenitor cell collections popularity.

Overall, bone marrow as a reservoir of stem cells continues to be a clinical and research necessity related to its well understood and documented history as a source of viable stem cells and track record of efficacy. According to the European Group for Blood and Marrow Transplantation, only one fatal event was recorded stemming from the first 27,770 hematopoietic stem cell transplants sourced from bone marrow during the period of 1993-2005.34 This undeniable track record of safety coupled with clinicians experience performing bone marrow transplant procedures guarantees the continued use of bone marrow as a source of HSCs for the near future.

Historically, the two most common types of pluripotent stem cells include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).35 However, despite the many research efforts to improve ESC and iPSC technologies, there are still enormous clinical challenges.35 Two significant issues posed by ESC and iPSC technologies include low survival rate of transplanted cells and tumorigenicity.35 Recently, researchers have isolated pluripotent stem cells from gestational tissues such as amniotic fluid and the placental membrane.35 Human amnion-derived stem cells (hADSCs), including amniotic epithelial cells and amniotic mesenchymal cells, are a relatively new stem cell source that have been found to have several advantageous characteristics.35,36

For background, human amniotic stem cells begin emerging during the second week of gestation when a small cavity forms within the blastocyst and primordial cells lining this cavity are differentiated into amnioblasts.36 Human amniotic epithelial stem cells (hAESCs) are formed when epiblasts differentiate into amnioblasts, whereas human amniotic mesenchymal stem cells (hAMSCs) are formed when hypoblasts differentiate into amnioblasts.35,36 This differentiation occurs prior to gastrulation, so amnioblasts do not belong to one of the 3 germ layers, making them theoretically pluripotent.3537

Previously, pluripotency and immunomodulation are qualities that have been thought to be mutually exclusive, as pluripotency has traditionally been regarded as a characteristic limited to embryonic stem cells whereas immunomodulation has been a recognized property of mesenchymal stem cells.36 However, many recent studies have found that these two qualities coexist in hADSCs.35,36

In recent years, hADSCs, including human amniotic epithelial stem cells (hAESCs) and human amniotic mesenchymal stem cells (hAMSCs) have been attractive cell sources for clinical trials and medical research, and have been shown to have advantages over other stem cells types.35,37 These advantages include low immunogenicity and high histocompatibility, no tumorigenicity, immunomodulatory effects, and significant paracrine effects.35 Also, several studies have evaluated the proangiogenic ability of hADSCs.35 Interestingly, they found that hAMSCs were shown to augment blood perfusion and capillary architecture when transplanted into ischemic limbs of mice, suggesting that hAMSCs stimulate neovascularization.35,38 Additionally, another advantage is that hADSCs are easier to obtain compared to other stem cell sources, such as bone marrow stem cells (BMSCs).35

Regarding the low immunogenicity, hADSCs have been shown to have a low expression of major histocompatibility class I antigen (HLA-ABC), and no expression of major histocompatibility class II antigen (HLA-DR), 2 microglobulin, and HLA-ABC costimulatory molecules, including CD40, CD80 and CD8635. Notably, there have been reports of transplantation of hAMSCs into patients with lysosomal diseases who had no obvious rejection.35 Moreover, a recent study demonstrated no hemolysis, allergic reactions, or tumor formations in mice who received intravenous hAESCs.35,39

Additionally, studies have demonstrated that both hAESCs and hAMSCs have great potential to play an important role in regenerative medicine. They both have demonstrated that they can differentiate into several specialized cells, including adipocytes, bone cells, nerve cells, cardiomyocytes, skeletal muscle cells, hepatocytes, hematopoietic cells, endothelial cells, kidney cells, and retinal cells.35

Multiple preclinical studies have revealed the potential for hADSCs to be used in the treatment of several diseases including premature ovarian failure, diabetes mellitus, inflammatory bowel disease, brain/spine diseases, and more.35,40,41 For example, one preclinical study investigated the effect of hAMSC-therapy on ovarian function in natural aging ovaries within mice.40 They found that after the hAMSCs were transplanted into the mice, the hAMSCs significantly improved follicle proliferation and therefore ovarian function.40 Another study investigated the effect of hAESC-therapy on outcomes after stroke in mice.41 They found that, administration of hAESCs after acute (within 1.5 hours) stroke in mice reduced brain infarct development, inflammation, and functional deficits.41 Additionally, they found that after late administration (1-3 days poststroke) of hAESCs, functional recovery in the mice was still improved.41 Overall, they concluded that administration of hAESCs following a stroke in mice showed a significant neuroprotective effect and facilitated repair and recovery of the brain.41

Although a number of preclinical studies, like the ones previously described, have shown considerable promise regarding the use of ADSC-therapy, more studies are needed. Future studies can continue to work toward determining if hADSCs are capable of being used for cell replacement and better elucidate the mechanisms by which hADSCs work.

