Disease Team Therapy Planning I
ALS, also called Lou Gehrig’s disease, is a rapidly progressive neurological disease for which we have no cure. ALS will kill about 50,000 current California residents unless better treatments are developed. Death from ALS occurs on average 3 years after the first symptoms appear, but, disease progression varies, ranging from a few months to decades. In this project, we will determine if insulin-like growth factor I (IGF) produced by mesenchymal stem cells (MSC) from adult bone marrow are safe in humans. This is a necessary step before we can test if IGF producing MSC can slow or reverse nerve death in ALS. Over the last 15 years many studies have shown that IGF markedly slows the progression of ALS in cell cultures and animals. However, the trials that have been conducted in humans have not shown a clear or conclusive effect. We and many others believe that this is due to the fact that the IGF does not get to the sick motor nerve cells in high enough doses. To overcome this limitation, we propose to provide the IGF directly to the motor nerve cells by placing the MSC at the motor nerve cell endings in muscles. MSC that do not have the ability to produce high doses of IGF are already currently being tested in ALS, and these cells have been safe in many human studies. In our facilities, we have produced the MSC that make high levels of IGF. We will now conduct experiments in mice with a type of ALS and in a large animal model to ensure the treatment is safe. In these experiments we will be injecting the stem cells into muscles and will follow the survival of the motor nerves using functional, electrophysiological, and pathological measures. In these animal studies, we will look for any signs of problems with the treatment. If our IGF producing MSC are safe in animals, then we will proceed to a human trial. We are planning to inject 15 people who have late stage ALS, in muscles that have the same spinal innervation as our most important breathing muscle - the diaphragm. Respiratory problems cause the vast majority of deaths in ALS. ALS is a fatal disease and many patients are willing to volunteer for a stem cell trial to find better treatments. MSC and IGF have already been shown to be safe in humans when tested separately, and we are hopeful that combining them will not change this. The biceps muscles, where treatment will begin, are easy to observe. If necessary the transplanted MSC can be removed surgically with little to no problems. The MSC will only make IGF as long as we give volunteers a particular medication – Doxycycline. We can also make the MSC self-destruct by giving them a medication which is safe for all other human cells – Ganciclovir. The fact that IGF and MSC are individually safe, the many ways that we can control the IGF MSC, the potential impact of our study, and the need for better treatments of ALS makes this a project that has a high chance of winning regulatory approval and becoming an effective treatment for ALS.
Statement of Benefit to California:
Amyotrophic lateral sclerosis (ALS) disease, also known as Lou Gehrig’s Disease, is a rapidly progressive and fatal neurological disease for which we have no cure today. ALS will kill about 50,000 current California residents unless better treatments are developed. The proposed research and treatment could directly help these people, their loved ones and our communities. The costs of care in ALS are very high and often reach $200,000 per year during the late stages of the disease. A treatment that can delay disability can prolong the working life time of people with ALS. The social and emotional costs to patients’ families and their community are also great, and an effective treatment would help improve their quality of life and ease suffering. Patients could be able to feed them self’s, walk, speak and breath on their own for a longer time. The suffering associated with ALS is well-recognized and specific legislation affords special succor for people with ALS. Examples of this are US Public Law 106-554 and California SB 1502 and 1503. MSC are adult derived stem cells that are free from any of the controversy surrounding embryonic stem cells, and therefore garner almost universal public approval. This research will be done in California at an institution affiliated with the State of California and as such it would reflect positively on the State if successful. Only volunteers residing in the state of California will be recruited for this study and future ALS trials would likely involve an established consortium of California ALS Clinics. Further development and production of this IGF MSC would likely take place in California since the technology necessary to manufacture this kind of treatment is not ubiquitous. We believe this project has the potential to help all people with ALS and also benefit all people of the State of California. Furthermore, what we learn from this research may be applied to other diseases where IGF has shown promise, such as Kennedy’s disease and Myotonic and Duchenne Muscular Dystrophy.
EXECUTIVE SUMMARY Project Synopsis: This Planning Award proposal focuses on a genetically-modified mesenchymal stem cell (MSC) therapy for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is a neurological disease in which motor neurons (MNs), which convey signals to muscles, progressively degenerate, resulting in paralysis and early death. The applicant proposes that MSCs genetically engineered to secrete insulin-like growth factor 1 (IGF-1) and injected into muscle will provide support to the MN terminals on those muscles, prolonging MN survival and function. For safety, the MSCs will also contain genetic modifications permitting control of IGF-1 production by oral drug administration and selective killing of the MSCs in case of an adverse event. For the Research Award, the applicant proposes one year of preclinical, IND-enabling work, followed by IND submission and a Phase I human trial beginning in year 2 of the research award. Significance and Impact: - ALS clearly presents an important unmet medical need with limited therapeutic options. Any advances could have a significant impact. - The impact of the proposed research could be severely limited by the applicant’s choice of patient population. Many muscles in late-stage ALS patients lack motor neuron terminals and thus the approach, of injecting cells into the muscle to preserve terminals that may not be present, is questionable. Project Rationale and Feasibility: - The scientific rationale for the use of IGF-1 for ALS is not compelling. Clinical trials have not been successful to date and preclinical data have been mixed. The applicant does not present data demonstrating that delivery via MSCs will increase the efficacy of IGF-1 in ALS. - The proposed timeline is overly aggressive and reviewers were not convinced the applicant could complete all proposed studies within four years. - The applicant’s therapeutic scorecard combines published data from other groups with the applicant’s own and does not reflect the state of research with the actual development candidate. - A reviewer strongly suggested that the applicant schedule a pre-pre-IND meeting with the FDA and inquire about the necessity of conducting studies in a second animal model. - The overall approach of targeting MN terminals is a strength of the application, as the literature suggests that protection of MN cell bodies will not be sufficient. - Some reviewers were concerned about potential regulatory challenges posed by the three transgene approach, but others noted that the FDA might look favorably at the inclusion of a suicide gene, as long as safety of the product is thoroughly demonstrated preclinically. Principal Investigator (PI) and Planning Leader: - The PI is relatively inexperienced to be leading a project of this size and scope. - The PI is a full-time clinician with experience treating ALS patients and serving as a site PI in several ALS clinical trials. However, designing and carrying out a trial is a much bigger endeavor. - The Planning Leader has many years of experience working on clinical trials involving stem cells. - The environment at the host institution is excellent, as are the identified collaborators.