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Stopping the Pain and Saving Lives: Successful Treatments for Sickle Cell Disease – Charlotte Lozier Institute

By Adult Stem Cells

The U.S. Food and Drug Administration (FDA) recently approved not just one, but two new gene therapies for sickle cell disease. The first, Casgevy, was co-developed by Vertex Pharmaceuticals and CRISPR therapeutics. The second, Lyfgenia, was developed by bluebird bio. What was all this gene editing and DNA swapping about, are the therapies successful, and is this an ethical advance in medicine?

Sickle cell disease is an inherited (genetic) condition that affects about 100,000 U.S. patients, and more than 20 million people globally. People with sickle cell have severe pain, anemia, and clogged blood vessels that can damage multiple organs. Half of adults with sickle cell disease die by their early 40s.

The disease name comes from the shape taken by red blood cells; instead of the normal flexible disc shape, cells form a sickle shape that can clump and block blood vessels to the point that organs and tissues do not receive oxygen. This can result in severe pain crises, blindness, stroke, and other organ damage.

Why do the red cells form a sickle shape, and how can gene editing reverse the disease? Sickling is the result of one small mutation in the DNA, a single letter of genetic code that is changed. Yet this single molecular change leads to profound changes in the character of the patients hemoglobin (the protein in red blood cells responsible for delivering oxygen to tissues throughout the body). One molecule of our normal adult hemoglobin contains four proteinstwo alpha-globin proteins and two beta-globin proteinscomplexed with an iron-containing heme molecule. Each red blood cell is basically a bag of hemoglobin, floating through the blood, grabbing oxygen and carrying it around the body to our cells and tissues.

The single genetic mutation in sickle cell leads to a single amino acid change in the beta-globin protein, changing the character of the protein so that it tends not to form oxygen-carrying molecules but rather causes the proteins to clump within the cell and form stiff rods, stretching the disc-shaped cells into a sickle shape.

It is important to note that during our development in the womb, our bodies use a slightly different form of hemoglobin, termed fetal hemoglobin, to carry oxygen. Fetal hemoglobin is made up of two alpha-globin proteins and two gamma-globin (rather than beta-globin) proteins complexed with heme. Around the time of birth, our body stops making gamma-globin by turning off that gene, and turning on the gene to start production of beta-globin for oxygen-carrying capacity once we are out of the womb.

Treatments for serious sickle cell disease have been few and difficult to obtain. While a couple of drugs and periodic red blood cell transfusions can ameliorate some of the diseases symptoms, so far only matched bone marrow adult stem cell transplants have been a curative option (more on this below.)

Genetic therapies such as the two now approved by the FDA aim to cure a disease, rather than simply manage its symptoms, attacking it at the genetic level to cause a permanent change. These two gene therapies are both what are termed somatic gene therapies. Their goal is to treat existing individuals and cure the disease without altering the germlinei.e., they are not heritable. In general, this type of gene therapy poses few ethical difficulties, although access to the treatment, including its cost, as well as complete informed consent regarding potential outcomes and side effects, can be issues.

On the other hand, genetic therapies which aim to prevent disease by altering the germline (heritable DNA) of eggs, sperm, or embryos, thereby affecting not only the treated (or manufactured) individual but also future generations, raise significant ethical concerns. The Charlotte Lozier Institutes Handbook of Nascent Human Beings has more information on the science, bioethics, and moral permissibility of genetic engineering and other new technologies.

The two newly approved gene therapies both accomplish their alleviation of sickle cell disease by altering bone marrow adult stem cells of the patient; theyve taken this route because using the patients own adult stem cells poses no problem of immune rejection of the therapy.Bone marrow adult stem cells are extracted from the patient and purified. In particular, the scientists are after what are called the CD34+ cells, which are the master stem cell for all blood and immune cells.The genetic alteration is done ex vivo, meaning in the lab and outside the patients body.