Although the use of bone marrow stem cells (BMSCs) is now standard, dilemmas regarding harvesting techniques and the potential for low cell yields has driven researchers to search for other mesenchymal stem cell (MSCs) sources.42 One source that has been investigated is human adipose tissue.42

After enzymatic digestion of adipose tissue, a heterogenous group of adipocyte precursors are generated within a group of cells called the stromal vascular fraction (SVF).42 Adipose-derived stem cells (ADSCs) are found in the SVF.42,43 Studies have demonstrated that ADSCs possess properties typically associated with MSCs, and that they have been found to express several CD markers that MSCs characteristically express.43 ADSCs are multipotent and have been shown to differentiate into other cells of mesodermal origin, including osteoblasts, chondroblasts, myocytes, tendocytes, and more, upon in vitro induction.4245 Additionally, ADSCs have demonstrated in vitro capacity for multi-lineage differentiation into specialized cells, like insulin-secreting cells.43,46

A significant advantage of ADSCs over BMSCs is how easy they are to harvest.43,45 White adipose tissue (WAT) contains an abundance of ADSCs.43 The main stores of WAT in humans are subcutaneous stores in the buttocks, thighs, abdomen and visceral depots.43 Due to this, ADSCs can be harvested relatively easily by liposuction procedures from these areas of the body.43,45 Moreover, ADSCs make up as much as 1-2% of the SVF within WAT, sometimes even nearing 30% in some tissues.43,45 This is a significant difference from the .0001-.0002% stem cells present in bone marrow.43 Given this difference in stem cell concentration between the sources, there will be more ADSCs per sample of WAT compared to stem cells per bone marrow sample, further demonstrating an easier acquisition of stem cells when using adipose tissue.

Another advantage of ADSCs is their immune privilege status due to a lack of major histocompatibility complex II (MHC II) and costimulatory molecules.42,43,45,47 Some studies have even demonstrated a higher immunosuppression capacity in ADSCs compared to BMSCs as ADSCs expressed lower levels of human antigen class I (HLA I) antigen.47 They also have a unique secretome and can produce immunomodulatory, anti-apoptotic, hematopoietic, and angiogenic factors that can help with repair of tissues characteristics that may support successful transplantations without the need for immunosuppression.4245 Moreover, ADSCs have the ability to be reprogrammed to induced pluripotent stem (iPS) cells.43

The number of ADSC clinical trials has risen over the past decade, and some have shown significant promise. They have demonstrated abilities to differentiate into multiple cell lines in a reproducible manner and be safe for both autogenetic and allogeneic transplantations.45 Several recent studies have demonstrated that ADSC-therapy may potentially be useful in the treatment of several conditions, including diabetes mellitus, Crohns disease, multiple sclerosis, fistulas, arthritis, ischemic pathologies, cardiac injury, spinal injury, bone injuries and more.4448

One clinical trial conducted in 2013 investigated the therapeutic effect of co-infusion of autologous adipose-derived differentiated insulin-secreting stem cells and hematopoietic stem cells (HSCs) on patients with insulin-dependent diabetes mellitus.46 Ten patients were followed over an average of about thirty-two months, and they found that all the patients had improvement in C-peptide, HbA1c, blood sugar status, and exogenous insulin requirement.46 Notably, there were no unpleasant side effects of the treatment and all ten patients had rehabilitated to a normal, unrestricted diet and lifestyle.46

In another 4-patient clinical trial in which ADSCs were used to heal fistulas in patients with Crohns disease, full healing occurred in 6 out of the 8 fistulas with partial healing in the remaining two.44 No complications were observed in the patients 12 months following the trial.44 Although these results are promising, the mechanism by which the healing took place remains unclear. When considering the properties of ADSCs, there are a number of factors that could have played a role in the healing, such as the result of paracrine expression of angiogenic and/or anti-apoptotic factors, stem cell differentiation, and/or local immunosuppression.44

