Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the US, someone develops AD every 69 seconds and there are over 5 million individuals suffering from AD, including approximately 600,000 Californians. Current treatments do not alter the disease course. The absence of effective therapies coupled with the sheer number of affected patients renders AD a medical disorder of unprecedented need and a public health concern of significant magnitude. In 2010, the global economic impact of dementias was estimated at $604 billion, a figure far beyond the costs of cancer or heart disease. These numbers do not reflect the devastating social and emotional tolls that AD inflicts upon patients and their families. Efforts to discover novel and effective treatments for AD are ongoing, but unfortunately, the number of active clinical studies is low and many traditional approaches have failed in clinical testing. An urgent need to develop novel and innovative approaches to treat AD is clear.
We propose to evaluate the use of human neural stem cells as a potential innovative therapy for AD. AD results in neuronal death and loss of connections between surviving neurons. The hippocampus, the part of the brain responsible for learning and memory, is particularly affected in AD, and is thought to underlie the memory problems AD patients encounter. Evidence from animal studies shows that transplanting human neural stem cells into the hippocampus improves memory, possibly by providing growth factors that protect neurons from degeneration. Translating this approach to humans could markedly restore memory and thus, quality of life for patients.
The Disease Team has successfully initiated three clinical trials involving transplantation of human neural stem cells for neurological disorders. These trials have established that the cells proposed for this therapeutic approach are safe for transplantation into humans. The researchers in this Disease Team have shown that AD mice show a dramatic improvement in memory skills following both murine and human stem cell transplantation. With proof-of-concept established in these studies, the Disease Team intends to conduct the animal studies necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients.
This project will be conducted as a partnership between a biotechnology company with unique experience in clinical trials involving neural stem cell transplantation and a leading California-based academic laboratory specializing in AD research. The Disease Team also includes expert clinicians and scientists throughout California that will help guide the research project to clinical trials. The combination of all these resources will accelerate the research, and lead to a successful FDA submission to permit human testing of a novel approach for the treatment of AD; one that could enhance memory and save lives.
The number of AD patients in the US has surpassed 5.4 million, and the incidence may triple by 2050. Roughly 1 out of every 10 patients with AD, over 550,000, is a California resident, and alarmingly, because of the large number of baby-boomers that reside in this state, the incidence is expected to more than double by 2025. Besides the personal impact of the diagnosis on the patient, the rising incidence of disease, both in the US and California, imperils the federal and state economy.
The dementia induced by AD disconnects patients from their loved ones and communities by eroding memory and cognitive function. Patients gradually lose their ability to drive, work, cook, and carry out simple, everyday tasks, ultimately losing all independence. The quality of life for AD patients is hugely diminished and the burden on their families and caregivers is extremely costly to the state of California. Annual health care costs are estimated to exceed $172 billion, not including the additional costs resulting from the loss of income and physical and emotional stress experienced by caregivers of Alzheimer's patients. Given that California is the most populous state and the state with the highest number of baby-boomers, AD’s impact on California families and state finances is proportionally high and will only increase as the AD prevalence rises.
Currently, there is no cure for AD and no means of prevention. Most approved therapies address only symptomatic aspects of AD and no disease-modifying approaches are currently available. By enacting Proposition 71, California voters acknowledged and supported the need to investigate the potential of novel stem cell-based therapies to treat diseases with a significant unmet medical need such as AD.
In a disease like AD, any therapy that exerts even a modest impact on the patient's ability to carry out daily activities will have an exponential positive effect not only for the patients but also for their families, caregivers, and the entire health care system. We propose to evaluate the hypothesis that neural stem cell transplantation will delay the progression of AD by slowing or stabilizing loss of memory and related cognitive skills. A single, one-time intervention may be sufficient to delay progression of neuronal degeneration and preserve functional levels of memory and cognition; an approach that offers considerable cost-efficiency.
The potential economic impact of this type of therapeutic research in California could be significant, and well worth the investment of this disease team proposal. Such an approach would not only reduce the high cost of care and improve the quality of life for patients, it would also make California an international leader in a pioneering approach to AD, yielding significant downstream economic benefits for the state.