Casgevy, the therapy produced by Vertex, injects the CRISPR gene editing tool into the cells, targeting a small control region on the DNA that, when turned on, stops production of fetal hemoglobin, in particular the gamma-globin.Essentially, the enzyme makes a snip in the control region, turning off the inhibitor, thereby turning on production of gamma-globin.The result is that adult hemoglobin is replaced in the patient by fetal hemoglobin, which carries oxygen just fine.

Lyfgenia, produced by bluebird, uses a benign, inactivated virus as a vector to inject a modified form of normal beta-globin into the patients adult stem cells in the lab. The new DNA instructions then insert into the cells genome, where it produces normal adult hemoglobin and restores normal oxygen-carrying capacity.The slight modification in the inserted beta-globin DNA is a one amino-acid change that inhibits any aggregation of beta-globin, further eliminating the molecular problem for the patient.

For both genetic therapies, after the gene editing in the lab and quality control checks to make sure the adult stem cells are correctly altered, the cells are reinfused back into the patient. Prior to reinfusion, the patient gets a dose of chemotherapy to wipe out old faulty bone marrow adult stem cells and make space for the corrected cells.The altered adult stem cells go to the bone marrow and make themselves at home, start producing blood cells, and these new red blood cells carry oxygen normally, thus curing the patients of sickle cell disease.

Using adult stem cells, rather than fetal stem cells, as the vehicle for the genetic alteration showcases another role for this gold standard of stem cells, the only stem cell with a documented record of providing successful treatments. Direct transplant of normal beta-globin-containing adult stem cells has also been used successfully to treat sickle cell disease and related blood disorders. Until the approval of these new genetic therapies utilizing stem cells from the ailing patients themselves, adult stem cell transplant was considered the only curative treatment available for sickle cell disease and similar conditions. Since the transplant relies on finding matched donors for each patient, the cure has been limited. New research suggests, however, the possibility of using haploidentical (half-matched) transplants to increase accessibility to this critical adult stem cell treatment.

Freedom from sickle cell disease is available now using adult stem cell transplants. You can watch Desirees story to see the success of using adult stem cells from cord blood. You can watch more of Desiree as she discusses the transplant experience with two other patients. The success of adult stem cell therapies continues to demonstrate that the progress of science and medicine need not rely on ethically compromised research and treatment approaches.

David A. Prentice, Ph.D. is former Vice President and Director of Research for the Charlotte Lozier Institute. This article may also be accessed at the Christian Medical & Dental Associations website.

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Stopping the Pain and Saving Lives: Successful Treatments for Sickle Cell Disease - Charlotte Lozier Institute

A low-cost device to make cell therapy safer – Tech Explorist

By Induced Pluripotent Stem Cells

In cell therapy, clinicians reprogram some skin or blood cells from patients to create induced pluripotent stem cells. They coax these stem cells to transform into progenitor cells for treating spinal cord injury. These progenitors are then transplanted back into the patient to regenerate part of the injured spinal cord. However, pluripotent stem cells that dont entirely change into progenitors can form tumors.

Scientists at MIT and the Singapore-MIT Alliance for Research and Technology have developed a tiny device to improve cell therapy treatments with more excellent safety and effectiveness. They developed a microfluidic cell sorter to remove undifferentiated cells without damaging fully-formed progenitor cells.

This newly developed device can sort more than 3 million cells per minute without special chemicals. In the study, scientists found that combining many devices can sort more than 500 million cells per minute.

Pluripotent stem cells were generally larger than the progenitor cells derived from them. It happens because pluripotent stem cells have many genes that havent been switched off in their nucleus. As these cells specialize in specific functions, they suppress many genes that are no longer required, hence shrinking the nucleus. The microfluidic device leverages this size difference to sort the cells.

The plastic chip contains tiny channels that create an inlet for cells to enter, a spiral pathway, and four outlets where cells of different sizes are collected. When cells pass through the spiral at high speeds, various forces, including centrifugal forces, push them around. These forces help gather the cells at a specific point in the fluid stream based on their size, effectively separating them into different outlets.

