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Effective Targeted Delivery of RNA-based Vaccines and Therapeutics


040 Effective Targeted Delivery of RNA-based Vaccines and Therapeutics

Direct to Phase II will be accepted

Fast Track will not be accepted

Number of anticipated awards: 1-2

Budget (total costs):

Phase I: $300,000 for up to one year

Phase II: $2,000,000 for up to 3 years


RNA-based vaccines and therapeutics have emerged as great promise for HIV prevention and treatment, respectively. However, many obstacles still need to be overcome, in particular RNA instability, manufacturing problems, and clinically relevant delivery mechanisms of RNA into target cells.

RNA vaccine approaches have some advantages in relation to other vaccine technologies; they can be delivered directly into the cytoplasm and do not require nuclear localization to generate expression. Improvements of methods for mRNA synthesis and stabilization and development of improved self-amplifying RNAs have recently yielded promising results. RNA approaches also stimulate the host’s innate defense system, in part through activation of the TLR pathways that recognize single and double stranded RNAs.

Furthermore, RNA-based therapeutics have shown the potential to silence HIV effectively upon direct transfection in vitro, but delivery into cells in vivo is still unsatisfactory. Vector-based (lentivirus, adeno-associated virus) delivery to quiescent cells has proven inefficient, and the vectors themselves pose a risk to the host. To enhance stability and to confer vehicle-free delivery, RNA-based drugs have been chemically modified to improve their properties. Progress was also made in chemical-based delivery strategies, e.g., liposomes, molecular-sized chemical conjugates, and supramolecular nanocarriers. An additional advantage is that RNA can be produced in vitro in a cell-free manner, avoiding safety and manufacturing issues associated with cell culture. Despite these advances, nucleic acids per se are relatively large, negatively charged polymers, and significant clinical challenges from the standpoint of delivery to cells still persist.

Project Goals:

The primary goal of this contract solicitation is to encourage small businesses to develop improved platform technologies for the delivery of RNA into specific cells and tissues to improve the efficacy of HIV vaccines or therapeutics. Examples of HIV RNA vaccines include, but are not limited to mRNA and self-amplifying RNAs. Examples of RNA therapeutics include small interfering RNA (siRNA), microRNA (miRNA), microRNA antagonists, aptamers, messenger RNA (mRNA), splice-switching oligonucleotides, antisense oligonucleotides, and plasmid or other circular DNAs encoding messenger RNAs and transcription regulatory sequences. To enhance the efficacy of traditional HIV vaccines and therapeutics, combinations of cytokines, adjuvants, broadly neutralizing monoclonal antibodies, immune checkpoint inhibitors, etc. can also be co-delivered in mRNA form.

The short-term goal of this project is to perform feasibility studies for the development and use of delivery mechanisms for RNA-based HIV vaccines and therapies. The long-term goal of this project is to enable a small business to bring fully developed delivery systems for RNA-based HIV vaccines and therapies to the clinic and eventually to the market.

Phase I activities may include:

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• Design and test in vitro small scale delivery strategies for RNA-based HIV vaccines or therapeutics, including exosomes, nanoparticles, liposomes, viral vectors, condensates, carriers, or delivery devices.

• Assess potency and stability of RNA-based HIV vaccines or therapeutics.

• Improve RNA stability through chemical modifications.

• Perform proof-of-concept HIV animal model studies for assessment of organ toxicity, HIV immune responses, innate immune responses (e.g., Toll-like receptor activation), and pharmacokinetic/pharmacodynamic studies, if applicable.

• For RNA-based therapeutics:

• Evaluate off-target effects in cell lines and primary PBMC.

• Develop strategies for eliminating off-target effects, including software tools for re-designing RNAs.

Phase II activities may include:

• Scale-up manufacturing of RNA-based vaccines or therapeutics

• IND-enabling studies, preferably in consultation with the FDA

• For RNA-based vaccines:

• Test improved delivery mechanism for efficacy and mechanism of action in animal models of HIV.

• For RNA-based therapeutics:

• Demonstrate that the RNA delivery approach is effective and non-toxic in animal models for HIV.

• When appropriate, demonstration of superiority of developed technology compared to other delivery mechanisms.

Where cooperation of other vendors or collaborators is critical for implementation of proposed technology, the offeror should provide evidence of such cooperation (through written partnering agreements, or letters of intent to enter into such agreements) as part of the Phase II proposal.

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