Funding opportunities

Funding Type: 
Strategic Partnership I
Grant Number: 
Principle Investigator: 
Funds requested: 
$9 363 335
Funding Recommendations: 
Grant approved: 
Public Abstract: 

[REDACTED] plans to carry out a Phase 1/2 study to evaluate the safety and efficacy of [REDACTED] for the treatment of β-Thalassemia Major(BTM). [REDACTED] consists of autologous patient hematopoietic stem cells(HSC) that have been genetically modified ex vivo with a lentiviral vector that encodes a therapeutic form of the β-globin gene. [REDACTED] is administered through autologous hematopoietic cell transplant(HCT), with the goal of restoring normal levels of hemoglobin and red blood cell(RBC) production in BTM patients who are dependent on RBC transfusions for survival.

Because they cannot produce functional hemoglobin, BTM patients require lifelong RBC transfusions that cause widespread organ damage from iron overload. While hemosiderosis can be mitigated with chelation therapy, poor compliance, efficacy and tolerability remain key challenges, and a majority BTM patients die in their 3rd-5th decade. The only cure for BTM is allogeneic HCT, which carries a significant risk of mortality and morbidity from immune-incompatibility between the donor and recipient, and is hampered by the limited availability of HLA matched sibling donors.

By stably inserting functional copies of β-globin into the genome of a patient’s own HSC, treatment with [REDACTED] promises to be a one-time transformative therapy for BTM. The β-globin gene in the [REDACTED] vector carries a single codon mutation [REDACTED] that allows for quantitative monitoring of therapeutic globin production but that does not alter oxygen carrying capacity. Treatment with an earlier version of the vector has been shown to correct β-thalassemia in mice [REDACTED]. In a clinical trial [REDACTED], 3 BTM patients were treated–one of whom became transfusion independent 1 year after treatment and remains so 4 years later.

Given the prevalence of patients with a common BTM genotype in California, [REDACTED] plans to open at least 2, and up to 4, clinical sites in California. Development activities are on track to initiate the trial in 1H 2013, and to complete the trial with 2 years of follow-up within the award window. [REDACTED] has completed a pre-IND meeting with the FDA and successfully manufactured a GMP lot of [REDACTED] vector that is available for clinical use. The Company expects to complete all IND enabling activities by Q4 2012.

In the last year, the company has made scientific advances that have allowed for a significant improvement in the efficiency of HSC genetic modification that will be help ensure clinical efficacy in BTM. Moreover, through collaborations with contract manufacturers, [REDACTED] is now producing large scale GMP lots of vector, and is on track to qualify a GMP cell processing facility with commercial capabilities prior to study initiation. [REDACTED].

Statement of Benefit to California: 

The company expects to spend a major component of its financial resources conducting business within the state of California during the period of this CIRM award. Specifically: 1) we will have at least two clinical sites in California, and more likely up to 4 sites, 2) our viral vector manufacturing will occur in California, 3) our cell processing will occur in California, 4) we will hire several consultants and full-time employees within California to support the program. Overall, several million dollars will be spent employing the services of people, academic institutions, and other companies within the state of California.

Moreover, the disease we aim to treat occurs at a substantially greater rate of in California than other parts of the United States. As such, it is a significant public health concern, for which our therapy could provide a dramatically improved outcome and significant reduction in the lifetime cost of treatment, along with increased productivity. Due to the prevalence of the disease in California, if brought to the market, the pharmacoeconomic and social benefit of our therapy will accrue disproportionately to the state of California.