Other exciting studies have demonstrated a use of ADSCs in the treatment of osteoarthritis (OA). One meta-analysis compared the use of ADSCs and BMSCs in the treatment of osteoarthritis.47 This meta-analysis included 14 studies comprising 461 original patient records.47 Overall, the comparison between treatment of OA didnt show a significant difference in the disease severity score change rate between patients treated with ADSCs and those treated with BMSCs.47 However, there was significantly more variability in the outcomes of those treated with BMSCs with the highest change rate being 79.65% in one study and the lowest being 22.57% in another study.47 Given this, ADSCs may represent a more stable cell source for the treatment of OA.47 Although this study is specific to OA treatment, it is worth acknowledging the possibility that ADSCs may also represent a more stable cell source for treatment of other diseases as well.

Though recent ADSC research, as described above, has been promising, unfortunately reproducible in vivo studies are still lacking in both quality and quantity.42 Therefore, further studies are necessary prior to progression to routine patient administration.42

Umbilical Cord stem cells can be drawn from a variety of locations including umbilical cord blood, umbilical cord perivascular cells, umbilical vein endothelial cells, umbilical lining, chorion, and amnion. Umbilical cord blood can be drawn with minimal risk to the donor, and it has been used since 1988 as a source for hematopoietic stem cells.49 When compared to stem cells obtained from bone marrow, umbilical cord derived stem cells are much more readily available. With a birth rate of more than a 100 million people per year globally, there is a lot of opportunity to use umbilical cord blood as a source for stem cells.

The process of extracting the blood is very simple and involves a venipuncture followed by drainage into a sterile anti-coagulant-filled blood bag. It is then cryopreserved and stored in liquid nitrogen. There are quite a few benefits to utilizing umbilical cord stem cells rather than stem cells drawn from adults. One of the biggest benefits is that the cells are more immature which means that there is a lower chance of rejection after implantation in a host and would lead to decreased rates of graft-versus-host disease. They also can differentiate into a very wide variety of tissues. For example, when compared with bone marrow stem cells or mobilized peripheral blood, umbilical cord blood stem cells have a greater repopulating ability.50 Cord blood derived CD34+ cells have very potent hematopoietic abilities, and this is attributed to the immaturity of the stem cells relative to adult derived cells. Studies have been done that analyze long term survival of children with hematologic disorders who were transplanted with umbilical cord blood from a sibling donor. These studied revealed the same or better survival in the children that received the umbilical cord blood relative to those that got transplantation from bone marrow cells. Furthermore, rates of relapse were the same for both umbilical cord blood and bone marrow transplant.51

One of the unique features of stem cells taken from umbilical cord blood is the potential to differentiate into a wide variety of cell types. There are three different kinds of stem cells that can be found in the umbilical cord blood which include hematopoietic, mesenchymal, and embryonic-like stem cells. Not only can these cell types all renew themselves, but they can differentiate into many different mature cell types through a complex number of signaling pathways. This means that these cells could give rise to not only hematopoietic cells but bone, neural and endothelial cells. There are studies taking place currently to see if umbilical cord blood derived stem cells can be utilized for cardiomyogenic purposes. Several studies have showed the ability to transform umbilical cord blood mesenchymal stem cells into cells of cardiomyogenic lineage utilizing activations of Wnt signaling pathways.52 Studies are also being conducted on the potential of neurological applications. If successful, this could help diseases such as cerebral palsy, stroke, spinal cord injury and neurodegenerative diseases. Given these cells ability to differentiate into tissues from the mesoderm, endoderm and ectoderm, they could be utilized for neurological issues in place of embryonic stem cells that are currently extremely controversial.53 There are currently studies involving in vitro work, pre-clinical animal studies, and patient clinical trials, all for the application of stem cells in neurological applications. There is big potential for the use of umbilical blood stem cells in the future of regenerative medicine.

