Disease Team Research I
Amyotrophic lateral sclerosis (ALS), a lethal disease lacking effective treatments, is characterized by the loss of upper and lower motor neurons. 5-10% of ALS is familial, but the majority of ALS cases are sporadic with unknown causes. The lifetime risk is approximately 1 in 2000. This corresponds to ~30,000 affected individuals in the United States and ~5000 in the Collaborative Funding Partner country. There is currently only one FDA-approved compound, Rilutek, that extends lifespan by a maximum of three months. Although the causes of ALS are unknown and the presentation of the disease highly variable, common to all forms of ALS is the significant loss of motor neurons leading to muscle weakness, paralysis, respiratory failure and ultimately death. It is likely that many pathways are affected in the disease and focusing on a single pathway may have limited impact on survival. In addition, as ALS is diagnosed at a time that significant cell loss has occurred, an attempt to spare further cell loss would have significant impact on survival. Several findings support the approach of glial (cells surrounding the motor neurons) transplants. Despite the relative selectivity of motor neuron cell death in ALS, published studies demonstrate that glial transporters critical for the appropriate balance of glutamate surrounding the motor neurons are affected both in animal models and in tissue from sporadic and familial ALS. The significance of non-neuronal cells in the disease process has been well characterized using SOD1 mouse models representing many of the key aspects of the human disease. In addition, transplantation using glial-restricted precursors (GRPs) that differentiate into astrocytes in SOD1 mutant rats has been shown to increase survival. Motor neurons have a process, the axon, up to a meter in length which connects the cell body to its target, the muscle. The ability to appropriately rewire and ensure functional connections after motor neuron replacement remains a daunting task with no evidence to date that this will be possible in humans. Therefore, we will focus on the development of an ALS therapy based on hES-derived astrocyte precursor cell transplants to prevent the progression of ALS. Our proposed project will develop clinical grade stem-cell derived astrocyte precursor transplants for therapy in a prospective Phase I clinical trial. We will: 1) generate astrocyte precursors from three different sources of human embryonic stem cell (hESC) lines; 2) identify the hESC line and glial progenitor combination that has the best characteristics of minimal toxicity, best efficiency in generating astrocytes, and reducing disease phenotypes in vivo in a rat model of ALS; 3) manufacture the appropriate cells in a GMP facility required by the FDA; 4) work with our established clinical team to design a Phase I safety trial; and 5) submit an application for an invesitgational new drug (IND) within the next four years.
Statement of Benefit to California:
Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's Disease) is a common and devastating adult motor neuron disease that afflicts many Californians. In the absence of a cure, or an effective treatment, the cost of caring for patients with ALS is substantial, and the consequences on friends and family members similarly takes a devastating toll. Our goal is to develop a safe and effective cell transplant therapy for ALS by starting with human embryonic stem cells. If successful, this advance will hopefully diminish the cost of caring for the many Californians with ALS, extend their useful lives, and improve their quality of life. In addition, the development of this type of therapeutic approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies in California with consequent economic benefit.