Review Summary: 


The goal of this proposal is to develop a gene-modified stem cell therapy for beta-Thalassemia Major (BTM), a severe blood disorder caused by a genetic defect in the beta-globin gene. Because they cannot produce functional hemoglobin, BTM patients require lifelong red blood cell (RBC) transfusions that cause widespread organ damage from iron overload. In the proposed therapeutic approach, a patient’s own hematopoietic stem cells (HSC) would be isolated and genetically modified ex vivo with a lentiviral vector encoding a therapeutic form of the beta-globin gene. The modified cells would then be returned to the patient via an autologous bone marrow transplant, with the goal of restoring normal levels of hemoglobin and RBC production in transfusion-dependent patients. Key project activities include filing an Investigational New Drug (IND) application, improving process development for larger scale manufacture, and completing a Phase 1/2 clinical trial to evaluate the safety and efficacy of this gene-modified stem cell therapy for adult BTM patients. Following the initial enrollment of adult patients and the accumulation of adequate safety and efficacy data, the applicant proposes to extend enrollment to a small number of adolescent subjects.

Significance and Impact

- Beta-Thalassemia is a widespread and devastating genetic disorder for which current treatment options are limited. The proposed project addresses a critical unmet need and if successful, the clinical competitiveness and impact will be very high.

- Although new therapies are being developed, the proposed approach offers the possibility of a lifetime cure with a single treatment and without the need for an immune matched tissue donor.

- The proposed project represents a potential leap forward for cell and gene therapies and would enhance our knowledge of corrective gene therapy for the treatment of one of the most common and devastating genetic disorders. If successful, the proposed approach could be widely adopted and would have major impact not only on BTM, but also on the development of cures or treatments for other types of genetic disorders. This could be a very important success for cell and gene therapy.


- The rationale for the proposed therapeutic is scientifically sound, based on a strong body of preliminary work and an established clinical precedent for curing BTM with allogeneic bone marrow transplant.

- Reviewers believed that the potential benefits of the proposed therapy strongly outweigh the risks, although they cautioned that a patient’s genotype and disease severity could influence this calculation, as could an unanticipated clonal expansion within the autograft.

- While the proposed approach does not avoid all risks inherent to bone marrow transplantation procedures, the use of autologous cells should minimize the possibility of graft versus host disease and may potentially reduce graft failure.

- Reviewers noted that the applicant has modified the vector in order to increase potential benefit and reduce potential risk in the proposed trial. However, based on the available data, reviewers were uncertain whether the re-engineered lentiviral vector would indeed prove safer or more efficacious in vivo than the original vector. In addition, there were no convincing data to suggest the product would not be immunogenic.

Design and Feasibility

- The overall development plan is well conceived, with appropriate assessment points and clearly defined milestones. A well-described clinical development plan, regulatory plan and quality plan are in place with defined aims and time lines and the clinical trial is well designed. In light of significant technology risk taking, the applicant presents an excellent, thoughtful, stepwise plan that is well-worth funding.

- It is feasible to complete the proposed clinical trial within 4 years, although reviewers cautioned that there could be delays, given the important but addressable issues identified by the Food and Drug Administration (FDA) during a key regulatory review.

- Reviewers considered the timeline for completing the next generation manufacturing process to be underestimated and the proposal did not address a comparability plan to establish comparability between the current and improved processes.

Principal Investigator (PI), Development Team and Leadership Plan

- The PI and applicant team have considerable experience in vector development and gene therapy. Reviewers believed that the PI is well suited to lead this endeavor but emphasized that since he/she has less expertise with process development, it will be critical to identify appropriate personnel for the key positions, including Project Manager.

- The subcontractors are all well qualified. The working relationships between applicant, contractors and clinical sites are clearly specified; appropriate leadership and communication plans are in place.

Collaborations, Assets, Resources and Environment

- The applicant has recruited a team of excellent clinical collaborators with large practices, making it highly feasible that sufficient numbers of patients will be enrolled in the planned clinical trial.

- All necessary resources concerning production and testing of the proposed therapeutic are in place, and the applicant holds relevant intellectual property.

(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.)

- $1.1M for vector yet application says it is complete. Is this for lentiviral vector, or new manufacturing? Need more details. In addition, $675K for 2 centers TBD – need to identify the centers and budget according to patient accrual.

Programmatic review: 
  • - Applications were addressed individually during programmatic review. A motion was made to recommend funding this application. The motion passed.
  • Barbara Matthews