Funding opportunities

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
Principle Investigator: 
Funds requested: 
$109 676
Funding Recommendations: 
Grant approved: 
Public Abstract: 

Successful stem cell therapy requires replacement of diseased or dysfunctional stem cells with healthy ones. These healthy stem cells can come from either a donor or can be stem cells that are modified by gene therapy techniques. One important step in this process of repair and replacement is to eliminate the existing diseased cells so that physical space is created for the healthy ones, and competition for environmental factors that nurture and support the stem cells are removed.

The oldest and most common form of stem cell-based therapy is bone marrow transplantation (BMT). Thousands of patients undergo BMT yearly to treat cancers or disorders of blood formation. Bone marrow contains mixtures of cells, but only a minority are the blood forming stem cells, which are critically important as only stem cells can permanently generate new blood cells. In a BMT, stem cells from a donor replace the recipient’s diseased stem cells. Currently, the only known way to eliminate the patient’s own blood forming stem cells is to treat the recipient to accept donor cells with toxic agents such as radiation and chemotherapy.

Our team will focus on the treatment of a disorder in children called severe combined immune deficiency (SCID). SCID children are born without a functional immune system and are therefore highly susceptible to serious infections. If children with SCID are not treated, most die by the age of two. BMT is the only established cure for this disease. Unfortunately, the likelihood of successful cure is reduced by the way transplants are currently performed, using toxic treatments to prepare the children to accept the donor cells.

We will test an antibody that recognizes a molecule called CD117 present on blood forming stem cells. This antibody can safely target and eliminate these cells. When used in mice, such an antibody enabled excellent donor stem cell engraftment and cured mice that had a condition equivalent to human SCID. Our objective is to test the antibody that targets human CD117 to safely prepare children with SCID to accept blood forming stem cells from a donor. Based on the animal studies we expect that this antibody will allow engraftment of stem cells at high levels, rapidly replacing diseased blood cells with healthy blood cells. Such a result would mean safer and better outcomes for these patients.

Success in this study would have impact that extends far beyond a superior treatment for SCID. If the antibody treatment results in a stronger blood system originating from a donor in SCID patients, this result would prove that the antibody could be used to optimize engraftment of gene-therapy modified cells and could be applied to the treatment the many other diseases that need a BMT. These diseases include, but are not limited to sickle cell anemia, thalassemia, and Fanconi’s anemia; autoimmune diseases like diabetes and multiple sclerosis; and cancers that originate from the blood system such as leukemias and lymphomas.

Statement of Benefit to California: 

Non-malignant diseases of the blood and the immune system plague thousands of Californians and millions of people world-wide. These diseases are quite diverse, ranging from blood diseases such as sickle cell anemia and beta thalassemia, to immune diseases such as severe combined immunodeficiency, HIV, and autoimmune disease including type I diabetes and multiple sclerosis. Current therapies do not fully control the symptoms of these diseases, leaving severe morbidity and early mortality as ongoing consequences. For the health of the citizens of California, both physical and financial, we need to develop cures, rather than marginally effective treatments, for a variety of these devastating blood and immune illnesses.

Hematopoietic stem cell (HSC) transplantation possesses the ability to provide a life-long cure for all of these diverse diseases, as it allows for the replacement of defective HSC. Although effective, the use of this form of treatment is severely limited because of the current need to administer chemotherapy or radiation prior to the transplant to permit engraftment of donor stem cells. As a result, there is 10-20% transplant-related mortality and associated toxicities such as infertility, secondary malignancies, endocrine dysfunction, organ damage, and in children, mental and physical growth impairment.

By developing a novel, non-toxic antibody-based conditioning method, HSC transplantation could be expanded to the treatment of non-life threatening yet debilitating diseases that are currently not transplanted due to the associated toxicity. We have shown this can be accomplished in mice and are studying similar agents that could be used in patients. We aim to begin safely treating patients that suffer from severe combined immunodeficiency (SCID), a diverse disorder that is caused by defects in HSCs. While the incidence of SCID has been thought to be rare, preliminary results of newborn screening in California suggest the incidence is 1/30,000 newborns. In addition, a number of previously treated patients with SCID who did not engraft with donor stem cells are now developing immune failure. The clinical trial to be performed will treat immunodeficient patients from across the state of California through the network of institutions incorporated into this disease team of world-renowned stem cell and transplantation experts.

After successfully treating patients with SCID, we plan to expand this conditioning technique to other diseases, and hopefully pave the way for safe transplantation of genetically modified HSC, thereby expanding stem cell transplantation in California tremendously. We hope this novel conditioning regimen will result in a direct benefit to patients who suffer from blood and immune diseases, as well as create definitive treatments that will lead to a reduction of the massive health care burden these diseases inflict on patients and their families in California.

Review Summary: 


Project Synopsis

The goal of this proposal is to develop a technology to prepare pediatric patients with severe combined deficiency (SCID) for allogeneic HSC transplantation to early stage clinical trails. The candidate therapy is a humanized monoclonal antibody (mAb) that recognizes and depletes endogenous hematopoietic stem cells (HSC). The applicants hypothesize that such an antibody would replace the toxic agents, such as radiation and chemotherapy, currently used to clear the niche and facilitate HSC engraftment. Proposed activities include pre-clinical and IND-enabling studies including pharmacological, toxicological and dose ranging studies in relevant animal models; acquisition of IND and appropriate regulatory approvals and initiation of Phase I/II clinical trial with children with newly diagnosed SCID and SCID patients who were previously transplanted but failing engraftment

Significance and Impact

- SCID is a fatal disease, and even with current matched bone marrow transplant treatments, traditional conditioning and secondary transplants are often required. If successful, this treatment would enable safer allogeneic engraftment of SCID patients, thereby fulfilling an unmet medical need in this SCID population and having dramatic impact.

- By reducing potential risk of regimen related toxicity, this approach may broaden the application of hematopoietic transplantation to non-malignant disorders. However, reviewers agreed the applicability of this treatment to immune competent settings would require further development.

Project Rationale and Feasibility

- Reviewers found the applicants’ rationale for a less toxic conditioning regimen that would enable long term, multilineage engraftment in SCID patients compelling.

- A discussant noted that SCID recipients do not have the confounding variable of rejection and therefore would be expected to benefit from good allogeneic HSC engraftment following niche clearing with the proposed treatment.

- The panel agreed the preliminary data supports the rationale and feasibility of the approach.

- The proposed therapeutic is well defined and consists of a humanized mAb already prepared under good manufacturing practices (mAb).

- Reviewers unanimously appreciated the logical and feasible research plan design and the use of appropriate in vivo models.

- Reviewers highlighted that access to the GMP mAb and its terms of use remain to be negotiated. If negotiations fail or the resultant agreement does not enable the applicants to access and utilize the owner’s materials, this would impact the proposed timeline.

- Preliminary results suggest toxicity may occur at doses lower than required for successful HSC engraftment. However, proposed dosing studies may demonstrate efficacy at lower levels of mAb.

- Reviewers were unclear if additional regulatory consideration will be required for the use of proposed HSC population for the targeted allogeneic recipients, which may impact the time lines.

PI and Planning Leader

- The panel appreciated the PI’s expertise in relevant animal models, the influence of the niche on engraftment and experience performing pediatric transplants. S/he has assembled a strong team including consultants with relevant regulatory and technical expertise to develop the proposed program.

- The planning leader has appropriate experience in both academic and industry IND preparation and clinical trial management.