Could you give us a brief overview of your experience before co-founding 4DMT?
I am the co-founder and CEO of 4D Molecular Therapeutics (4DMT) and a professor of bioengineering at UC Berkeley. My journey in both industry and academia spans about 30 years as a physician scientist, entrepreneur, innovator, serial CEO, and faculty member. I completed my undergrad at UC Berkeley, received my MD from UC San Francisco Medical School, and completed my residency in internal medicine at Harvard's Brigham and Women's Hospital.
My fascination with viruses, particularly their impact on human health and their biological and immunological interactions, led me to explore their therapeutic potential. This interest culminated in the founding of 4DMT, focusing on novel viral vector-based therapeutics, immunology, and genetic medicines.
Can you explain the concept of directed evolution and how it relates to 4DMT's platform, Therapeutic Vector Evolution?
Directed evolution, a Nobel Prize-winning technology, involves leveraging the principles of evolution to invent novel customized biologics. This approach was initially developed by scientists Francis Arnold, Greg Winters, and George Smith. In directed evolution, massive diversity in a particular enzyme or molecule is generated, then subjected to iterative selection processes and re-diversification to find the most functional variant for a desired profile.
At 4DMT, we applied this concept to the capsid of Adeno-Associated Virus (AAV) for gene delivery. Our process starts by generating roughly a billion different capsid versions, then selecting the most effective for targeting specific cells and tissues by a preferred method of administration.
This results in a customized delivery vehicle that is vastly superior in safety, efficacy, and convenience for patients compared to naturally occurring vectors.
Could you clarify whether your technology can be applied both in vivo and in vitro? What about in utero?
Our technology platform is able to invent novel genetic medicines for both children and adults, whether in vivo or in vitro. While in utero applications are possible, our focus is not on editing germ cells. In vivo, we deliver DNA inside a proprietary AAV vector to replace missing or mutant genes. For example, in treating age-related macular degeneration or diabetic eye disease, we introduce genes into patients' retinas at the back of their eyes to treat these vision-threatening diseases. Our technology makes possible the expression of biologics, such as proteins and nanobodies, within targeted tissues, enhancing treatment efficacy and patient convenience.
What happens when your technology is applied to a person with a rare disease?
When applied to a person with a rare inherited disease, our technology can deliver a normal version of a mutant or missing gene, effectively treating the condition. For instance, in cystic fibrosis, we deliver a normal CFTR gene to lung airway cells to replace the defective one. Importantly, our technology is not limited to gene replacement; we can also express biologic medicines directly in the diseased tissue. For example, in treating wet AMD, our vector can express a version of a highly effective protein medicine directly and continuously within the retina, eliminating the need for frequent eye injections. This approach is highly versatile, allowing for multiple therapeutic applications using the same delivery vehicle.
What products do you currently have in clinical trials?
We have five products in clinical trials, focusing on eye, lung and heart diseases. These include treatments for rare inherited eye conditions like X-linked retinitis pigmentosa (XLRP) and choroideremia (CHM), where we deliver a correct version of the defective gene. Another eye product, for both wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME), is advancing towards phase three. We are leveraging the same delivery vehicle across these products, swapping in different DNA for each specific condition. This efficiency streamlines the development of multiple therapeutics in a particular therapeutic area. Our cystic fibrosis trial is for an aerosolized product candidate that has demonstrated positive delivery and expression data, and is advancing through a phase 1/2 trial.
Do you believe your platform can be utilized for any genetically related disease in the future?
We are confident that our platform can be used to invent customized vectors and to develop effective genetic medicines for virtually any disease or tissue type. The primary limitation is with genes too large to fit into AAV vectors, such as in muscular dystrophy. Here, gene editing delivered with our vectors may be effective, where instead of delivering a new gene, the existing one is fixed in the patient. This adaptability and versatility of our platform make it a promising solution for a wide range of genetic conditions.
Partnerships seem to be at the heart of your work. What are some of your most promising collaborations?
We have several exciting collaborations, each following different models of partnership. One approach involves in-licensing or acquiring payloads to engineer into our vectors, where we develop the product and offer royalties to our partners. For example, we have collaborated with the University of Pennsylvania to develop a medicine for geographic atrophy, an eye condition affecting millions.
Another model is licensing our vectors to other companies, like our partnership with Astellas Pharma, who utilize our vector for treating rare eye diseases. Lastly, our most recent and innovative business collaboration is with Arbor Biotechnologies, a gene editing company. This 50-50 partnership combines Arbor's small, efficient CRISPR technology with our advanced AAV delivery vehicles. It allows us to co-develop and co-commercialize products, retaining significant control and value, which is beneficial for both companies and patients.
Finally, patient advocacy organizations are critical partners for us. The Cystic Fibrosis Foundation has been an invaluable partner in developing our CF product candidate.
How many treatments are usually required with your technology, and what are the potential side effects?
The number of treatments depends on the tissue type. For stable tissues like the retina, a single treatment could last over 10 years, providing lifelong benefits. However, for tissues like the lungs, which have a turnover of every two to three years, we might need to redose every three to five years.
As for side effects, the biggest challenge for the field has been inefficient delivery, leading to low expression levels and safety issues, especially with high-dose IV therapy. Our solution is directed evolution, creating customized, highly specific, and efficient vectors. This allows us to use lower doses, reducing inflammation and side effects. Our products, like the 4D-150 for the treatment of wet AMD and DME retinal diseases and 4D-710 in our cystic fibrosis program, have demonstrated this increased safety and efficacy.
Have you faced any negative public perception, especially give some connotations of "directed evolution"?
In terms of public perception, especially around the concept of "directed evolution," we have not faced significant issues. Our focus is on treating specific conditions, not altering germ cells or the human genome. Our clinical trials are designed to ensure we are not affecting germ cells. This differentiates our work from more controversial areas like germline editing, which would impact offspring. Our AAV-based treatments are targeted and do not involve altering the genetic makeup of future generations.
What are the main objectives for 4DMT in the coming years?
Our primary objective is to expand the reach of our directed evolution-based therapeutics to more patients. With strong proof of concept in multiple therapeutic areas, our focus is on advancing these treatments through clinical trials to regulatory approval and commercialization. We are particularly excited about our 4D-150 product for wet AMD and DME, aiming for phase three trials and approval. Our 4D-710 cystic fibrosis program targets patients without existing disease-modifying therapies, and we're committed to bringing this promising product candidate to the market.
Additionally, we are developing a cardiology product for Fabry disease cardiomyopathy and exploring treatments for severe brain diseases like ALS, possibly even Alzheimer's, in collaboration with Arbor. Our goal is to transform patient outcomes with these innovative therapies.