Title of proposed idea: Gene-Based Therapeutics: Manipulating the Output of the Genome to Treat Disease
Nominator: NIH Institutes/Centers
Major obstacle/challenge to overcome: Gene-based therapeutics are tools to manipulate the output of the genome to treat disease. The most well-known gene-based therapeutic is gene therapy, which is most commonly done using viral vectors, although other vehicles (e.g. nanoparticles), can be used as well. Other gene-based therapies include small interfering RNA (siRNA) and oligonucleotide therapeutics, and zinc-finger nucleases and transposons to modify the genome directly.
For many gene-based therapies, development and proof of principle preclinical studies are within the budget of a typical RO1 grant award. The major obstacle is moving from preclinical research into clinical trials. Major hurdles at the preclinical level include limitations on the size and sequence of nucleic acids used in gene-based therapeutics, as well as tissue and cell-type specific targeting. Moving to the clinic, hurdles include the practical reality of scaling up production, funding for GMP drug manufacture and toxicology testing, and funding for clinical trials themselves.
What is needed to overcome this obstacle is a program dedicated to making gene-based therapies a clinical reality. Our proposal is for the Common Fund to support such mechanism, which would facilitate the translation of current gene-based therapies into clinical trials.
Emerging scientific opportunity ripe for Common Fund investment: Gene-based therapies are clearly ripe for investment by the Common Fund. It has now been established that viral vector based gene therapy is effective in humans. In addition, novel gene targeted therapies are being developed and validated at an accelerating pace. In 2011 alone, we have seen the first evidence that zinc-finger nucleases can be effective in a mouse model of hemophilia , and the use of exosomes to deliver therapeutic siRNA across the blood-brain barrier in mice .
NIH ICs have provided the majority of funding for the discovery and preclinical developments of multiple gene-based therapies, and will do so in the future. However, they not positioned to support translation to the clinic at the level that is necessary.
Common Fund investment that could accelerate scientific progress in this field: We envision a program that combines aspects of RAID (Rapid Access to Investigational Drugs) and TRND (Therapeutics for Rare and Neglected Diseases), but is focused exclusively on gene-based therapeutics. Projects will be chosen for support by streamlined competitive process, and funding provided in a step-wise manner dependent upon continued progress and meeting project targets (similar to RID). For some viral-vector based therapies, the new program could support investigators to utilize the NHLBI gene therapy resource program. For other types of therapeutics, the fund could provide support large scale production of GMP grade nucleic acids, or zinc-finger nucleases, as well as CROs for animal toxicology testing. By funding such a large effort, significant cost savings would be expected based upon economies of scale.
Another aspect of the program, modeled after the TRND program, would be to carry out Phase 0 and Phase 1 clinical studies to de-risk gene–based therapies, and thereby encourage adoption by industry. It is possible that industry could be involved with this program at an earlier stage in a public-private partnership.
It should be emphasized that TRND does not work with biologics or gene therapy, so the new program would complement TRND, rather than duplicate effort. While gene therapy and biologics are a part of RAID, given the rate of development of new technologies in this area, and the potential clinical impact, we believe that a much larger program, exclusively focused on gene-based therapeutics, is needed.
Potential impact of Common Fund investment: If the proposed Common Fund program were to achieve its objectives, the impact would be that one or more gene-based therapies would become established as a treatment option for patients with genetic disease. As a benchmark, gene-based therapy would become as common as bone marrow transplantation is currently at major academic medical centers. Such an outcome could transform the clinical outlook and lives of patients with genetic disease. This would be especially important for rare diseases where in most cases no other treatment options exist.
Importantly, we anticipate that this program would dramatically impact basic science as well. A commitment to gene-based therapeutics by the Common Fund, would certainly stimulate even more preclinical studies in this field, which would in term feed into the new program, and also provide new tools for basic science. As an example, if the program achieved its objectives, tools could be available that would make manipulating the genome of a mouse, in a specific cell population, as routine as transformation of bacteria is today. If this were to become reality, it would dramatically change the way biomedical science is done. With support from the Common Fund, these impacts are feasible within the 10 year time frame specified by the Common Fund criteria.
Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. Mar 2010;18(3):643-650.
Aiuti A, Roncarolo MG. Ten years of gene therapy for primary immune deficiencies. Hematology Am Soc Hematol Educ Program. 2009:682-689.
Li H, Haurigot V, Doyon Y, et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature. Jul 14 2011;475(7355):217-221.
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. Apr 2011;29(4):341-345.