Funding opportunities

Development of RNA-based approaches to stem cell gene therapy for HIV

Funding Type: 
Early Translational II
Grant Number: 
TR2-01771
Principle Investigator: 
Funds requested: 
$3 124 130
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Despite significant advances in treatment and prevention programs, HIV infection with progression to Acquired Immunodeficiency Syndrome (AIDS) is still prevalent in California. The CDC Estimates >56,000 new cases of HIV infection each year in the US with over 148,000 cumulative cases reported in California alone (as of 2009). Multi-drug therapy has been helpful in reducing the severity of disease and prolonging lifespan but sixteen of every one hundred HIV patients will eventually fail to control the virus after attempting at least 2 drug treatment regimens. The Centers for Disease Control (CDC) recently estimated the lifetime cost of medical care for AIDS to be in excess of $600,000 per patient, over 85% of which is attributable to prescription drug costs. Additionally, medication non-compliance, intolerance of drugs due to side effects and the development of resistant strains of virus are all complicating factors in obtaining consistent clinical benefit with lifelong drug therapy. Therefore, there is a need to provide a longer lasting, cost effective therapy for this disease. Our project builds on prior work from our laboratories in which genetically engineered blood stem cells were transplanted into HIV patients and shown to give rise to gene-marked peripheral blood cells that last for up to 2 years. These cells may protect HIV patients from progression to AIDS if they are present in sufficient numbers. Our therapeutic candidate is a gene modified human blood stem cell carrying multiple anti-HIV molecules that prevent virus infection, replication and spread and a gene that allows us to chemically “enrich” the number of disease resistant cells present in a patient’s blood. The anti-HIV molecules are made of ribonucleic acid (RNA) and were developed and tested in our laboratories. We have already conducted a first generation stem cell therapy clinical trial to test these molecules with promising results. We now propose to refine and further develop this treatment with second generation RNA molecules and gene transfer procedures that will improve the number of disease resistant cells in the blood of HIV patients. We will develop an animal model system to test newer, more efficient anti-HIV molecules and a drug treatment method to enhance the number of HIV resistant stem cells circulating in the blood of patients that receive gene modified blood stem cells. At the end of the proposed experiments, we expect to have selected the most efficient combination of RNA molecules and drug selection strategy to provide a sufficient number of disease resistant cells in the peripheral blood to prevent progression to clinical immunodeficiency (AIDS).
Statement of Benefit to California: 
California has ~14% of all cases of AIDS in the U.S., and this translates into a medical and fiscal burden larger than any other state except NY. Antiviral chemotherapy accounts for approximately 85% of AIDS-related medical costs, and federal and state law requires that in California the AIDS Drug Assistance Program (ADAP) be the payer of last resort for these medications. Antiretroviral drugs currently cost about $12,000 per year and account for about $350 million of the California AIDS Drug Assistance Plan's budget. The Governor's spending plan (2009-09 Budget Act) called for $418M to support this program, with funds from several sources including federal (Ryan White Care Act), from an ADAP Rebate Fund, and from the California State General Fund. The ADAP Rebate Fund consists of monies paid to the state by the manufacturers of the drugs provided to the HIV/AIDS clients under the program. The ADAP budget has grown by ~15% yearly for several years, and based on an Legislative Analyst's Office (LAO) review, the problem faced is that, as the case load is increasing, support from the Rebate Fund is decreasing. It is projected by LAO that from a level of $80.3 million at end 2008, the Fund will decrease to $24M by the end of 2010. The General Fund currently provides $96.3M to the ADAP budget, and it is projected that as the ADAP Rebate Fund shrinks, the shortfall will have to be met by increases from the General Fund by 2012. The alternative, as noted by LOA, is to implement cost-cutting measures that would likely increase the barriers to receiving care for some patients, impacting the health of some HIV/AIDS patients and increasing the associated public health risks.
Review Summary: 
This application for a Development Candidate Award focuses on a gene-modified autologous hematopoietic stem cell (HSC) therapy for HIV/AIDS. The proposal builds on a clinical trial performed by the applicant that demonstrated safety and feasibility of the approach but no clinical efficacy due to insufficient gene marking of HSC. To improve on this approach, the applicant plans to test novel vectors containing different combinations of anti-HIV genes to prevent virus infection along with a gene allowing chemical enrichment of the number of disease resistant cells in patient’s blood following transplant. The applicant proposes three specific aims: (1) to develop an immunodeficient mouse model of human HSC transplantation and HIV infection; (2) to develop a number of viral vector constructs containing different combinations of anti-HIV genes along with a gene allowing in vivo selection; and (3) to use the mouse model to evaluate the efficacy of these vectors in establishing HIV resistance and allowing drug selection of transplanted human HSCs. Reviewers agreed that this proposal addresses a significant unmet medical need. There are currently no curative therapies for HIV/AIDS and existing treatment options are accompanied by significant toxicity and quality of life issues and do not restore full immune system functionality. Reviewers felt this proposal would have an important impact if successful, although they acknowledged that its impact may be limited by the target population of HIV-lymphoma patients. They appreciated the incorporation of an in vivo selection strategy and felt it has a high likelihood of improving efficacy. Reviewers weren’t entirely convinced that there is a need to improve the specific HIV-resistance genes, since the low level of gene marking in the previous study precluded any assessment of their efficacy. However, they noted that this additional work should not delay any timelines. The reviewers described the research plan as well thought out, straightforward and feasible. They appreciated the detailed research plan presented in the form of a Gantt chart and found the timeline and milestones to be reasonable and clearly defined. Reviewers noted that this proposal is essentially a refinement of approaches used in a recent clinical trial by this group and thus has a high likelihood of successful clinical translation. Their one criticism of the research plan is that the process development studies proposed do not utilize HSCs from HIV-lymphoma patients, or even HIV+ patients. Reviewers noted that these cells could behave differently than normal HSCs and it would be useful to ensure similar responses to vector transduction and in vivo selection. The reviewers found the Principal Investigator (PI) and co-PI to be well-qualified to carry out the proposed research. They noted that the PI has critical experience in the development, scale-up and manufacturing of cell products for clinical trials. The co-PI is well published in the fields of stem cell therapy, HIV gene therapy and RNA therapeutics and has extensive experience with vector design. Reviewers praised the strong, ongoing collaborations within the research team and the excellent environment at the applicant’s institution. With regard to the budget, reviewers noted that the purchase of an additional cell separation device is not completely justified. Overall, reviewers were strongly supportive of this proposal for a gene-modified autologous HSC therapy. They appreciated the strong scientific rationale and feasible research plan. Reviewers agreed that the research team is excellent and ensures a high likelihood of success in bringing the proposed therapy to IND-enabling studies at the end of three years.
Conflicts: 

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