“I can’t control my body”
The importance of studying rare movement disorders in understanding the larger role of cell therapy in the neurological health landscape
Early this year, Hope Biosciences Research Foundation (HBRF) received Food and Drug Administration (FDA) authorization to administer a year-long course of adult cell therapy treatment to a single patient living with ataxia. The protocol marks HBRF’s sixth single-patient study in a rare neurological condition, and follows work in cerebral palsy with severe complications, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), congenital muscular dystrophy, and drug-resistant epilepsy. HBRF also conducts larger, Phase II studies in central nervous system disorders such as Parkinson’s Disease and multiple sclerosis. The Parkinson’s research suite in particular, is one of the most diverse and comprehensive cell therapy research undertakings in this condition, in the world.
Why, then, continue to study individuals with rare conditions? What is the value of allocating precious resources to single-patient protocols, in the quest for better understanding the total neurological health landscape and where mesenchymal cell therapy fits into prevention and treatment of degenerative neurological disease?
About ataxia
The protocol that sparks this conversation is in ataxia, a rare neurodegenerative disease that damages the cerebellum and impairs movement coordination, among other symptoms. Ataxia afflicts sufferers of any age, varies in rate of progression, and can cause life-threatening complications and early death. Ataxia is classified by the underlying cause. Primary classifications include cerebellar ataxia, arising from damage to the cerebellum and impacting coordination of movement; sensory ataxia, caused by damage to the sensory nerves and impairing ability to sense the body’s position in space; and vestibular ataxia, related to problems with the inner ear and balance. According to the National Ataxia Foundation, nearly 20,000 people in the United States (U.S.) suffer from spinocerebellar ataxia. The Foundation estimates tens of thousands more are affected by recessive, sporadic, and yet-unknown forms. Causes may be genetic, acquired, or unknown. Progressive genetic disorders; brain injuries, strokes, multiple sclerosis, tumors; infections that impact the brain, such as chickenpox or meningitis; and environmental factors such as exposure to toxins or prolonged alcohol abuse, may all contribute to development of ataxia.
The lived experience of ataxia is one of, in a word, literal instability. This patient, a 75-year-old male, began exhibiting ataxic symptoms like dysarthria, gait disturbance, and a lack of balance in 2010, coinciding with his recovery from multiple shoulder surgeries. Though he has no previous history of neurological disease, he struggled with steps during physical therapy after a right shoulder operation. In 2012, a fall in his driveway led to significant injuries, including a broken nose, cracked teeth, and a possible concussion with a scalp laceration requiring sutures. Despite undergoing an array of comprehensive diagnostic tests, the cause for his symptoms remained unknown. In recent years, the patient has experienced a marked increase in symptoms, including emergent speech difficulty and repeated falls, one resulting in a fractured left leg. Again, test remain inconclusive, though doctors concur that this man’s experience is not one of age-related health decline.
There are currently no effective FDA-approved therapeutics for ataxia. Treatment often centers on addressing the underlying cause, if known, and controlling symptoms to maintain or improve quality of life, often including measures such as physical and occupational therapy. People living with ataxia often require progressively supportive mobility aids, such as walkers or wheelchairs; living adaptations such as moves to homes without stairs, handrails, and similar measures; and emotional and psychological support to combat depression and social isolation.
About mesenchymal stem cell therapy in neurological conditions
Cell therapy is a form of regenerative medicine whose unique multi-faceted capabilities make it uniquely promising in treating complex conditions like ataxia. “Regenerative medicine” refers to scientific efforts to restore diseased or injured tissues or organs, supporting the body in its natural processes whenever and to the greatest extent possible, rather than implanting devices or engineered parts that may require years of stringent pharmaceutical support before ultimately failing.[1] [2] “Cell therapy” specifically denotes the practice of transferring cellular material into a person for medical purposes.[3]
Stem cells are an unspecialized type of cell that can transform into a variety of specialized cell types in the body. For example, a stem cell might be capable of becoming a liver cell, brain cell, heart cell, and so on, if exposed to the necessary stimuli and conditions. Stem cells also have potential to divide for an indefinite period, which means they can make many copies of both themselves and differentiated cells. Stem cells “work” by realizing their potential and becoming other cell types when, where, and as needed by the body, making them particularly promising in complex conditions that affect multiple bodily symptoms, like many central nervous system conditions, and in conditions with undetermined underlying cause, such as in this ataxia protocol.