The researchers discovered they could enhance the sorters performance by running it twice. First, they operate it at a lower speed, causing more giant cells to stick to the walls while smaller cells are sorted out. Then, they run it faster to separate the larger cells.

The device works similarly to a centrifuge, but it doesnt need human intervention to collect the sorted cells.

The device could remove almost 50% of larger cells in one pass. Whats more, the device doesnt use any filtration. The limitations with filters are that they become clogged or break down over time so that a filter-free device can be used for much longer.

Having demonstrated success on a small scale, the researchers are now moving on to larger studies and animal models to determine if the purified cells work better when introduced into living organisms.

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A low-cost device to make cell therapy safer - Tech Explorist

Scientists develop world’s first 3D-printed brain tissue that functions like human brain – WION

By Induced Pluripotent Stem Cells

In a path-breaking scientific endeavour, researchers have created the worlds first 3D-printed brain tissue that behaves like a natural brain tissue. This is being considered a major leap towards the development of advanced solutions to neurological and neurodevelopmental disorders.

This will greatly aid research programmes for scientists specially focused on treatments for a broad range of neurological and neurodevelopmental disorders, such as Alzheimers and Parkinsons disease.

This could be a hugely powerful model to help us understand how brain cells and parts of the brain communicate in humans, Su-Chun Zhang, professor of neuroscience and neurology at UWMadisons Waisman Center, was quoted as saying by Neuroscience.

It could change the way we look at stem cell biology, neuroscience, and the pathogenesis of many neurological and psychiatric disorders, he added.

The 3D printer employed by scientists here ditched the traditional approach in favour of stacking layers horizontally. They situated brain cells, neurons grown from induced pluripotent stem cells, in a softer bio-ink gel than previous attempts had employed.

Watch:Are brain implants the future of computing?

The tissue still has enough structure to hold together but it is soft enough to allow the neurons to grow into each other and start talking to each other, Zhang added.

Yuanwei Yan, a scientist in Zhangs lab, said the tissues stayed relatively thin, which allowed the neurons to easily access oxygen and enough nutrients from the growth media.

The neurons communicate with each other, send signals and interact through neurotransmitters, and even form proper networks with support cells that were added to the printed tissue.

We printed the cerebral cortex and the striatum and what we found was quite striking, Zhang said. Even when we printed different cells belonging to different parts of the brain, they were still able to talk to each other in a very special and specific way, he added.

As per experts, the printing technique offers an advanced level of precision not seen in other approaches, including brain organoids, miniature organs used to study brains. The technique offers control over the types as well as arrangements of cells, with proper organisation and control.

This provides scientists with flexibility in their research endeavours, which paves the way for radical advancements in the field.

(With inputs from agencies)

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Scientists develop world's first 3D-printed brain tissue that functions like human brain - WION

Neurona Raises $120M, Buoyed by Early-Stage Data for Epilepsy Cell Therapy – BioSpace

By Stem Cell Treatment

Pictured: 3D illustration of stem cells used for cell therapy/iStock,Maksim Tkachenko

Neurona Therapeutics on Thursday announced that it has secured $120 million in funding, which will help it advance its pipeline of investigational off-the-shelf cell therapies.

The California-based biotech will use the money to advance its lead candidate NRTX-1001, a regenerative neural cell therapy candidate being assessed in a Phase I/II trial for drug-resistant mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy that can trigger ongoing seizures despite medical treatment.

Neuronas financing on Thursday was co-led by Viking Global Investors and Cormorant Asset Management. Other institutional supporterssuch as UC Investments, UCB Ventures, Euclidean Capital, The Column Group and Alexandria Venture Investmentsalso participated in the funding round.

Neurona has pioneered development of a fully-differentiated cell therapy for drug-resistant focal epilepsy that is designed to be disease-modifying, repairing the affected neural network, and is yielding very promising initial clinical data, Raymond Kelleher, managing director at Cormorant, said in a statement, adding that NRTX-1001 could be a game-changer with its potential to control seizures and preserve neurocognitive function.

