Transforming Gene Therapy: Battelle's HIT SCAN™ and the Rise of Polymer Nanoparticles

Gene therapy is an innovative approach to treating diseases by delivering genetic material directly to cells to achieve a desired therapeutic outcome. It has made significant strides over the past decade, particularly with the advent of CRISPR technology. While it holds immense promise, the field is still grappling with challenges pertaining to delivery methods, safety, and efficacy. Traditional delivery systems, such as adeno-associated viruses (AAVs) and lipid nanoparticles (LNPs), have been widely used but face limitations in terms of payload capacity and immune response.

Researchers at Battelle are working to unlock the potential of polymeric nanoparticles (PNPs) to deliver safe, effective therapies for previously untreatable conditions, paving the way for new therapeutic possibilities in gene therapy. In this blog, we’ll cover some of the most frequently asked questions about gene therapy and this novel delivery vehicle technology.

How Does Gene Therapy Work?

Gene therapy approaches leverage one of several existing technologies to achieve a desired therapeutic outcome. These approaches include gene replacement, gene silencing, gene addition, and gene editing. Of these approaches, gene editing is the most recently discovered and involves permanently altering the genetic material of specific cells. CRISPR technology allows for precise modifications by substituting, deleting, or inserting nucleic acids to correct genetic mutations. The process is driven by DNA-cleaving proteins programmed to target specific DNA sequences. Advances in CRISPR have led to more precise tools like base editors and prime editors, enabling both mutation correction and precise genetic regulation.

What Challenges and Hurdles Are Associated with Gene Delivery?

Despite advancements, gene therapy's future depends on overcoming delivery challenges. Effective delivery systems must protect the genetic payload, target specific cells, cross cell membranes, and release functional cargo. Traditional viral delivery methods face several hurdles:

• Scalability: Viral vectors are difficult to mass-produce, leading to high costs and inefficiencies.
• Low Cargo Capacity: Gene therapy payloads are often too large for viral delivery.
• Prolonged Expression: Persistent viral genomes can cause off-target effects over time.
• Immunogenicity: A risk of triggering an immune response due to exposure to the viral delivery vehicle exists, which can limit the therapy's effectiveness and pose safety concerns.
• Unintended Immunity: The body may develop immunity to the viral vectors used, thereby limiting therapeutic capabilities for approaches requiring administration of multiple doses.

What Role do PNPs Play in Enhancing Gene Therapy?

Polymeric nanoparticles (PNPs) offer a promising non-viral delivery method for gene therapy. They can carry larger payloads than viral vectors and are versatile enough to target specific cell types, minimizing off-target effects. PNPs also allow for repeat applications without triggering immune responses, and the gene editing machinery can be tightly controlled to prevent off-target effects besides modifying the intended cells.

What Potential Do PNPs Hold for Gene Therapy?

PNPs offer several advantages over traditional methods:

• Larger Payload Capacity: PNPs can load and deliver payloads significantly larger than 5 kilobases, including payloads of approximately 20-50 kilobases. PNPs can also accommodate entire genes and complex payloads.
• Lower Immunogenicity: The inert nature of PNPs reduces the risk of triggering an undesired immune response, even when the PNPs are used in multiple rounds of treatment.
• Tissue Targeting: PNPs enable precise delivery to specific cells or organs using active and/or passive targeting approaches.
• Cost-Effective Manufacturing: PNP production can be simplified using cell-free processes to enhance efficiency and lower costs, compared to the cell-based methods used in viral vector manufacturing.
• Shelf Stability: PNPs simplify transportation logistics and storage conditions without the need for specific cold-chain requirements, as often needed for viral vectors and LNPs.

How is Battelle using PNPs to advance the field of gene therapy?

Battelle's HIT SCAN™ platform addresses the safety, efficacy, scalability, and reproducibility issues associated with existing delivery technologies. This discovery and development platform enables rapid exploration of a vast and highly tunable delivery vehicle design space with the intent to enhance safety and efficacy while reducing development time and costs. In particular, Battelle’s HIT SCAN™ platform integrates:

• Automated Polymer Synthesis: Ensures consistent PNP production using reversible addition-fragmentation chain transfer (RAFT) polymerization in an agile, automated manner.
• High-Throughput Screening: Facilitates rapid identification of high-performing PNPs both in vitro and in vivo using a variety of specialized screening tools.
• Machine Learning: Employs predictive computational modeling to differentiate and identify successful PNP designs, ultimately facilitating future discovery and development processes to translate lead candidates into the clinic.

These technologies enable reliable PNP development, reduce variability, and facilitate commercial production scalability for clinical applications. By streamlining the discovery and development processes for novel non-viral delivery vehicles, Battelle is accelerating the pairing of next-generation therapies with PNP delivery vehicles, bringing innovative treatments to patients more quickly and efficiently.