A total of six participants will be included in the Phase 1 trial that will track the patients for 12 months and beyond to determine the safety of the procedure and monitor for any improvements in Parkinson’s disease. Following the first 6 patients transplanted in the Phase 1 study, the researchers hope to expand and recruit more patients as part of Phase 2A study.

This novel therapeutic approach for treating Parkinson’s disease incorporates the use of stem cells derived from a patient’s own blood that had been converted into induced pluripotent stem cells (iPSCs). These cells are then reprogrammed to turn into specific midbrain dopaminergic neurons ready for transplantation. The autologous transplantation approach of using a person’s own cells circumvents the requirement for immunosuppressive treatments, which are necessary when cells from other donors are used.

Cell replacement for Parkinson’s disease replaces the dopamine neurons lost to degeneration and can restore dopaminergic function in the brain, providing a completely new treatment modality compared to the currently available treatments. The NRI’s founding director, Ole Isacson, Dr Med Sci, who is also a professor of neurology (neuroscience) at Harvard Medical School and Mass General Brigham, has pioneered work in cell therapy for Parkinson’s disease over the past 30 years and laid the foundation for this clinical trial.

“Seeing this transformational new patient cell-based replacement of their own dopamine neurons come to fruition — from the very basic science breakthroughs in our lab to be completely translated into a clinical application for patient’s suffering from Parkinson’s disease — is very gratifying,” said Isacson. “We believe this approach may open up a new treatment paradigm and lead to the development of many additional cell therapies to restore damaged brain systems and replace degenerated brain cells in other diseases.”

Under Isacson’s leadership, the NRI at McLean has developed and patented autologous cell-based restoration in Parkinson’s disease with a pioneering preclinical publication in 2002 using stem cells and the first preclinical demonstration of effective human iPS cell-derived dopamine neuron use in 2010. In 2015, the NRI team, led by Isacson and Penny Hallett, PhD, co-director of the NRI at McLean and associate professor of psychiatry at Harvard Medical School, provided the first evidence of long-term safety and benefits of autologous stem cell therapy in a highly relevant Parkinson’s disease non-human primate animal model.

The NRI received official authorization from the U.S. Food and Drug Administration (FDA) on August 23, 2023, approving its Investigational New Drug (IND) application for a phase 1 clinical trial to test this unique, autologous dopamine neuron cell therapy.

Following this FDA approval for the phase 1 clinical trial, the NRI’s innovative preclinical work was translated into the clinic with the first patient treated on September 9, 2024. This collaboration includes NRI investigators James Schumacher, MD, and Oliver Cooper, PhD, and colleagues in the Neurology (Michael Hayes, MD) and Neurosurgery (John Rolston, MD, PhD, principal investigator of the Phase 1 trial) Departments at Brigham and Women’s Hospital. Isacson is not directly involved in the clinical trial because he is the innovator patent holder of the technology and also a co-founder of Oryon Cell Therapies, which has the license to this technology. The trial is directed by Hallett and colleagues within the Mass General Brigham healthcare system and its Harvard Medical School-affiliated institutions.

“It is extraordinary to witness that investigators at our institution can bring new treatments to patients through the entire process of laboratory “bench to bedside,” and it inspires many investigators to similarly pursue their scientific and medical insights to reach patients in need,” said Kerry Ressler MD, PhD, chief scientific officer at McLean Hospital.

The Phase 1 open-label clinical trial will be the first such trial to test blood-derived autologous iPSC-derived dopamine neurons in patients with Parkinson’s disease and is funded by the National Institute of Health’s National Institute of Neurological Disorders and Stroke (NINDS). The NINDS awarded the highly competitive Cooperative Research to Enable and Advance Translational Enterprises for Biologics (CREATE Bio) grant for this work in 2020.