According to the biotechs website, NRTX-1001 is a cell therapy comprised of human inhibitory GABAergic interneurons, which can potentially address the underlying hyperactive neural networks in epileptic seizures.

In December 2023, at the annual meeting of the American Epilepsy Society, Neurona presented data from two patients enrolled in the Phase I/II study of NRTX-1001, who saw at least a 95% drop in overall seizure frequency more than one year after treatment. NRTX-1001 was also safe overall, with adverse events categorized as mild to moderate in severity.

Neurona is also testing NRTX-1001 in Alzheimers disease, for which it is currently in the preclinical evaluation stage.

Beyond NRTX-1001, Neurona will also channel some of Thursdays haul into its other pipeline projects including investigational myelinating glial cells and gene-edited cells, both for yet-undisclosed indications.

Neuronas funding comes nearly a year after the biotech laid off 18 employees, or 25% of its total headcount, to streamline its budget in the face of the current tight funding environment and extend available cash to support the ongoing clinical trial of NRTX-1001, a spokesperson told Fierce Biotech at the time.

The financing could also be a sign of an uptick in the industrys fundraising activities. This week alone, there have been two initial public offeringsKyverna and Metagenomiwhich follow the earlier debuts of Alto Neuroscience, Fractyl Health, ArriVent Biopharma and CG Oncology.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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Neurona Raises $120M, Buoyed by Early-Stage Data for Epilepsy Cell Therapy - BioSpace

Unlocking the power of stem cell therapy – Drug Target Review

By Stem Cell Medicine

In this Q&A, founder of Scheer Medical Wellness Dr Alexander Scheer shares his insights, discussing the current challenges in stem cell therapy and how these can be addressed, the advancements in delivery techniques, and stem cells overall potential in regenerative medicine.

Adipose-derived stem cells (ADSCs) have garnered attention due to their remarkable ability to differentiate into various cell types crucial for tissue regeneration and repair. Their plasticity allows them to adapt to the microenvironment of host tissues, facilitating integration and functional restoration. Additionally, ADSCs possess immunomodulatory properties, enabling them to modulate immune responses and promote tissue healing. These characteristics position ADSCs as promising candidates for addressing a wide range of medical conditions, from degenerative diseases to traumatic injuries.

Despite their potential, ADSC therapy faces several challenges in preclinical studies. These include ensuring controlled differentiation of ADSCs into desired cell types, addressing safety concerns such as the risk of tumorigenicity or immunogenicity, and optimising large-scale production methods. To overcome these challenges, researchers employ rigorous preclinical assessments, refine culture techniques to enhance cell purity and functionality, and develop standardised protocols for consistent results.

Researchers commonly use a combination of in vitro cell culture assays and in vivo animal models to assess the therapeutic potential of ADSCs. While in vitro assays provide controlled environments for studying cellular behaviour and differentiation, in vivo models offer insights into tissue-level interactions and responses. However, translating findings from these models to clinical trials requires careful consideration of factors such as disease complexity, species differences, and the relevance of model systems to human physiology.

Recent advancements in delivery techniques have significantly enhanced the precision and effectiveness of ADSC treatments. Biomaterial-based scaffolds provide structural support and mimic the extracellular matrix, facilitating tissue regeneration and integration. Additionally, innovations in 3D bioprinting enable the fabrication of complex tissue structures, offering tailored solutions for patient-specific needs. These delivery techniques improve cell retention, viability, and functionality post-transplantation, maximising therapeutic outcomes.

ADSC therapy holds promise for a multitude of medical conditions, including but not limited to wound healing, organ repair, autoimmune disorders, and cancer treatment. In wound healing, ADSCs accelerate tissue regeneration and reduce scarring, offering hope for chronic wound management. Similarly, in organ repair, ADSCs contribute to tissue regeneration and functional restoration, potentially revolutionising treatments for conditions such as myocardial infarction and liver cirrhosis. Moreover, their immunomodulatory properties make them valuable assets in managing autoimmune diseases by suppressing aberrant immune responses. Furthermore, ongoing research explores the potential of ADSCs in cancer therapy, both in supporting conventional treatments and directly targeting cancer cells. Overall, ADSC therapy represents a versatile and promising approach in personalised and regenerative medicine, with the potential to improve patient outcomes and quality of life across diverse medical fields.