To date, HBRF has conducted and currently runs FDA-authorized studies using mesenchymal stem cells (MSCs),[4] a cell type with particular promise in resolving central nervous system disease. MSCs are multipotent adult stem cells[5] capable of making many other types of tissue cells and contributing to physiological processes in myriad ways. MSCs can differentiate into various local cell types at injured sites, secrete growth factors that help in tissue regeneration, produce new secretory pathways at a cellular level, and effectively communicate with stressed or injured somatic cells to transfer their cytoplasmic elements and organelles.[6] MSCs are also capable of penetrating the blood brain barrier,[7] and are increasingly explored as a vehicle for gene therapy.[8]
Several studies have revealed that in addition to their ability to differentiate into different cell types, MSCs may also exert therapeutic effects through cell “enhancement,” which generally means the production and release of trophic and anti-inflammatory factors whose therapeutic effects may help to restore the body’s natural physiological environment. Furthermore, MSCs have a function in the modulation of the inflammatory and immunological responses in the body. MSC research has been conducted for at least 50 years, and MSC therapy has an established and accepted safety profile.
Introduction of stem cells can also stimulate continued regeneration. MSCs have a documented homing ability; that is, they migrate to injured tissues in areas the body tells the stem cells are in need, whether that need is apparent on anything larger than a cellular level yet or not. Tactically, this homing ability means that MSC therapy can introduce cells into the body through intravenous infusion, a minimally invasive process and one ideally accessible to medically fragile patients, such as those with ataxia. The cells can be trusted, if we want to think of it that way, to end up where and as most needed, whether that need is visible to external physicians and researchers or not.[9]
About the protocol
HBRF’s work will establish safety of the investigational product, adipose-derived mesenchymal stem cells cultured by Hope Biosciences (HB-adMSCs), in unspecified ataxia. Hope Biosciences utilizes proprietary technology to culture MSCs to unprecedented volume and viability, meaning that work with their cell line allows HBRF to explore what happens when extremely large numbers (in this case, 2.4 billion!) of cells are administered over a sustained period of time. This capacity is unprecedented in cell therapy research.
A secondary objective is to explore effects of the therapeutic on an ataxia patient’s quality of life, which may include improvement in common symptoms such as lack of coordination, slurred speech, trouble eating and swallowing, deterioration of fine motor skills, difficulty walking, gait abnormalities, eye movement abnormalities, tremors, and heart problems, and reduced dependency on mobility aids such as wheelchairs, walkers, or scooters. HBRF’s protocol dictates 12 intravenous infusions of 200 million cells each over a 38-week period, with end of study at 52 weeks. HBRF intends to pursue peer-reviewed publication of results, as the organization does with all clinical research.
Impact
Again, the question emerges — why study ataxia in a single patient? Why put 2.4 billion stem cells to work here, instead of somewhere else, or at all?
HBRF believes in the value of this protocol for two primary reasons:
Advancing research through extension to underserved populations. The clinical research landscape can be more homogenous than is ideal for productive findings. To consider a single logistical facet, participation in clinical research in any condition often requires an ability to reach the research site, which means participants are clustered in urban areas. Though HBRF extends treatment to research participants at no cost, both to protect integrity of the data and broaden the pool of potential participants, our stance is unique. Participation in clinical research often comes with a price tag for treatment, in turn limiting the participant pool to individuals with disposable income. Because current FDA policies require examination of a single disease or injury condition, young participants are overwhelmingly preferred, as they are less likely to present with age-related degenerative conditions that can complicate or skew results.
The gentleman in this ataxia study is in his 70s, and would be ineligible for participation in clinical research anywhere else. HBRF believes in the importance of studying disease conditions in older adults and has an established commitment to include older populations in clinical research. Last year, for example, HBRF successfully concluded a 10-patient Expanded Access protocol in Parkinson’s Disease for patients older than 76 years, the first work of its kind in cell therapy in the world. This ataxia protocol continues and upholds HBRF’s commitment to underserved populations and demonstrated community needs.
Potential for extrapolation of results to other conditions. In addition to the strategic and philosophical importance, there is real scientific benefit to conducting single-patient research in rare conditions because study of rare diseases can inform protocol design for larger studies that include a far greater number of participants. Some more prolific diseases HBRF studies in larger clinical trials can cause ataxia themselves, reinforcing the idea that the diseases that plague us may be more closely related than we know.
