Approaching Capsid Engineering with Patients in Mind
By: Ben Deverman, PhD, Scientific Founder of Apertura and Senior Director of Vector Engineering at the Broad Institute of MIT and Harvard
Gene therapies are only as effective as their delivery systems, and like the transport vehicles used to move goods and people, they are most effective when custom designed. As the field of gene therapy advances the safety and efficacy of genetic medicines to treat a variety of genetic conditions, our focus has shifted to improving the efficiency and specificity of our delivery strategies. Engineering AAV capsids to make them more effective for treating a wider range of debilitating diseases is the focus of my lab at the Broad Institute.
I became interested in gene delivery to the brain when I was a postdoctoral scientist in neuroscience at Caltech. Delivering genes to the brain seemed like an insurmountable challenge, but we developed AAV capsids that crossed the blood-brain-barrier in mice which, for the first time, made it possible to efficiently deliver genes throughout the adult brain via the vasculature. Our breakthrough exceeded my wildest expectations, and from that point on, I was hooked on developing gene delivery technology because of the potential impact in spurring new research avenues and treatments for patients. A few years after starting my own lab at the Broad Institute, I co-founded Apertura with Deerfield Management to advance the core technologies behind gene therapy delivery and expression to improve our ability to treat a broader set of diseases with genetic medicines.
Ben Deverman, PhD Scientific Founder of Apertura
The Deerfield team and I shared the view that next-generation gene therapies will utilize bespoke technologies precisely optimized for the requirements of specific genetic diseases with patients in mind. We aim to develop more effective treatments for a broader range of debilitating diseases. This expansion requires that we dramatically improve gene delivery technologies.
My lab focuses primarily on addressing genetic medicine delivery challenges through fine-tuned capsid engineering. We have developed and are applying several new platform technologies, which are the scientific basis for Apertura, including Fit4Function, a high-throughput machine learning platform that facilitates systematic multi-trait capsid engineering, as well as techniques for targeting AAV capsids to specific human protein targets (receptors) for improved and predictable tropisms.
Leveraging Machine Learning for Next-Generation Capsid Engineering
It is paramount that we develop vehicles to deliver gene therapies to affected cells and tissues with much greater efficiency. Increasing the delivery efficiency and reducing the biased uptake in certain organs like the liver can also improve specificity, especially if we can also administer lower doses.
My lab developed a way to systematically map AAV capsid sequences to target tissues and demonstrated the applicability of the screening approach with novel AAVs that demonstrate higher tropism for target tissues. The Fit4Function pipeline approach creates a framework for in silico vector predictions of multiple traits simultaneously rather than sequentially, optimizing our search for capsids that have several key characteristics required for a successful delivery vehicle1. A further benefit of the Fit4Function approach is that we accumulate knowledge as we screen our libraries across many functional measures. We are effectively creating a machine learning ‘atlas’ of AAV capsid ‘sequence-to-function maps’ that we can use to predict vector tropism and design next-generation, bespoke gene therapies to treat a wide array of genetic conditions.
Engineering Capsid Tropisms Using Function- and Mechanism-Based Approaches
While Fit4Function provides a method for engineering capsids with a specific function in mind (such as targeting a specific tissue type), my lab has also focused on designing gene therapy vectors for targets with known mechanisms of action.
Viruses enter target cells through receptor binding. By leveraging the rapidly accumulating knowledge of gene expression on each of the individual cell types that make up our organs, we can take a mechanism-based approach to capsid design. My lab introduced an approach to generate capsids that bind particular target proteins, yielding AAV capsids directly targeted to the CNS in mice as a proof-of-concept2. We are now putting this same technology to work to design capsids that engage specific human proteins.
Broadening the Applicability of Genetic Medicines
By engineering capsids from multiple angles using functional and mechanistic approaches and pairing these capsids with customized gene expression technologies, Apertura is working to overcome current limitations in gene therapy delivery and develop critical therapies for patients. I look forward to contributing further technological advances and helping fulfill Apertura’s mission of driving the next breakthroughs across an entire spectrum of genetic disorders.
Learn more about how Apertura is re-envisioning AAV capsid engineering at aperturagtx.com.