People seeking more information in the trial can email: @bwh.harvard.edu” title=”mailto:neurosurgerycrc@bwh.harvard.edu”>neurosurgerycrc@bwh.harvard.edu

For More Information:

• McLean Hospital Receives Coveted NIH Grant to Clinically Study Autologous Stem Cell Therapy for Parkinson’s Disease
• Patient-derived stem cells could improve drug research for Parkinson’s

Funding: The study was supported by a NINDS CREATE Bio grant (U01NS109463).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Disclosure:Isacson has co-founded a company (Oryon Cell Therapies) which has licensed the patents and know-how for developing autologous cell therapies for Parkinson’s disease. Isacson’s interests were reviewed and are managed by McLean Hospital and Mass General Brigham in accordance with their conflict of interest polices.

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About Mass General Brigham

Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.

Manganese, selenium, magnesium and copper are among the essential metals important for a healthy body because their anti-oxidation and anti-inflammatory properties may help protect against cardiovascular disease. Previous research has found that higher levels of manganese were associated with a lower risk of preeclampsia (high blood pressure during pregnancy). However, it is not known whether higher levels of essential metals during pregnancy may influence the risk of developing high blood pressure later in life. Additionally, chronic exposure to the non-essential metals lead, cadmium and arsenic is associated with an increased risk of cardiovascular disease, according to the Association’s 2023 scientific statement “Contaminant Metals as Cardiovascular Risk Factors.”

“People are constantly exposed to heavy metals and trace elements, and much research has shown that exposure to those metals and elements may have an impact on cardiovascular health, especially hypertension,” said lead study author Mingyu Zhang, Ph.D., M.H.S., an epidemiologist and instructor in medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. “In our study, we wanted to examine how levels of essential metals and elements during pregnancy may affect blood pressure and hypertension risk in midlife.”

The researchers analyzed data from Project Viva, an ongoing, long-term study that began in 1999 of women and their children who live in eastern Massachusetts. Nearly 500 women enrolled in the study during early pregnancy, between 1999 and 2002. Researchers measured concentrations of non-essential metals (arsenic, barium, cadmium, cesium, mercury and lead), essential minerals (copper, magnesium, manganese, selenium and zinc), folate and vitamin B12 in blood samples collected during study enrollment.

After nearly twenty years of follow-up, researchers conducted a “midlife” study visit between 2017 and 2021 with the same study participants, who were now at a median age of 51.2 years. Researchers measured blood pressure to assess potential associations of individual metals with blood pressure and high blood pressure risk. Participants were categorized as having high blood pressure if blood pressure measures were greater than 130/80 mm Hg or if participants confirmed taking anti-hypertensive medication. In addition, the potential collective effects of all eleven metals and two micronutrients on blood pressure were analyzed.

The study found:

• After researchers adjusted for sociodemographic factors, as levels of copper and manganese doubled in the blood during pregnancy, the risk of high blood pressure in midlife was 25% and 20% lower, respectively.
• As blood levels of vitamin B12 doubled during pregnancy, women had an average 3.64 mm Hg lower systolic blood pressure and 2.52 mm Hg lower diastolic blood pressure almost two decades later. About 95% of the study participants had vitamin B12 levels within the normal range, the researchers noted.
• Blood levels of the mixture of copper, manganese, selenium and zinc were also associated with lower blood pressure in a relationship that increased with dose. Nonessential metals did not have a significant impact on blood pressure.

“Circulating levels of these metals and minerals in blood were measured, however, the sources of exposure, such as food or dietary supplements, were not quantified so these findings should not be interpreted as recommendations,” Zhang said. “Optimizing these essential metals, minerals and vitamins, particularly copper, manganese and vitamin B12, during pregnancy may offer protective benefits against hypertension in midlife, an especially critical time period for women’s future cardiovascular risk in later life.”

“More research including clinical trials is needed to determine the optimal dietary intake of these minerals and micronutrients,” he added. The researchers hope to ultimately identify women at high risk for developing high blood pressure later in life and intervene during pregnancy, either with enhanced nutrition or supplements.