Cell therapy is uniquely capable of approaching disease and injury in a wholistic manner, potentially rectifying not only illness seen from the outside, but internal dis-ease not yet apparent to an external eye. It is also well-established that mesenchymal stem cells, the type utilized for this ataxia protocol, home to the area of greatest need in the body. It is common in studies executed to date, for example, for Parkinson’s patients at HBRF to not only experience improved quality of life but marked improvement in measurable heart health. One patient, aged nearly 90 years, obtained a clean EKG for the first time in decades after a series of cell therapy treatments for Parkinson’s Disease. Though FDA mandates designation of a single symptom as the focus of study, symptomology is often expansive and intricately interconnected. Single-patient rare disease work allows organizations like HBRF to look with increasing refinement at what we study, why, and perhaps most nuanced, how, to capture these ripple effects in increasingly sharp detail.
Bottom line: HBRF is comprised of passionate people on a mission to deliver promising biotechnologies to real people, with real needs, right here in the United States. We envision a revolution in the way America treats and prevents disease and injury. We only get there by upholding our foundational value — “patients first,” everything else follows. By all markers important to us, treatment should be extended to this patient. Studying him will advance science and technology. We believe we should treat him. We can treat him. So, we will. So, we are.
More to come, with hope…
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Founded in 2020 and headquartered in Sugar Land, Texas (west of Houston), in its fourth year of operation HBRF remains the only entity in the world exploring the effects of high volume, sustained application of adult stem cells on diseases and conditions that currently have no cure and affect substantial portions of the American population. In addition to the ataxia protocol, HBRF has conducted and is pursuing work in central nervous system conditions such as Parkinson’s Disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), cerebral palsy, spinal cord injury, polyneuropathy, muscular dystrophy, and drug-resistant epilepsy. To date HBRF has obtained FDA authorization for more than 35 clinical protocols in these and other conditions, including clinical trials in COVID-19 and “Long Haul” COVID and expanded access protocol authorizations in lupus, chronic musculoskeletal pain, severe osteoarthritis, psoriatic arthritis, stroke, palliative care, and pancreatic cancer. Learn more at hopebio.org.
[1] See Chris Mason and Peter Dunnill’s opinion editorial “A Brief Definition of Regenerative Medicine” in Regenerative Medicine, 2008 (3)1, 1–5.
[2] Mao AS, Mooney DJ. Regenerative medicine: Current therapies and future directions. Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):14452–9. doi: 10.1073/pnas.1508520112. PMID: 26598661; PMCID: PMC4664309.
[3] El-Kadiry AE, Rafei M, Shammaa R. Cell Therapy: Types, Regulation, and Clinical Benefits. Front Med (Lausanne). 2021 Nov 22;8:756029. doi: 10.3389/fmed.2021.756029. PMID: 34881261; PMCID: PMC8645794.
[4] Debate continues over which words best describe MSCs, whose functions mechanistic researchers continue to learn about. Common monikers include “Mesenchymal Stem Cell,” “Mesenchymal Stromal Cell,” and “Medicinal Signaling Cell.” HBSCRF holds “mesenchymal stem cells” to be defensible and accurate.
[5] Academic debate persists surrounding the technical status of MSCs as “pluripotent” or “multipotent.” As of this writing, academia tends to use “multipotent,” while semi-popular and popular writing trends toward use of “pluripotent.” We will use the term “multipotent” for this conversation, though arguing the terminology is not of great concern for this conversation — the capabilities of the stem cells remain as they are, no matter how we categorize them at this juncture in scientific discovery.
[6] N. Attia, et al., “Mesenchymal Stem Cells as a Gene Delivery Tool: Promise, Problems, and Prospects,” Pharmaceutics 13, no.6 (2021): 843. https://doi.org/10.3390/pharmaceutics13060843
[7] A. Weiss & M.H. Dahlke, “Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs,” Frontiers in immunology 10 (2019): 1191. https://doi.org/10.3389/fimmu.2019.01191
[8] Attia, “Mesenchymal Stem Cells,” 843.
[9] S. Kim, et al., “The Preventive Therapeutic Effects of Intravenous Human Adipose-Derived Stem Cells in Alzheimer’s Disease Mice,” (2012). https://doi.org/10.1371/journal.pone.0045757