Author bio

Dr Alexander Scheer

Founder of Scheer Medical Wellness

Dr Alexander Scheer, the founder of Scheer Medical Wellness, is a New York-based physician, with more than 20 years of expertise. He serves as the Medical Director (MD) of Scheer Medical Wellness, a cutting edge practice which provides a comprehensive range of high-quality services. These services encompass pain management, neurosurgery, spinal surgery, orthopedic surgery, primary care, physical therapy, physical medicine and rehabilitation, podiatry, plastic surgery, acupuncture, weight loss management, gastroenterology, and sports medicine.

Dr Scheer earned his medical degree from New York Medical College and subsequently completed his Surgical internship at Mount Sinai Beth Israel, followed by training in neurological surgery at the Albert Einstein College of Medicine until 2009. Dr Scheer is licensed to practice medicine in the state of New York and has dedicated his career to enhancing the well-being of his patients, enabling them to lead long and healthy lives.

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Unlocking the power of stem cell therapy - Drug Target Review

Improving stem cell research – Harvard School of Engineering and Applied Sciences

By Stell Cell Research

Repetitive, manual tasks are an inevitability in managing daily operations in a research setting. But the more time researchers spend on basic maintenance, the less time they have to do cutting-edge research.

Third-year students at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) worked with the Harvard Stem Cell Institute iPS Core Facility last fall to design a pair of solutions to reduce the time spent on day-to-day operations. They created an automated task management and scheduling system called WorkFlow, and a semi-robotic cell imaging system called CytoScope. The students presented their designs as their final project for ES96: Engineering Problem Solving and Design Project, a core course for third-year SEAS students pursuing S.B. engineering degrees. This section was taught by David Mooney, Robert P. Pinkas Family Professor of Bioengineering.

This was the best design project Ive ever been part of, said project co-lead Ryan Link, a mechanical engineering concentrator. We started from scratch, didnt know what wed have at the end. It was this whole design process: start from literally a blank piece of paper, create each piece, go through and solve problems along the way, and build something in the end.

The iPS Core Facility derives and distributes induced pluripotent stem cells (IPSCs). Unlike embryonic stem cells, IPSCs can be taken from adults and start off as cells that have already differentiated into a specific use, such as kidney or heart cells. The cells can then be regressed into stem cells, which can differentiate into a new function.

I could walk up to an adult, take some cells, turn them into stem cells and use them to recreate their kidney or liver, Link said.

Because IPSCs can be taken from adults, they have the potential to enable stem cell research without the ethical and political issues associated with embryonic stem cells.

As bioengineers, a lot of the stuff that we research has ethical concerns in mind, said Aaron Zheng, a bioengineering concentrator and project co-lead. So, it was very interesting for us to work on this project to further a field that has a lot of scientific implications without the preexisting ethical implications.

The iPS Core Facility challenged the 13 ES96 students to identify ways to improve productivity and operations in the lab. That led to a full month of background research and interviews to identify the most-pressing needs.

We spent a month deriving a one-sentence problem statement, which is what we framed the rest of the semester around, Zheng said. It was about what our client needed the most, what their biggest challenges were, and what solution would best address that problem.

The students then brainstormed potential solutions, slowly whittling down the list based on factors that included cost of materials, level of impact, and feasibility of delivery by the end of the semester.

The students worked hard, demonstrated significant creativity and ingenuity, and I think really learned how to work as a team on a complex, multicomponent project, Mooney said. The Teaching Fellows, Shawn Kang and Kyle Ruark, and Active Learning Labs staff Melissa Hancock and Avery Normandin provided access to critical resources and important training, and the students worked closely with the iPS Core Facility Director Dr. Laurence Daheron to both identify the key issues and develop solutions.