The goal of this proposal is to develop a novel cellular therapy for amyotrophic lateral sclerosis (ALS), a disease characterized by motor neuron degeneration. The proposed therapeutic candidate is human astrocyte precursors (hAPs) derived from human embryonic stem cells (hESCs). The applicant’s hypothesis is that transplanted hAPs will mature into astrocytes in vivo and provide support for diseased spinal motor neurons. Astrocytes are capable of clearing excess neurotoxic glutamate and could thereby slow or halt the progression of ALS by preventing motor neuron degeneration. To test this hypothesis, the applicant proposes to first compare six hESC lines to determine which are most suitable for hAP differentiation and scale up. These candidate hAP lines will then be tested in vivo for differentiation into mature astrocytes, potential tumorigenicity, and efficacy in a rat model of ALS. Finally, the applicant plans to test a cell delivery device in a relevant model, generate a GMP master cell bank and confirm safety and efficacy of hAPs from this bank before submitting an Investigational New Drug (IND) filing with the FDA. The reviewers were enthusiastic about this proposal and its potential impact for patients. They found the scientific rationale compelling and praised the carefully detailed research plan. Reviewers described the proposal as ambitious but feasible and were impressed by the world-class research team. Reviewers agreed that there is a strong rationale for pursuing a cell therapy for ALS and specifically for choosing hAPs as the therapeutic candidate. They cited increasingly strong evidence that motor neuron degeneration in ALS is mediated by astrocytes and that healthy astrocytes can be neuroprotective. They agreed that human stem cells are the only obvious source of hAPs. One reviewer felt that the relatively slow progression of ALS could be an advantage as it affords time for intervention and rescue of some neurons. Reviewers did note that the preclinical work would be performed in a model of the genetic form of ALS (an SOD1 mutant) that may not accurately predict outcomes in sporadic ALS patients, which make up approximately 90% of cases. However, they pointed out that astrocytes are known play a role in sporadic as well as genetic ALS, and that the mutant SOD1 rodent model(s) of genetic ALS is the best preclinical model available. One reviewer questioned the rationale for focal delivery of hAPs into the spinal cord and wondered whether this is the best approach given that the disease affects the whole spinal cord. This reviewer cautioned that the benefits of focal delivery might be restricted to one limb or muscle group. The reviewers found the proposal to be highly significant. ALS is a devastating neurodegenerative disease with no effective therapy. Thus any novel treatment option would be clinically competitive and could have a major impact for patients. Reviewers believed that the proposed strategy is unlikely to cure ALS but has the potential to significantly extend lifespan and improve patient quality of life. Reviewers noted that if successful, this proposal may provide proof-of-principle for cell therapies for other motor neuron diseases such as spinal muscular atrophy and spinal cord injury. Reviewers generally acknowledged the quality of the preliminary data and agreed that it supports the feasibility of the proposal. The applicant has hESC lines and differentiation protocols in place compatible with scalable GMP production of sufficient numbers of hAPs, has delivered human cells into an ALS model and shown engraftment and functional improvement. The applicant has also shown engraftment of human cells in a large animal model and survival of hESC-derived hAPs in a rat model of ALS. Reviewers noted that specific evidence for disease-modifying activity of hAPs comes from the published literature but appreciated that demonstration of this disease-modifying activity with the applicant’s proposed therapeutic candidate is a key go/no-go decision point. The reviewers found the proposal’s timeline and milestones to be ambitious but possible. They praised the well-written and carefully designed research plan. Reviewers appreciated the attention paid to key regulatory issues such as cell characterization, tumorigenicity testing, GMP manufacturing, and toxicology testing. One reviewer expressed concern that the markers proposed by the applicant for identifying and validating hESC-derived hAPs may not be adequate to define the relevant cell population. This reviewer recommended the use of functional markers, such as the glutamate transporter, for assessment of hAPs. Reviewers noted that manufacturing details are not described in great detail but appear sufficiently well established to enable the transition to GMP production. One reviewer cautioned that the applicant would have to complete development of candidate hAP lines early in the course of the research program in order to file an IND within four years. This reviewer appreciated that the applicant has an agreement in place to use a GMP-grade hESC line to accelerate the process if necessary. Another reviewer would have liked more clinical trial detail, specifically a discussion of patient eligibility criteria. Reviewers found the research team to be a major strength of the proposal. The team brings together world-class experts in hESC biology, motor neuron biology and relevant preclinical animal models. The co-PIs have published much of the critical work suggesting that astrocytes are central to ALS pathology. The Partner PI has derived a number of hESC lines and has extensive neurobiology and ALS experience. The research team includes a project manager, although one reviewer would have preferred an individual in this position with drug development experience. Reviewers noted that the roles of team members are clearly described and the leadership plan is well organized. Collaborations with biotechnology companies will facilitate GMP manufacturing and well-qualified consultants will provide both regulatory and clinical expertise. Reviewers appreciated that the application reflects thoughtful planning for interaction with the FDA. They found the collaborations, resources and environment to be outstanding and the budget appropriate for the proposed studies. Overall, reviewers were impressed by this proposal’s scientific rationale and its outstanding assembled research team. They noted the ambitious timeline and milestones but praised the well thought out and detailed research plan. Ultimately, the reviewers were confident that this team could achieve an IND filing within four years for a devastating disease sorely in need of a therapy.
- Jonathan Glass
- Joy Cavagnaro
- Darin Weber
- Andrew Balber