drug development

The growth of virtual clinical trials during COVID-19

/ Yimy Villa / 3 Comments
A participant in a virtual study run by the California firm Science 37 receives materials at home. Credit: Christian Alexander

In the midst of the coronavirus pandemic, there has been a desire to continue to conduct ongoing clinical trials while maintaining social distancing as much as possible. Clinical trial participants have been hesitant to attend routine check-ups and monitoring due to the risk of exposure and health-care workers are stretched beyond their capacity treating COVID-19 patients. As a result of this, many clinical trials have been put on hold.

Since the coronavirus began to spread, Science 37, a company that supports virtual clinical trials conducted mostly online, began to receive hundreds of inquiries every week from pharmaceutical companies, medical centers, and individual investigators. These inquiries revolve around how best to transition to a virtual clinical trial structure, where consultations are performed online and paperwork and data are collected remotely as much as possible.

In an article published in the journal Nature, Jonathan Cotliar, chief medical officer of Science 37, discusses the impact that COVID-19 has had on the company.

“It’s exponentially accelerated the adoption curve of what we were already doing. That’s been a bit surreal.”

One example of a virtual clinical trial was conducted at the University of Minnesota in Minneapolis by Dr. David Boulware and his colleagues. They conducted a randomized, controlled, virtual trial of the malaria drug hydroxychloroquine to find out if it was effective at protecting people from COVID-19 (the results found that it was not). The trial included more than 800 participants and sent them medicine by FedEx delivery while monitoring their health via virtual appointments.

It is anticipated that even as the coronavirus pandemic and social distancing measures come to an end, virtual clinical trials will continue to be used in the future. Patient advocates have long pushed for these kinds of trials to ease the burden of clinical trial participation, which tends to be more challenging for underrepresented and underserved communities. As a result of the increase in virtual trials, the FDA has released guidelines for conducting virtual trials in order to streamline the process. It is possible that virtual trials might speed up enrollment of participants, which could help speed up the drug-development process while still maintaining rigorous standards.

Four Challenges to Making the Best Stem Cell Models for Brain Diseases

/ Karen Ring / Leave a comment

Neurological diseases are complicated. A single genetic mutation causes some, while multiple genetic and environmental factors cause others. Also, within a single neurological disease, patients can experience varying symptoms and degrees of disease severity.

And you can’t just open up the brain and poke around to see what’s causing the problem in living patients. It’s also hard to predict when someone is going to get sick until it’s already too late.

To combat these obstacles, scientists are creating clinically relevant human stem cells in the lab to capture the development of brain diseases and the differences in their severity. However, how to generate the best and most useful stem cell “models” of disease is a pressing question facing the field.

Current state of stem cell models for brain diseases

Cold Spring Harbor Lab, Hillside Campus, Location: Cold Spring Harbor, New York, Architect: Centerbrook Architects

Cold Spring Harbor Lab, Hillside Campus, Location: Cold Spring Harbor, New York, Architect: Centerbrook Architects

A group of expert stem cell scientists met earlier this year at Cold Spring Harbor in New York to discuss the current state and challenges facing the development of stem cell-based models for neurological diseases. The meeting highlighted case studies of recent advances in using patient-specific human induced pluripotent stem cells (iPS cells) to model a breadth of neurological and psychiatric diseases causes and patient symptoms aren’t fully represented in existing human cell models and mouse models.

The point of the meeting was to identify what stem cell models have been developed thus far, how successful or lacking they are, and what needs to be improved to generate models that truly mimic human brain diseases. For a full summary of what was discussed, you can read a Meeting Report about the conference in Stem Cell Reports.

What needs to be done

After reading the report, it was clear that scientists need to address four major issues before the field of patient-specific stem cell modeling for brain disorders can advance to therapeutic and clinical applications.