Placental tissue contains both stem cells and epithelial cells that can differentiate into a wide variety of tissue types which include adipogenic, myogenic, hepatogenic, osteogenic, cardiac, endothelial, pancreatic, pulmonary, and neurological. Placental cells can differentiate in to all these different kinds of tissues due to lineages originating from different parts of the placenta such as the hematopoietic cells that come from the chorion, allantois, and yolk sac while the mesenchymal lineages come from the chorion and the amnion.54 It can be helpful to think of human fetal placental cells as being divided into four different groups: amniotic epithelial cells, amniotic mesenchymal stromal cells, chorionic mesenchymal stromal cells and chorionic trophoblast cells.54

Human amniotic epithelial cells (hAECs) can be obtained from the amnion membrane where they are then enzymatically digested to be separated from the chorion. When cultured under certain settings hAECs have been found to be able to produce neuronal cells that synthesize acetylcholine, norepinephrine as well as dopamine.55,56 This ability would mean they have potential for regenerative purposes in diseases such as Parkinsons Disease, multiple sclerosis, and spinal cord injury. There is also research being done to utilize hAECs for ophthalmological purposes, lung fibrosis, liver disease, metabolic diseases, and familial hypercholesterolemia. Once cultured, hAECs have been shown to produce both albumin and alpha-fetoprotein as well as showing ability to store glycogen. Furthermore, they have been found to metabolize ammonia and testosterone. In more recent studies conducted in mouse models, these cells have been found to have therapeutic efficacy after transplantation for cirrhosis.57

Mesenchymal stem cells are in many different tissues such as the bone marrow, umbilical cord blood, adipose tissue, Whartons jelly, amniotic fluid, lungs, muscle and the placenta. Placental mesenchymal stromal cells specifically originate from the extraembryonic mesoderm. Human amniotic mesenchymal stromal cells (hAMSCs) and chorionic mesenchymal stromal cells (hCMSCs) have both been found to have very low levels of HLA-A,B,C. This means that they have immune privileged profiles for potential transplantation.58,59 Placental derived mesenchymal stem cells have been shown to have expression of CD29, CD44, CD105 and CD166 which is the same as adipose derived mesenchymal stem cells. These markers have been shown to have osteogenic differentiating abilities.57 An interesting element of placental mesenchymal stem cells is that their properties differ depending on the gestational age of the placenta. When cells are harvested at lower gestational ages, they show faster generation doubling times, better proliferative abilities, wider differentiation potential and more phenotypic stability than cells harvested from placental tissue that is considered to be at term.60 Furthermore, they have great potential to be used clinically. Placental mesenchymal stromal cells have been studied for use in treating acute graft-versus-host disease that was refractory to steroid treatment. Studies have shown that the 1-year survival rates in patients treated with placenta derived stromal cells were 73% while retrospective control only showed 6% survival.61 Placenta derived MSCs have also been found to aid in wound healing and could potentially be used to aid with certain inherited skin conditions such as epidermolysis bullosa.62

Stem cells are diverse in their differentiation capacity as well as their source of origin. As we can see from this review, there are similarities and differences when these cells are extracted from different sources. Research has shown initial promise in neurodegenerative diseases such as Alzheimers and Parkinsons Disease. It has also shown to be beneficial in the areas of musculoskeletal regenerative medicine and other pain states. Organ bioengineering for transplantation is another potential benefit that stem cells may offer. For these reasons, extensive research is still needed in this area of medicine to pave the way for new developing therapy modalities.

none

This review is dedicated to Dr.Justine C. Goldberg MD

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Virginia to offer diabetes-prevention classes – Essentia Health

Posted: March 1, 2024 at 2:44 am

Virginia to offer diabetes-prevention classes  Essentia Health

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What’s the Connection Between Diabetes and Oral Health? – Medscape

Posted: March 1, 2024 at 2:43 am

What's the Connection Between Diabetes and Oral Health?  Medscape

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Smart pens and insulin pump therapy for people with Type 2 diabetes – Omnia Health Insights

Posted: January 14, 2024 at 2:34 am

Smart pens and insulin pump therapy for people with Type 2 diabetes  Omnia Health Insights

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Integration of Traditional, Complementary, and Integrative Medicine (TCIM) in the Institutionalization of Evidence … – World Health Organization

Posted: January 14, 2024 at 2:33 am

Integration of Traditional, Complementary, and Integrative Medicine (TCIM) in the Institutionalization of Evidence ...  World Health Organization

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Menopausal Hormone Therapy | Johns Hopkins Medicine

Posted: January 6, 2024 at 2:40 am

When a woman's body no longer makes estrogen, hormone therapy may be an option. But, hormone therapy (HT), in which estrogen and progestin (a synthetic progesterone) are used in combination, has been controversial over the years.

To learn more about women's health, and specifically hormone therapy, theNational Institutes of Health (NIH) did a study called the Women's Health Initiative (WHI)beginning in 1991. The studyinvolved more than 161,000 generally healthy postmenopausal women.

