Current & Future State of Gene Therapy

Sheila Mikhail, CEO and Co-Founder of AskBio, was recently named EY’s 2021 Entrepreneur Of The Year National Overall Award winner. The preeminent competitive awards recognize the unstoppable entrepreneurs transforming our world.
 
Sheila is a business leader changing lives by advancing genetic technology and adeno-associated virus (AAV) gene therapy. AskBio’s technology arms viruses with healthy biomaterial that rewrites disease-causing DNA mutations, significantly fortifying the frontline against cancer, muscular dystrophy and more. In her role as CEO, Sheila ensured AskBio’s gene trials continued through the pandemic, helping blind people see and giving children in wheelchairs the ability to walk and even play baseball.
 
AskBio is a pioneer of AAV technology, which can be used as a delivery system for therapeutic genetic material into living tissues, curing disease. Bayer purchased the company in December 2020.
 
Sheila discusses breakthroughs with gene therapies and the impact they’ve had on the industry, what we can expect for the gene therapy market going forward, and the challenges that remain.
 

 
Sheila Mikhail: After an extended period of stagnation, gene therapy has recently experienced a renaissance because of significant advances in technology and manufacturing scale. Over the last several years, scientists have developed safer, more efficient viral vectors (most notably, adeno-associated viral vectors, or AAV) with better targeting capability and controlled gene expression. Manufacturing processes have also been advanced, leading to significantly scaled up manufacturing capabilities. This allows us to achieve larger yields in the manufacturing process, and significantly reduce the cost of goods.
 
 
SM: The innovation in technology and manufacturing capabilities have had a profound impact on the industry and advance of gene therapies. Technology advances have enabled transformative therapeutics to be brought to patients including ZOLGENSMA to treat Spinal Muscular Atrophy (SMA), LUXTURNA to treat inherited retinal disease and blindness, and hopefully soon, several gene therapy candidates to treat Duchenne Muscular Dystrophy (DMD). AskBio’s technology is used in each of these therapeutics.
 
As an industry, we are also beginning to tackle pathway diseases. At AskBio, we are developing two gene therapies to potentially treat Parkinson’s disease as well as Chronic Heart Failure.
 
The future in gene therapy is bright. There are currently approximately 400 gene therapy clinical trials ongoing, and we expect to see additional new gene therapies gain regulatory approval in the years ahead. This is critically important for patients and patient communities who are waiting for therapeutic advances to treat their unmet genetic diseases.
 
 
One of these issues is precise tissue targeting without off-target implications to improve therapeutic performance. At AskBio, we have been working to advance the capsid engineering process to improve treatment for patients. A critical component of our gene therapy technology platform is a proprietary application of bioinformatics, crystal structure analytics, in vivo/in vitro modeling, and genome sequencing techniques. This allows us to alter the natural tropism range of chimeric AAV vectors.
 
Another area we are focused on is synthetic AAV promoter technology to enable precise cell and tissue selectivity with inducible capability. Synthetic promoters are customizable to drive gene expression from therapeutic vectors by leveraging naturally occurring transcriptional elements and yield many patient benefits. Essential to advancing gene therapeutics, we can design promoters at any length with novel sequences, unique combinations of regulatory elements, and specified activity characteristics. Our goal is to create more efficient control of gene expression, regulation of overall gene activity, and increased RNA stability.
 
In addition, AskBio is also working on several approaches to tackle the challenges of repeat dosing in gene therapy, as well as addressing pre-existing neutralizing antibodies, which are both significant challenges we must address to advance more efficient and effective gene therapy treatments.
 
We are also working to further advance gene therapy manufacturing by increasing manufacturing yields while also advancing synthetic biology approaches to DNA manufacturing.
 
AskBio’s system, known as the Pro10™, is believed to have the highest yields in the industry. We have also invested significantly in advancing Doggybone™ DNA (dbDNA™). Plasmid DNA, which is widely used in the industry, uses an E. coli process, which leaves many bacterial contaminants in the end product. Through the innovation of dbDNA, we can generate DNA with no bacterial impact and produce in higher volumes in significantly less time than plasmid DNA. AskBio continues to innovate to reduce manufacturing costs to bring more affordable products to patients. AskBio is developing a producer cell line to further reduce these costs. 
 
 
SM: While the first generation of gene therapies focused on gene augmentation approaches, gene editing approaches have recently entered the clinic, which allow for more precise modification of human genome sequences.  Gene editing technologies are evolving quickly from nuclease-based systems to base editing and prime editing that enable the precise alteration of genomic sequences in the absence of DNA beaks and without reliance on the activity of endogenous DNA repair pathways.  Further advancements in the technology will continue to fuel innovation in gene therapy and have a profound impact for patients.
 
In addition, there will be expanded focus and need for approaches to treat ultra-rare diseases. The industry does not want to leave patients behind, especially children with ultra-rare diseases, so it becomes important to look at different models and approaches to advance gene therapies in these ultra-rare conditions. At AskBio, our founders led an effort to form the Columbus Children’s Foundation, which is a non-profit focused on developing and providing gene therapy treatment for children battling ultra-rare conditions. Currently CCF is advancing therapeutic gene therapy for aromatic l-amino acid decarboxylase (AADC) deficiency. So far, ~30 children with AADC deficiency have been treated through the Foundation’s efforts at no cost, and we have seen transformative results for these children.
 
 

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Sheila Mikhail has over 20 years of biopharmaceutical leadership experience and is Chief Executive Officer and co-founder of Asklepios BioPharmaceutical, Inc. (AskBio), a company she started in 2001. She most recently served as Chief Executive Officer and co-founder of Bamboo Therapeutics, which in 20 months raised $50 million, advanced a therapeutic for GAN into the clinic, completed pre-IND studies for a Duchenne muscular dystrophy therapeutic, and built a GMP manufacturing facility. Bamboo was acquired by Pfizer in August 2016 in a deal valued at $827 million. Prior to that, she was part of the management team at Chatham Therapeutics, which was acquired by Baxter in 2014. Ms. Mikhail practiced law for more than 15 years. During that time, she founded Life Sciences Law, which serviced clients including Bayer, Gilead, GSK, Sanofi and Aventis.