As a problem statement, the students decided the facilitys biggest need was to improve the inefficiencies in its monitoring technology and process of culturing sample cells. The CytoScope addresses those inefficiencies by automating the imaging process for stem cell plates stored overnight in incubators.

When researchers would check on the IPSCs every morning, theyd have to take them out, put them under a microscope, examine them by hand and try to determine what was going on, Link said. Theyd have to do that for every cell plate or cell well, which means a lot of manual labor for a pretty simple task. Our idea was to create a system inside the incubator that could image the cells autonomously overnight, and the researchers could just look at the images in the morning without having to do all these extra steps.

WorkFlow is a software system that combines calendar, messaging, spreadsheet and task-management programs, making it easier for researchers to track what their colleagues are doing and when. Both final products stressed the importance of feasibility, of designing engineering solutions that can be delivered to a client by a specific date.

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Improving stem cell research - Harvard School of Engineering and Applied Sciences

Amneal Announces Complete Response Resubmission for IPX203 New Drug Application

By Global News Feed

BRIDGEWATER, N.J., Feb. 08, 2024 (GLOBE NEWSWIRE) -- Amneal Pharmaceuticals, Inc. (NASDAQ: AMRX) (“Amneal” or the “Company”) today announced that it has provided a Complete Response resubmission to the U.S. Food and Drug Administration (FDA) for IPX203, a novel, oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules for the treatment of Parkinson’s disease (PD).

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Amneal Announces Complete Response Resubmission for IPX203 New Drug Application

Gritstone bio Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)

By Global News Feed

EMERYVILLE, Calif., Feb. 08, 2024 (GLOBE NEWSWIRE) -- Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company that aims to develop the world’s most potent vaccines, today announced that the Compensation Committee of the company’s Board of Directors granted six employees nonqualified stock options to purchase an aggregate of 147,000 shares of its common stock with an exercise price of $2.26, which is equal to the closing price of Gritstone’s common stock on February 6, 2024, the date of the grant. These stock options are part of an inducement material to the new employees becoming an employee of Gritstone, in accordance with Nasdaq Listing Rule 5635(c)(4).

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Gritstone bio Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)

Travere Therapeutics to Report Fourth Quarter and Full Year 2024 Financial Results

By Global News Feed

SAN DIEGO, Feb. 08, 2024 (GLOBE NEWSWIRE) -- Travere Therapeutics, Inc. (NASDAQ: TVTX) today announced it will report fourth quarter and full year 2023 financial results on Thursday, February 15, 2024, after the close of the U.S. financial markets. The Company will host a conference call and webcast to discuss the financial results and provide a general business update at 4:30 p.m. ET.

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Travere Therapeutics to Report Fourth Quarter and Full Year 2024 Financial Results

Telomir Pharmaceuticals Announces Pricing of Initial Public Offering

By Global News Feed

BALTIMORE, Feb. 08, 2024 (GLOBE NEWSWIRE) -- Telomir Pharmaceuticals, Inc., a pre-clinical-stage pharmaceutical company focused on the development and commercialization of TELOMIR-1, is developing Telomir-1 as the first novel small molecule, to lengthen the DNA’s protective telomere caps in order to affect age reversal, today announced the pricing of its initial public offering of 1,000,000 shares of its common stock at a public offering price of $7.00 per share. All of the shares of common stock are being offered by Telomir. In addition, Telomir has granted the underwriters a 45-day option to purchase up to an additional 150,000 shares of common stock at the initial public offering price, less underwriting discounts and commissions. The shares are expected to begin trading on the Nasdaq Capital Market on February 9, 2024 under the ticker symbol "TELO." The gross proceeds to Telomir from the initial public offering, before deducting underwriting discounts and commissions and estimated offering expenses, are expected to be $7 million. The initial public offering is expected to close on February 13, 2024, subject to satisfaction of customary closing conditions.

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Telomir Pharmaceuticals Announces Pricing of Initial Public Offering

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