A Multipoint Injection Technology for Highly Efficient Convection-Enhanced Delivery of Gene-Based Therapeutics

PROJECT SUMMARY/ABSTRACT The rapid development of novel molecular therapies for neurological disorders has led to a rapid progress in the translational pipeline: to date, there are multiple active clinical trials and one therapy has already been approved by FDA. Most commonly, gene therapies rely on Adeno Associated Virus (AAV) due to its safety, transduction

efficiency, and long-term gene expression. In programs where AAV delivers cargo to restricted brain regions, it requires direct intracerebral injection. For instance, in Parkinson’s (PD) and Huntington’s disease (HD) a deep forebrain nucleus known as the putamen is often the target. However, complete coverage and efficient

transduction of the entire putamen with AAV is challenging. Current delivery methods require multiple stereotactic injections through a single cannula. The serial nature of these injections is not only time consuming, but adds the risks of multiple brain penetrations and iterative displacement of the target. Furthermore, even in

the most successful cases, the transduction efficiency of gene vectors delivered via single point injections is < 50%, which ultimately severely affects therapeutic efficacy. Beyond gene therapy, inadequate delivery is also critically affecting the efficacy of a number of other therapies relying on direct brain delivery, such as chemical

and molecular platforms for treatment of glioblastoma. Inspired by this critical unmet need, we have developed a novel device for highly efficient intracerebral injections that minimizes risks. The Multipoint Injection Technology (MINT) consists in a central catheter integrating three moveable microcannulas connected to a central actuation

mechanism for precise targeting and positioning, as well as maximization of volume coverage. Compared to current single cannula systems, MINT allows simultaneous injections from multiple microcannulas, thus eliminating the need for serial trajectories and potentially significantly reducing complexity, duration, and cost of

the surgery. Furthermore, MINT is compatible with magnetic resonance imaging (MRI) and can be seamlessly integrated with the current surgical workflows based on MR-guidance and monitoring. Finally, the radial configuration and the multiple injections sites along each microcannula result in a more uniform distribution of

the infusate in the tissue, thus maximizing the volume distribution and enabling targeting of different brain regions. In this project, we will advance this highly efficient intracerebral injection technology by validating it for MR-guided injections with benchtop tests and in vivo in non-human primates. Upon completion of this project,

we expect to move the field forward by generating and validating a new delivery device that will significantly improve coverage, while reducing surgical time and number of transcortical trajectories. Overall this proposal will establish the future clinical potential of the multipoint injection device as a potentially transformative and

enabling solution for highly efficient intracerebral delivery of gene-based, molecular, and pharmacological therapies and pave the way for fundamental innovations in the clinical care of neurological disorders.