The goal of this proposal is to develop human neural stem cells (hNSCs) as a potential therapy for Alzheimer’s disease (AD). Although Alzheimer’s disease affects over 5 million individuals in the US and is the sixth leading cause of death, the few therapies available are only palliative and do not alter the disease course. The rationale behind the proposed therapy is that hNSCs transplanted into the hippocampus will express proteins that promote survival of host neurons, thereby slowing or preventing loss of memory and cognitive functions. The applicant proposes to conduct clinical grade manufacturing of hNSC and to complete preclinical safety and efficacy studies, culminating in the filing of an Investigational New Drug (IND) application for initiation of a Phase I human clinical trial in AD patients.
Significance and Impact
- The reviewers agreed there is a significant unmet medical need for more efficacious and safe therapeutics for AD.
- The Target Product Profile (TPP) was vague, lacking demonstration of how the proposed product would be evaluated and ultimately distinguished from marketed competitor products and other cellular therapies currently in clinical trials.
- A major weakness of this proposal was the lack of a rationale for how a localized injection of hNSCs could treat a diffuse neurological disease.
- The optimal location for transplantation of the hNSCs is not established. In the preclinical models the hippocampus area was investigated but no alternatives were discussed. While the applicant presents a good rationale for focusing on the hippocampus, at least one reviewer cautioned that this may be too restrictive of an approach.
- Some reviewers commented that the use of only small animal models may not be predictive for humans considering the much smaller ratio of treatment area to brain in the human.
- Reviewers were not convinced that in the engrafted animals the level of formation of functional circuits and repair would be predictive of a therapeutic effect in humans.
- The applicant presents data to support the role of a specific growth factor in achieving preclinical benefit. Alternative methods to deliver the growth factor are not addressed.
Therapeutic Development Readiness
- This application is supported by some very good nonclinical toxicology work in relevant animal models, including a tumorigenicity study.
- One efficacy experiment using human hNSC transplanted in a preclinical model resulted in improvements in context recognition and place recognition when tested at one month, as well as evidence of engraftment of the human stem cell progeny (glia and neurons).
Feasibility of the Project Plan
- Efficacy endpoints described for the clinical trial may be difficult to quantify which may make it difficult to assess preliminary efficacy readout.
- Reviewers were concerned about the commercial feasibility of the cell supply since each working cell bank will be sufficient for a very limited number of patients. It was not clear if this calculation took into consideration higher doses that might be required based on clinical trial dose-finding studies.
- In general reviewers agreed the preclinical model was appropriate, however questioned how adequate this model would be to perform dose-ranging studies, due to potential anatomical limitations, thus potentially advancing suboptimal doses to the clinic.
Principal Investigator and Development Team
- The PI is an experienced investigator in the neurological field and has previous successful experience with filing IND applications.
- The team has a strong expertise with the preclinical models as well as prior experience testing neural stem cells in clinical trials.
- The leadership plan is well articulated and appropriate.
Collaborators, Resources and Environment
- The resource subcontractors are all excellent and of high quality, including preeminent contract research organizations very experienced in IND-enabling studies, manufacturing and quality control.
- There is a significant amount of Intellectual Property filed around the composition of matter and methods to manufacture, however no Freedom to Operate (FTO) was provided or described.
Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding.)
- The budget proposed for the preclinical safety studies was excessive. Reviewers suggested perhaps the team could leverage prior safety data from previous IND studies with this proposed cell line.
- Reviewers had mixed opinions about the appropriateness of the manufacturing costs. Some felt the manufacturing costs were excessive while others felt the cost was attributable to the need to remanufacture.
- A motion was made to move this application into Tier 3, Not Recommended for Funding. The panel recognized that the cell source was potentially ready for clinical development, but expressed strong concerns that aspects of the preclinical and clinical rationale need to be further developed to warrant moving this candidate toward an IND in the Alzheimer’s disease indication. The motion carried.
- David Pepperl
- Lauren Black
- Mark Noble