Early Translational II
Traumatic brain injury (TBI) affects 1.4 million Americans a year; 175,000 in California. When the brain is injured, nerve cells near the site of injury die due to the initial trauma and interruption of blood flow. Secondary damage occurs as neighboring tissue is injured by the inflammatory response to the initial injury, leading to a larger area of damage. This damage happens to both neurons, the electrically active cells, and oligodendrocytes, the cell which makes the myelin insulation. A TBI patient typically loses cognitive function in one or more domains associated with the damage (e.g. attention deficits with frontal damage, or learning and memory deficits associated with temporal lobe/hippocampal damage); post-traumatic seizures are also common. Currently, no treatments have been shown to be beneficial in alleviating the cognitive problems following even a mild TBI. Neural stem cells (NSCs) provide a cell population that is promising as a therapeutic for neurotrauma. One idea is that transplanting NSCs into an injury would provide “cell replacement”; the stem cells would differentiate into new neurons and new oligodendrocytes and fill in for lost host cells. We have successfully used “sorted“ human NSCs in rodent models of spinal cord injury, showing that hNSCs migrate, proliferate, differentiate into oligodendrocytes and neurons, integrate with the host, and restore locomotor function. Killing the NSCs abolishes functional improvements, showing that integration of hNSCs mediates recovery. Two Phase I FDA trials support the potential of using sorted hNSC for brain therapy and were partially supported by studies in my lab. NSCs may also improve outcome by helping the host tissue repair itself, or by providing trophic support for newly born neurons following injury. Recently, transplantation of rodent-derived NSCs into a model of TBI showed limited, but significant improvements in some outcome measures. These results argue for the need to develop human-derived NSCs that can be used for TBI. We will establish and characterize multiple “sorted” and “non-sorted“ human NSC lines starting from 3 human ES lines. We will determine their neural potential in cell culture, and use the best 2 lines in an animal model of TBI, measuring learning, memory and seizure activity following TBI; then correlating these outcomes to tissue modifying effects. Ultimately, the proposed work may generate one or more human NSC lines suitable to use for TBI and/or other CNS injuries or disorders. A small reduction in the size of the injury or restoration of just some nerve fibers to their targets beyond the injury could have significant implications for a patient’s quality of life and considerable economic impact to the people of California. If successful over the 3-year grant, additional funding of this approach may enable a clinical trial within the next five years given success in the Phase I FDA approved trials of sorted hNSCs for other nervous system disorders.
Statement of Benefit to California:
The Centers for Disease Control and Prevention estimate that traumatic brain injury (TBI) affects 1.4 million Americans every year. This equates to ~175,000 Californian’s suffering a TBI each year. Additionally, at least 5.3 million Americans currently have a long-term or a lifelong need for help to perform activities of daily living as a result of suffering a TBI previously. Forty percent of patients who are hospitalized with a TBI had at least one unmet need for services one year after their injury. One example is a need to improve their memory and problem solving skills. TBI can also cause epilepsy and increases the risk for conditions such as Alzheimer's disease, Parkinson's disease, and other brain disorders that become more prevalent with age. The combined direct medical costs and indirect costs such as lost productivity due to TBI totaled an estimated $60 billion in the United States in 2000 (when the most recent data was available). This translates to ~$7.5 billion in costs each year just to Californians. The proposed research seeks to generate several human neural-restricted stem cell lines from ES cells. These “sorted” neural-restricted stem cell lines should have greatly reduced or no tumor forming capability, making them ideally suited for clinical use. After verifying that these lines are multipotent (e.g. they can make neurons, astrocytes and oligodendrocytes), we will test their efficacy to improve outcomes in TBI on a number of measures, including learning and memory, seizure activity, tissue sparing, preservation of host neurons, and improvements in white matter pathology. Of benefit to California is that these same outcome measures in a rodent model of TBI can also be assessed in humans with TBI, potentially speeding the translational from laboratory to clinical application. A small reduction in the size of the injury, or restoration of just some nerve fibers to their targets beyond the injury, or moderate improvement in learning and memory post-TBI, or a reduction in the number or severity of seizures could have significant implications for a patient’s quality of life and considerable economic impact to the people of California. Additionally, the cell lines we have chosen to work with are unencumbered with IP issues that would prevent us, or others, from using these cell lines to test in other central nervous system disorders. Two of the cell lines have already been manufactured to “GMP” standards, which would speed up the translation of this work from the laboratory to the clinic. Finally, if successful, these lines would be potentially useful for treating a variety of central nervous system disorders in addition to TBI, including Alzheimer’s disease, Parkinson’s disease, stroke, autism, spinal cord injury, and/or multiple sclerosis.
