Celularity and the Promise of Off-the Shelf Stem Cell Therapies
Today is Rare Disease Day, a time for reflecting on past success and taking stock of the challenge of finding effective treatments or cures for the nearly 10,000 rare diseases affecting 30 million individuals in the U.S. and 400 million people worldwide.
How can a strategy be developed for diagnosing and treating so many conditions? Who will do the research, who will provide the treatment, and who will pay for each cure or treatment?
Within the next 15 years, mass-producing genetically edited DNA and stem cells will be possible so that people suffering from rare disorders will have cures or treatments affordable as vaccines. The development of off-the-shelf stem cells to regenerate healthy tissue and stem-cell-derived Natural Killer (NK) cell therapy that harnesses the body's immune cells to fight disease provides a template for ramping up gene therapy as well as a source for treatments for many rare conditions that have long challenged the medical community.
Automating gene editing is not only possible but is becoming increasingly feasible with advancements in technology and bioinformatics. Automation in gene editing encompasses several aspects, from designing guide RNAs (gRNAs) for CRISPR-Cas systems to delivering gene-editing components into target cells and the subsequent screening and analysis of edited cells. Automation aims to increase efficiency, accuracy, and scalability while reducing human error and labor costs associated with manual processes.
Specifically, it will be possible to mass-produce gene editing tools. Ongoing improvements in production processes and regulatory advancements will play a critical role in making these powerful tools widely available for scientific and medical applications. The guide RNA, which directs the Cas9 enzyme to the specific site in the genome for editing, can be synthesized in large quantities using automated synthesizers. These RNA molecules can be custom-made to target virtually any genetic sequence.
The Cas9 protein can be produced in bacterial cultures, such as Escherichia coli, and is genetically engineered to express the Cas9 enzyme. Large quantities of Cas9 protein can be harvested through fermentation and purification processes. Finally, the components of this CRISPR-Cas9 system, including the gRNA and Cas9 protein, can be assembled into delivery vectors, such as plasmids or viral vectors. Bacterial or mammalian cell cultures can also produce these vectors in bulk.
An even greater opportunity awaits through the application of pluripotent stem cells. Such cells can be genetically edited to correct mutations in nuclear DNA that affect normal cell functions such as immune responses, tissue regeneration, and mitochondrial function. These cells can then be differentiated into the required cell types and transplanted back into the patient, potentially restoring normal function with reduced risk of immune rejection.
One company, in particular, is dedicated to mass-producing programmable pluripotent cells so that it and other companies and researchers can deploy them to target other conditions. Celularity is producing an array of pluripotent cells from placental stem cells in sufficient quantities and with such consistency that physicians and researchers can investigate and use them no differently than they use small molecules or biological agents.
Celularity has played an unsung but critical role in creating the capacity to mass-produce off-the-shelf therapies that combine genetic instructions and the immune environment necessary to address a wide range of rare diseases. Nearly 25 years ago, Dr Robert Hariri, Celularity’s CEO and founder, discovered that the placenta provides a continuous supply of nutrients and growth factors, maintaining an optimal milieu for the proliferation of pluripotent cells. The placental tissue, with its intricate network of blood vessels and specialized niches, serves as an ideal 'incubator' or bioreactor for generating cells that are inherently geared towards promoting tissue repair, angiogenesis, and immune modulation.
Celularity CEO Dr. Robert J. Hariri alongside part of the company’s stem cell ‘factory’
Celularity has isolated a unique regenerative function of natural killer (NK) cells in creating large-scale manufacturing capacity. Natural killer cells, a critical component of our immune system, have long been recognized for their ability to fight viruses and tumors. Yet, their role does not end there. The placenta – which forms first – envelopes the fetus and produces abundant NK cells. Hariri discovered that these NKs play a lifesaving function.
During embryogenesis (when an embryo develops from a fertilized egg), senescent cells play a whole host of functions, including tissue remodeling, tumor suppression, and immune regulation. The aging cells are cleared out of the embryo by a component of the innate immune system called the natural killer (NK) cell, which the placenta produces in abundance. These cells protect the developing fetus and newborn from various threats and work in the process of fetogenesis to “prune” cells targeted to be eliminated by expressing molecules called stress ligands.
It turns out that these molecules are found in cancer cells, virally infected cells, and aging or ‘senescent’ cells. This process of cellular pruning is essential for two reasons: senescent cells release inflammatory mediators that cause many problems, and these senescent, sometimes called zombie cells, take up space and interfere with the necessary regenerative replacement process by healthy stem cells. NK cells engage in what Hariri calls ‘senoablation,’ a process of pruning bad cells to make room for new healthy cells. For two reasons, NK senoablation is critical to successful fertilization and fetal development: senescent cells release inflammatory mediators that cause many problems. Second, senescent cells take up space and interfere with the necessary regenerative replacement process by healthy stem cells that can differentiate. So, in a nutshell, placental stem cells can give rise to important NK cells and the essential regenerative cells that fill in after the NK’s clean up!
NK cells can potentially reverse hundreds of rare cancers and immune dysfunctions. Cancer cells hijack the energy metabolism and nutrient utilization that would otherwise go to cellular regeneration. By removing senescent cells, NK cells can help stop tumors from growing and spreading. This process is known as senoablation. Essentially, NK cells help keep the tumor environment less favorable for cancer growth and prevent the cancer from evading the immune system.
In diseases characterized by specific deficiencies in the immune response (e.g., SCID or Hyper IgM Syndromes), NK cell therapy could potentially provide a temporary bolster to the immune system. For instance, in conditions where T-cell function is compromised, NK cells might help bridge the gap in immune surveillance against infections and malignancies.
NK cells have regulatory functions that can modulate the immune response. In autoimmune conditions, where the immune system mistakenly attacks the body's cells, NK cells could theoretically be engineered or modulated to suppress autoreactive immune cells, reducing inflammation and autoimmunity.
Many rare immune disorders stand to benefit from the NK approach.
Severe Combined Immunodeficiency (SCID) and Wiskott-Aldrich Syndrome are conditions where the immune system is severely compromised. Correcting the underlying genetic defects and providing enhanced NK cells can restore immune function and protect against infections.
Chronic Granulomatous Disease (CGD) involves a defect in the immune system's ability to kill bacteria and fungi. Correcting this defect and employing NK cells could significantly reduce infections in affected individuals.
A mutation in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) leads to the immune system attacking the body's tissues. Correcting this mutation and modulating the immune response with NK cells could alleviate autoimmune symptoms and combat candidiasis.
In Chronic Granulomatous Disease (CGD) or DiGeorge Syndrome, where patients are at increased risk of infections due to specific immune defects, NK cell therapy could enhance the body's ability to fight off infectious agents. NK cells' natural ability to target infected or abnormal cells makes them a potential adjunctive therapy to reduce the frequency or severity of infections.
While the promise is immense, the rate-limiting factor is the adequate supply of gene therapy vectors, pluripotent stem cells, and NK cells to support the expansion of clinical development.
The ability to mass produce gene editing tools in the same way Celularity is scaling up the manufacturing of stem cell and NK cell therapies will lead to a revolution in the treatment of rare diseases. The promise of transforming treatment paradigms can be realized by allowing everyone with rare conditions access to treatments. Innovation, ultimately, is an invention available to all.