The study was designed to test the effects of postmenopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer in women.

The study had 2 arms:

Women with a uterus were given progestin in combination with estrogen, which is known to prevent endometrial cancer. All women were randomly assigned to either the hormone medicine being studied or to placebo (inactive substance).Compared with placebo, the estrogen plus progestin treatmentresulted in:

Small increase inrisk of heart attack (in women younger than 60 when combined hormone therapy is started in perimenopause, it may reduce risk of heart attack)

Small increase inrisk of stroke

Small increase inrisk of blood clots

Small increase in risk of breast cancer

Reduced risk of colorectal cancer

Fewer fractures

No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)

Compared with the placebo, treatment with estrogen alone resulted in:

No difference in risk for heart attack

Increased risk of stroke

Increased risk of blood clots

Reduced risk of breast cancer

No difference in risk for colorectal cancer

Reduced risk of fracture

The WHI recommends that women follow the FDA advice on hormone (estrogen-alone or estrogen-plus-progestin) therapy. It says that hormone therapy should not be taken to prevent heart disease.

These products are approved therapies for relief from moderate to severe hot flashes and symptoms of vaginal dryness. Although hormone therapy may be effective in preventing fractures, it should only be considered for women at high risk of osteoporosis who cannot take other medicines. The FDA recommends that hormone therapy be used at the lowest doses for the shortest time needed to achieve treatment goals. Postmenopausal women who use or are considering using hormone therapy should discuss the possible benefits and risks to them with their healthcare providers.

The National Heart, Lung, and Blood Institute offers the following suggestions for women who are deciding whether or not to use hormone therapy:

The most important thing a woman can do in deciding to continue hormone therapy is discuss the current research with her healthcare provider.

Women need to be aware that taking a combined progesterone and estrogen regimen or estrogen alone is no longer recommended to prevent heart disease. A woman should discuss other ways of protecting the heart with her healthcare provider.

Women should discuss with their healthcare providers the value of taking combined progesterone and estrogen therapy or estrogen to prevent osteoporosis. There may be other treatments based on a woman's health profile.

Always consult your healthcare provider for more information.

Asa woman approaches menopause, the production of estrogen and progesterone fluctuates and then decreases significantly. Symptoms such as hot flashes often result from the changing hormone levels. After a woman's last menstrual period, when her ovaries make much less estrogen and progesterone, some symptoms of menopause might disappear, but others may continue.

To help relieve these symptoms, some women use hormones. This is called menopausal hormone therapy (MHT). This approach used to be called hormone replacement therapy or HRT. MHT describes several different hormone combinations available in a variety of forms and doses.

Hormone therapycan be given in a variety of methods, including the following:

For women who are appropriate candidates, this type of therapy can often be customized to provide the most benefits with the least side effects. It is important for women to talk with their healthcare providers about any discomfort or menstrual symptoms experienced with hormone treatment, as treatment approaches and dosages can be adjusted.

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5 Best Testosterone Replacement Therapy Services 2023 – Men’s Health

Posted: January 6, 2024 at 2:38 am

Welcome to Testosterone HQMen's Health's guide to the exciting, complicated, and revolutionary world of testosterone. For everything you need to know about T, click

TOPICAL TREATMENTS FOR hair loss. Gummy multivitamins. Generic formulations of Viagra. The online market for mens wellness is booming. And in the last couple years, that includes testosterone, which is easier to get than ever before.

Critical for regulating the male sex drive, testosterone plays a number of other key functions in the body. Its required for generating sperm. It helps to increase muscle mass, distribute body fat, and generate red blood cells. For men lacking in testosterone, the symptoms can be debilitating. Severe fatigue and depression. Irritability. No sex drive, brain fog, and anemia. Low-T guys have a harder time putting on muscle, and generally see more fat around their abdomen.

Testosterone levels, which are measured in nanograms per deciliter of blood, naturally wane as we age. The conventional wisdom, as spelled out by the American Urological Association, is that a healthy level is higher than 300 ng/dL; some experts argue that low is a little lower and starts at 264 ng/dL. Either way, doctors who specialize in hormone therapies say they are seeing a glut of guys whose testosterone levels are above 300 and are dealing with all the symptoms associated with a clinical diagnosis of testosterone deficiency.