This Development Candidate Feasibility award application seeks to develop an allogeneic, FACS purified, human embryonic stem cell (hESC)-derived neural stem cells (hNSC) therapy for traumatic brain injury (TBI). The applicants plan to select the most promising starting hESC source for hNSC generation based upon the fates of its NSC derivatives and it’s in vitro myelination potential. hNSC from the most promising line will then be tested in a model of TBI for their ability to promote behavioral recovery, reduce seizures and improve brain tissue by histological measures. Reviewers unanimously agreed that TBI presents a major, life altering unmet medical need with few treatment options. In recent years, the urgent need for effective treatments has amplified due to the increased incidence of TBI in young soldiers. Even a partial recovery, such as a reduction in seizures, could greatly improve quality of life. TBI damages neural circuits and demyelinates axons, causing secondary functional decline and neuronal loss. Reviewers agreed the need for re-myelination is critical. The panel also noted that both the complexity of TBI and the fact that it is so understudied make it difficult to predict what might constitute the best regenerative therapy. hNSC could positively impact the injury by multiple mechanisms including neuroprotection, increased host neurogenesis and re-myelination. Therefore, they ultimately agreed that the proposed program represented a very strong development candidate feasibility study. Overall, reviewers were impressed with the proposal and felt its detailed timeline and go/ no go decision points demonstrated a high level of consideration. They appreciated the selection of GMP compatible hESC and multiple relevant neurological functional tests and neuroanatomical readouts that should facilitate rapid translation to human studies. The established method for purifying hNSC further strengthened the proposal. The panel also noted that the PI’s background in spinal cord injury (SCI), which shares some pathobiology with TBI, together with the inclusion of a TBI expert on the team should enable transition to TBI work. The groups’ experience with required techniques bolstered confidence that the studies could be successfully completed. Reviewers were hesitant however, regarding the re-myelinating ability of hNSC. They noted that this remains under debate in the field, and they found this aspect of the preliminary data unconvincing. Reviewers also cautioned that the presented in vitro myelination assay may not predict in vivo re-myelination competence. However, in discussion, the panel re-iterated the multiple potential mechanisms by which hNSC could positively impact TBI and agreed that the in vivo work should be performed. Given the diffuse nature of the injury, they suggested that a rigorous evaluation of multiple cell administration sites would strengthen the proposal. Despite these minor concerns, reviewers were enthusiastic that the proposed work should be conducted. The PI and team have the appropriate experience to successfully complete the proposed studies. Reviewers lauded the 10% effort of a TBI expert to the team, and they noted that individual’s contribution is critical to the success of this proposal. The applicants will meet weekly via videoconferencing. In addition, the PI and co-Investigator have an established collaboration, have published extensively in the hNSC field and have contributed to relevant approved INDs. Institutional support, environment, facilities as well as access to the required equipment and reagents are excellent. In summary, this is a proposal to test feasibility of hNSC transplantation as a TBI therapy. Strengths of the proposal include its focus on the urgent unmet medical need presented by this understudied injury, the likelihood that NSC may benefit the condition and the team’s extensive experience, all of which raised the enthusiasm to recommend this proposal for funding.