1. Define the different states of brain cells: The authors of the report emphasized that there needs to be a consensus on defining different cell states in the brain. For instance, in this blog we frequently refer to pluripotent stem cells and neural (brain) stem cells as a single type of cell. But in reality, both pluripotent and brain stem cells have different states, which are reflected by their ability to turn into different types of cells and activate a different set of genes. The question the authors raised was what starting cell types should be used to model specific brain disorders and how do we make them from iPS cells in a reproducible and efficient fashion?

2. Make stem cell models more complex: The second point was that iPS cell-based models need to get with the times. Just like how most action-packed or animated movies come in 3D IMAX, stem cell models also need to go 3D. The brain is comprised of an integrated network of neurons and glial support cells, and this complex environment can’t be replicated on the flat surface of a petri dish.

Advances in generating organoids (which are mini organs made from iPS cells that develop similar structures and cell types to the actual organ) look promising for modeling brain disease, but the authors admit that it’s far from a perfect science. Currently, organoids are most useful for modeling brain development and diseases like microencephaly, which occurs in infants and is caused by abnormal brain development before or after birth. For more complex neurological diseases, organoid technology hasn’t progressed to the point of providing consistent or accurate modeling.

The authors concluded:

“A next step for human iPS cell-based models of brain disorders will be building neural complexity in vitro, incorporating cell types and 3D organization to achieve network- and circuit-level structures. As the level of cellular complexity increases, new dimensions of modeling will emerge, and modeling neurological diseases that have a more complex etiology will be accessible.”

3. Address current issues in stem cell modeling: The third issue mentioned was that of human mosaicism. If you think that all the cells in your body have the same genetic blue print, then you’re wrong. The authors pointed out that as many as 30% of your skin cells have differences in their DNA structure or DNA sequences. Remember that iPS cell lines are derived from a single patient skin or other cell, so the problem is that studies might need to develop multiple iPS cell lines to truly model the disease.

Additionally, some brain diseases are caused by epigenetic factors, which modify the structure of your DNA rather than the genetic sequence itself. These changes can turn genes on and off, and they are unfortunately hard to reproduce accurately when reprogramming iPS cells from patient adult cells.

4. Improve stem cell models for drug discovery: Lastly, the authors addressed the use of iPS cell-based modeling for drug discovery. Currently, different strategies are being employed by academia and industry, both with their pros and cons.

Industry is pursuing high throughput screening of large drug libraries against known disease targets using industry standard stem cell lines. In contrast, academics are pursuing candidate drug screening on a much smaller scale but using more relevant, patient specific stem cell models.

The authors point out that, “a major goal in the still nascent human stem cell field is to utilize improved cell-based assays in the service of small-molecule therapeutics discovery and virtual early-phase clinical trials.”

While in the past, the paths that academia and industry have taken to reach this goal were different, the authors predict a convergence between the paths:

“Now, research strategies are converging, and both types of researchers are moving toward human iPS cell-based screening platforms, drifting toward a hybrid model… New collaborations between academic and pharma researchers promise a future of parallel screening for both targets and phenotypes.”

Conclusions and Looking to the Future

This meeting successfully described the current landscape of iPS cell-based disease modeling for brain disorders and laid out a roadmap for advancing these stem cell models to a stage where they are more effective for understanding the mechanisms behind disease and for therapeutic screening.

I agree with the authors conclusion that:

“Moving forward, a critical application of human iPS cell-based studies will be in providing a platform for defining the cellular, molecular, and genetic mechanisms of disease risk, which will be an essential first step toward target discovery.”

My favorite points in the report were about the need for more collaboration between academia and industry and also the push for reproducibility of these iPS cell models. Ultimately, the goal is to understand what causes neurological disease, and what drugs or stem cell therapies can be used to cure them. While iPS cell models for brain diseases still have a way to go before being more clinically relevant, they will surely play a prominent role in attaining this goal.