Various boutique health companies, in response, now offer a spectrum of testosterone therapies, which have been extolled by the likes of Joe Rogan and Sylvester Stallone. There are straight-up replacement therapiesTRT, as its calledthat replenish levels of the hormone via creams, gels, pellets, or injections of either the subcutaneous or intramuscular kind. Tablets and supplements, intended to optimize the testosterone a guys already got, are also increasingly available. And forget in-person visits: The wellness businesses of today sell products that are shipped directly to consumers.

Administering testosterone is not like popping a multivitamin, to be sure. Replacing testosterone exogenously shuts down the bodys own production, which means you have to stay on it to maintain any positive effects. Younger guys should also consider their own fertility, since TRT can hinder or stop sperm production. And there are certainly ways to naturally keep your own testosterone levels at their peak: proper exercise, a good diet, and sufficient sleep are all good places to start. But many men with low or lower-than-average levels notice that their moods, muscles, and movesin the gym and in the bedroomare all improved by boosting or optimizing their T.

We recognize, though, that sifting through the options out there can be a bit daunting. What you need and where to get it are important questions. To say nothing of if you need testosterone therapy at all. So consider this your what-to-know-before-you-go shopping guide to online testosterone therapy.

Roman is a wellness company known for its array of services and its simplicitythat is, ease of use. Part of the reason is how Roman gets you going: a DIY blood test shipped to your home. The kit comes with all the materials required for finger-prick draws on two consecutive days. A smartphone app guides you step-by-step through the draws. The kit also comes with pre-printed postage so you can mail it back for analysis, which is completed in a week.

The other part? Roman has only two offerings. One is a supplement billed as testosterone support for guys with healthy levels. It contains ingredients common in multivitamins, as well as ashwagandha, a plant that has been shown, in some studies, to modestly increase your bodys natural testosterone levels.

Clomiphene citrate is the other, although its better known by its brand name, Clomid. Assume your blood test comes back showing low or lower-than-average T. A call with a doctor or nurse practitioner follows, and theyll help you decide your dosage of Clomid (if signs point to that drug being right for you in the first place, of course). The drug itself is not testosterone replacement at all. Rather, Clomid is a pill that stimulates more natural testosterone production, which it does by blocking estrogen receptors in the brain. (When that happens, the pituitary gland boosts production of luteinizing hormone, which acts on the Leydig cells in the testes to make more testosterone endogenously.)

Clomids main advantage is fewer of the side effects associated with traditional testosterone replacement, which can include testicular shrinkage and, in some cases, infertility. Our approach really has to do with maximizing the interaction between safety and efficacy, says Tzvi Doron, D.O., Romans chief clinical officer.

Costs:

Maximus caters to all men looking to optimize their testosterone, but its an appealing option for young guys who want to maintain their fertility but also need a boost in T.

Founded by clinical psychologist Cameron Sepah, Maximus doesnt offer testosterone replacement therapy at all. He calls it testosterone stimulation rather than replacement. (And his personal view is that TRT should be a last resort.) The company prescribes custom compounds of pure enclomiphene, one of Clomids two ingredients. Sepah says the reason for this is that Clomids other ingredient, zuclomiphene, can have estrogenic side effects. His sales pitch is pretty easy to boil down: The enclomiphene will quickly help your body generate more natural testosterone, minus the side effects that sometimes accompany replenishing with synthetic testosterone or popping Clomid.

Of the options here, Maximus is the quickest way to get going on testosterone optimization. You start with a quantitative ADAM, a series of questions on symptoms associated with low testosterone. Within 24 hours, a doctor makes an eligibility decision, and initiates a blood test thats shipped to consumersin this case, a shoulder-mounted device that uses microneedles to remove about a pinky-tips worth of blood. Within a week of shipping your blood sample back, youll have your first bottle of enclomiphene, if you qualify. A follow-up blood test after 30 days determines if your dosage needs any tinkering.

All Maximus patients are assigned a physician; all communication is done asynchronously through text and email. The company also provides health coaching to help guys optimize their diet, exercise, sleep schedules, and stress levels.

Our philosophy is that pharmacology and behavior change are synergistic, says Sepah. One of the biggest benefits of testosterone is increased motivation. We find it helps people make the behavior changes.

Costs:

If youre unclear about whether testosterone therapy is right for you, try Hone Health. According to Jack Jeng, M.D., Hones chief medical officer, the company only accepts patients with lower-than-normal testosterone levels. For guys who are borderline, Hones clinicians might suggest lifestyle changes (sleep, exercise, diet) for three months before jumping into a prescription.