Study details, background and design:

• The analysis included 493 women enrolled in Project Viva, a prospective study examining the effects of environmental and lifestyle factors during pregnancy on the short and long-term health of women and their children.
• Project Viva enrolled women in early pregnancy between 1999 and 2002. The women had a median age of 32.9 years at enrollment. Participants were followed for 18.1 years, through 2021.
• 72% of participants self-identified as white women; 11% were self-identified as Black women; and 17% self-identified as Hispanic or Latina, Asian or Pacific Islander, American Indian or Alaskan Native, or selected “Other” race, more than one race or “do not know.”
• Blood samples were collected at study enrollment and stored in freezers for subsequent analyses. The researchers accessed blood samples and analyzed them for this study in 2018. Folate and vitamin B12 were also measured in blood plasma samples during pregnancy.
• Blood pressure was measured in study participants during a “midlife” (median age of 51 years) study visit between 2017 and 2021. During this visit, trained research assistants measured participants’ blood pressure up to five times, at one-minute intervals. Blood pressure measurements were then averaged.
• The analyses were adjusted for maternal age at study enrollment, pre-pregnancy body mass index, race and ethnicity, education, household income, parity (the number of pregnancies carried to term), use of anti-hypertensive medication, DASH diet score in early pregnancy and multivitamin intake.

The study’s limitations include that it was an observational study, meaning other confounding factors that were not measured in the study may have affected the results; the researchers only included a subset of the original Project Viva participants; and there were demographic differences between participants included and excluded. In addition, the researchers did not have measurements for metal levels between delivery and midlife; and participants were predominantly white women who resided in Eastern Massachusetts, which may limit the generalizability of the study’s findings.

“When the heart cannot replace injured cardiomyocytes with healthy ones, it becomes progressively weaker, a condition leading to heart failure. In this study, we investigated a new way to stimulate cardiomyocyte proliferation to help the heart heal,” said co-corresponding author Dr. Riham Abouleisa, assistant professor in the Division of Cardiothoracic Surgery at Baylor.

Previous studies showed that calcium plays an important role in cardiomyocyte proliferation. In the current study, Abouleisa and her colleagues explored how modulating calcium influx in cardiomyocytes would affect their proliferation.

“We found that preventing calcium influx in cardiomyocytes enhances the expression of genes involved in cell proliferation,” Abouleisa said. “We prevented calcium influx by inhibiting L-Type Calcium Channel (LTCC), a protein that regulates calcium in these cells. Our findings suggest that LTCC could be a target for developing new therapies to induce cardiomyocyte proliferation and regeneration.”

The study demonstrates that both pharmacological and genetic inhibition of LTCC can induce cardiomyocyte replication and that this occurs by modulating the activity of calcineurin, a known regulator of cardiomyocyte proliferation. This innovative approach showed promising results both in human cardiac slices grown in the lab and in live animals.

“Abouleisa’s multi-continent collaborations led to a discovery that can revolutionize the use of current medicines that regulate calcium entry to the cells, such as Nifedipine, in heart failure patients,” said Dr. Tamer Mohamed, co-author and director of Baylor College of Medicine’s Laboratory for Cardiac Regeneration.

Co-author Dr. Todd K. Rosengart, chair and professor of the Michael E. DeBakey Department of Surgery, emphasized that, “The premise of regenerating heart tissue, which once seemed like an impossible dream, is getting closer almost daily. The work of Dr. Abouleisa and the Baylor cardiac regeneration team represents a major step toward human trials that I believe are in the not-too-distant future.”

Abouleisa and her colleagues’ research highlights the importance of targeting calcium signaling pathways to unlock the regenerative potential of the heart and opens new avenues for developing cardiac regenerative therapies, potentially transforming the treatment landscape for patients suffering from heart failure.

Other contributors to this work include Lynn A C Devilée, Abou Bakr M Salama, Jessica M Miller, Janice D Reid, Qinghui Ou, Nourhan M Baraka, Kamal Abou Farraj, Madiha Jamal, Yibing Nong, Douglas Andres, Jonathan Satin and James E Hudson.

In a new study, Northwestern University researchers have discovered why the role of stretching is so important. By simulating spider silk in a computational model, the team discovered the stretching process aligns the protein chains within the fibers and increases the number of bonds between those chains. Both factors lead to stronger, tougher fibers.

The team then validated these computational predictions through laboratory experiments using engineered spider silk. These insights could help researchers design engineered silk-inspired proteins and spinning processes for various applications, including strong, biodegradable sutures and tough, high-performance, blast-proof body armor.