Meeting Attendees

Meeting Attendees

Bringing out the Big Guns: Scientists Weigh in on How Best to Combat Deadly Diseases of the Brain

/ cirmweb / Leave a comment

Despite our best efforts, diseases of the brain are on the rise. Neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases threaten not only to devastate our aging population, but also cripple our economy. Meanwhile, the causes of conditions such as autism remain largely unknown. And brain and spinal cord injuries continue to increase—leaving their victims with precious few options for improving their condition.

This special review issue of addresses some of the key challenges for translational neuroscience and the path from bench to beside. [Credit: Cell Press]

This special review issue of Neuron addresses some of the key challenges for translational neuroscience and the path from bench to beside. [Credit: Cell Press]

We need to do better.

The scientific community agrees. And in a special issue of the journal Neuron, the field’s leading researchers lay out how to accelerate much-needed therapies to the many millions who will be affected by brain disease or injury in the coming years.

The journal’s leadership argues that now is the time to renew efforts in this field. Especially worrying, say experts, is the difficulty in translating research breakthroughs into therapies.

But Neuron Editor Katja Brose is optimistic that the answers are out there—we just need to bring them to light:

“There is resounding agreement that we need new approaches and strategies, and there are active efforts, discussion and experimentation aimed at making the process of therapeutic development more efficient and effective.”

Below are three papers highlighted in the special journal, each giving an honest assessment of how far we’ve come, and what we need to do to take the next step.

Fast-tracking Drug Development. In this perspective, authors from the Institute of Medicine (IOM) and the Salk Institute—including CIRM grantee Fred Gage—discuss the main takeaways from an IOM-sponsored workshop aimed at finding new avenues for accelerating treatments for brain diseases to the clinic.

The main conclusion, according to the review’s lead author Steve Hyman, is a crucial cultural shift—various stakeholders in academia, government and industry must stop thinking of themselves as competitors, but instead as allies. Only then will the field be able to successfully shepherd a breakthrough from the lab bench and to the patient’s bedside.

Downsized Divisions’ Dangerous Effects. Next, an international team of neuroscientists focuses their perspective on the recent trend of pharmaceutical companies to cut back on funding for neuroscience research. The reasoning: neurological diseases are far more difficult than other conditions, and proving to be too costly and too time-consuming to be worth continued effort.

The solution, says author Dennis Choi of State University of New York Stonybrook, is a fundamental policy change in the way that market returns of neurological disease drug development are regulated. But Choi argues that such a shift cannot be achieved without a concerted effort by patient advocates and nonprofits to lead the charge. As he explains:

“The broader neuroscience community and patient stakeholders should advocate for the crafting and implementation of these policy changes. Scientific and patient group activism has been successful in keeping the development of therapies in other areas—such as HIV and cancer—appropriately on track, but this type of sector-wide activism would be a novel step for the neuroscience community.”

Indeed, here at CIRM we have long helped support the patient community—a wonderful collection of individuals and organizations advocating for advances in stem cell research. We are humbled and honored that so many patients and patient advocates have stepped forward as stem cell champions as we move towards the clinic.

The Road to Preclinical Diagnosis. Finally, we hear from Harvard University neuroscientists highlighting how far the research has come—even in the face of such extraordinary difficulty.

Specifically focused on Alzheimer’s disease, the authors touch on the discoveries of protein markers, such as amyloid-beta and tau, that serve as an indicator of neurodegeneration. They make the important point that because Alzheimer’s is almost certainly is present before the onset of physical symptoms, the ultimate goal of researchers should be to find a way to diagnose the disease before it has progressed too far.

“[Here we] highlight the remarkable advances in our ability to detect evidence of Alzheimer’s disease in the brain, prior to clinical symptoms of the disease, and to predict those at greatest risk for cognitive decline,” explained lead author Reisa Sperling.

The common thread between these perspectives, say Neuron editors in an accompanying editorial, is that “by leveraging shared resources, tools and knowledge and approaching these difficult problems collaboratively, we can achieve more together.”

A sentiment that we at CIRM fully support—and one that we will continue to foster as we push forward with our mission to accelerate stem cell-based therapies to patients in need.