We turn away a lot of patients, Dr. Jeng says. You have to make sure the benefits of treatment outweigh the risks.

You start with a blood test, usually self-administered at home via finger prick, to check biomarkers such as your levels of testosterone and estrogen. A 30-minute telehealth visit follows, and if the doctor deems you a good candidate for testosterone therapy, a second blood test is ordered to confirm the first reading. Within a few weeks, you could be on testosterone replacement, delivered at home in the form of creams, injections, or troches, depending on your preference.

If replacement isnt warranted, Hone can instead send Clomid. Unique to Hone is anastrozole, an inhibitor that blocks the conversion of testosterone to estrogenthat conversion can happen when aromatase, an enzyme contained in fat cells, breaks down testosterone. Whatever the case, patients receive follow-up blood tests and telehealth visits every three months in the first year to check for side effects and titrate dosages if necessary.

Give it at least 10 weeks before deciding whether or not this is working for you, says Dr. Jeng. Thats around the time when people start to notice that the benefits have started to really kick in.

Costs:

Blokes is for anyone who wants doctors controlling their testosterone therapy from start to finish. Every interaction with Blokes begins with a blood test, but these arent self-administered. Instead, Blokes schedules an appointment at a Labcorp or Quest Diagnostics facility. (For a surcharge, a phlebotomist can meet you at your home or workplace.)

These tests are the more conventional CBC, or complete blood count. Testosterone and estrogen levels are assessed, and so are your levels of luteinizing and follicle-stimulating hormonesthe pituitary hormones responsible for testosterone and sperm production, respectivelyas well as your cholesterol and lipids. A one-on-one clinical visit of at least 30 minutes then follows.

You want to know who that patient is before you start prescribing anything, says Amy Killen, M.D., one of Blokes clinicians. You dont want to throw this stuff out like candy.

Once youre in the Blokes system, youre assigned a physician and health coach who guide your therapy and make recommendations on nutrition, exercise, and other lifestyle factors. Testosterone replacement options include creams, injections, and troches, as well as nasal sprays and pellets (inserted into the body via a minor procedure). Clomid is on hand, too, as is pure enclomiphene. After 30 days: another blood test, along with another telehealth appointment. Its usually at this mark that Blokes consults with you to figure out if youre on the right form of testosterone therapy or drug.

We prioritize service over automation, says founder Josh Whalen. Every patient is getting some type of one-on-one follow-up with a provider.

Costs:

If youre as interested in health span and longevity medicine as you are in testosterone, then Opt Health is for you. Graham Simpson, M.D., one of the cofounders, has himself been on testosterone therapy for 27 years; hes 72, but doesnt look much older than 50.

Opt Health starts its prospective patients with a blood draw like all the other companies. These are done at a local Labcorp (or at home, with a visit from a nurse or phlebotomist). The blood test triggers an initial consultation, at which point Simpson, his cofounder Jeremie Walker, M.D., or one of Opts other half-dozen clinicians can take you through their testosterone options, which include creams, injections, and Clomid that are shipped directly in three-month allotments. Chances are that any testosterone treatment you end up taking will be paired with Opts offerings of amino-acid peptides or nutraceuticals.

Testosterone is a big part of our business, says Dr. Walker. But I actually have guys that are not on testosterone. Were focused on lifestyle optimizations.

Every three to four months, Opt Health repeats a blood draw followed by a consult with your clinician. A personalized online dashboard helps you track your progress, side effects, symptoms, and something Dr. Simpson calls your DNA age. (Theres your chronological ageyour birthdayand your biological age, he says.) In Opts view, fighting insulin resistance and inflammation is just as important to Opt as prescribing the right form of testosterone treatment.

Were very focused on reversing biological age, Dr. Simpson says. We look at nutrition, we look at exercise, we look at hormones, we look at stress, we look at sleep. We look at many, many things that optimize mens health.

Costs:

Andrew Zaleski, a writer based near Washington, D.C., covers science, technology, and business.

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New gene therapy for sickle cell disease has been a long time coming, but is it a complete game-changer? – UCLA Health Connect

Posted: December 29, 2023 at 2:34 am

New gene therapy for sickle cell disease has been a long time coming, but is it a complete game-changer?  UCLA Health Connect

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