The study will be published on Friday (March 7) in the journal Science Advances.

“Researchers already knew this stretching, or drawing, is necessary for making really strong fibers,” said Northwestern’s Sinan Keten, the study’s senior author. “But no one necessarily knew why. With our computational method, we were able to probe what’s happening at the nanoscale to gain insights that cannot be seen experimentally. We could examine how drawing relates to the silk’s mechanical properties.”

“Spiders perform the drawing process naturally,” said Northwestern Jacob Graham, the study’s first author. “When they spin silk out of their silk gland, spiders use their hind legs to grab the fiber and pull it out. That stretches the fiber as it’s being formed. It makes the fiber very strong and very elastic. We found that you can modify the fiber’s mechanical properties simply through modifying the amount of stretching.”

An expert in bioinspired materials, Keten is the Jerome B. Cohen Professor of Engineering, professor and associate chair of mechanical engineering and professor of civil and environmental engineering at Northwestern’s McCormick School of Engineering. Graham is a Ph.D. student in Keten’s research group.

Stronger than steel, tougher than Kevlar

Researchers long have been interested in spider silk because of its remarkable properties. It’s stronger than steel, tougher than Kevlar and stretchy like rubber. But farming spiders for their natural silk is expensive, energy-intensive and difficult. So, scientists instead want to recreate silk-like materials in the lab.

“Spider silk is the strongest organic fiber,” Graham said. “It also has the advantage of being biodegradable. So, it’s an ideal material for medical applications. It could be used for surgical sutures and adhesive gels for wound-closure because it would naturally, harmlessly degrade in the body.”

Study coauthor Fuzhong Zhang, the Francis F. Ahmann Professor at Washington University (WashU) in St. Louis, has been engineering microbes to produce spider-silk materials for several years. By extruding engineered spider silk proteins and then stretching them by hand, the team has developed artificial fibers similar to threads from the golden silk orb weaver, a large spider with a spectacularly strong web.

Simulating stretchiness

Despite developing this “recipe” for spider silk, researchers still don’t fully understand how the spinning process changes fiber structure and strength. To tackle this open-ended question, Keten and Graham developed a computational model to simulate the molecular dynamics within Zhang’s artificial silk.

Through these simulations, the Northwestern team explored how stretching effects the proteins’ arrangement within the fibers. Specifically, they looked at how stretching changes the order of proteins, the connection of proteins to one another and the movement of molecules within the fibers.

Keten and Graham found that stretching caused the proteins to “line up,” which increased the fiber’s overall strength. They also found that stretching increased the number of hydrogen bonds, which act like bridges between the protein chains to make up the fiber. The increase in hydrogen bonds contributes to the fiber’s overall strength, toughness and elasticity, the researchers found.

“Once a fiber is extruded, its mechanical properties are actually quite weak,” Graham said. “But when it’s stretch up to six times its initial length, it becomes very strong.”

Experimental validation

To validate their computational findings, the team used spectroscopy techniques to examine how the protein chains stretched and aligned in real fibers from the WashU team. They also used tensile testing to see how much stretching the fibers could tolerate before breaking. The experimental results agreed with the simulation’s predictions.

“If you don’t stretch the material, you have these spherical globs of proteins,” Graham said. “But stretching turns these globs into more of an interconnected network. The protein chains stack on top of one another, and the network becomes more and more interconnected. Bundled proteins have more potential to unravel and extend further before the fiber breaks, but initially extended proteins make for less extensible fibers that require more force to break.”

Although Graham used to think spiders were just creepy-crawlies, he now sees their potential to help solve real problems. He notes that engineered spider silk provides a stronger, biodegradable alternative to other synthetic materials, which are mostly petroleum-derived plastics.

“I definitely look at spiders in a new light,” Graham said. “I used to think they were nuisances. Now, I see them as a source of fascination.”

The study, “Charting the envelope of mechanical properties of synthetic silk fibers through predictive modeling of the drawing process,” was supported by the National Science Foundation (grant numbers OIA-2219142 and DMR-2207879).