By Allyson Berent, DVM, DACVIM

 At the annual Foundation for Angelman Syndrome Therapeutics (FAST) Global Summit in December, Jodi Cook, Ph.D., Chief Operating Officer for Agilis Biotherapeutics (Agilis), presented on gene therapy development for Angelman Syndrome (AS). Her presentation was very exciting for the community as we prepare to bring gene therapy treatment into human clinical trials.

You may be asking, what is gene therapy?  When we discuss gene therapy in Angelman Syndrome, we are often referring to the use of a modified virus (such as the adeno-associated virus, or AAV for short) that has all of the pathogenic or illness-causing components removed in order to carry a functional copy (DNA construct) of the missing UBE3A gene into the nerve cells (neurons) of the brain.  This allows cells in the brain to begin making the protein that is normally produced by the missing or mutated UBE3A gene, thus treating the condition at its source. Our scientists are currently working diligently to determine the most effective DNA construct, as well as the most effective viral delivery, to obtain global brain gene/protein expression. This may involve direct delivery through an injection into the cerebral spinal fluid (CSF), into a peripheral vein, or potentially into the brain itself.

Gene therapy was first attempted in 1989. Over the past several decades and with much research, increased knowledge and understanding has led to clinical successes.   The benefit of this type of therapy is that the virus can infect the targeted cell and then allow for long-term gene expression. The virus DNA will persist for many years, potentially a lifetime, in non-dividing cells (neurons). With over 1,500 gene therapy trials currently underway for other conditions, this approach has been found to be safe and well tolerated.  Replacing the missing or mutated gene that causes Angelman Syndrome is no longer a matter of science fiction or an impossible feat; it’s now just a matter of time and funding.

It is well documented that the brain in individuals with Angelman Syndrome is anatomically normal and that AS is not degenerative, as such; the expectation is that replacing the gene will eventually restore function and the symptoms of AS can be rescued. Compared to other more devastating neurologic disorders where the brain is not anatomically normal and degeneration of function and structure are present, treating AS seems very promising and thus, has garnered interest from several pharmaceutical and biotherapeutic companies. It is expected that a meaningful impact can be made using gene therapy for ALL individuals with Angelman Syndrome, not just young babies.

In a study published by Dr. Weeber’s lab (Dailey et al, 2011), it was found that after the AAV-Ube3a gene construct was inserted into the brains of mice with AS, Ube3a expression was increased and cognition was improved. This study was conducted on adult mice, suggesting the potential that adults with AS will also see a benefit in UBE3A recovery.  In the AS mice, improvements were seen in learning, memory, cognition, seizures, neuronal/synaptic plasticity and motor coordination. This effect could have a major impact on humans that have a more dramatic ability to learn and create synaptic pathways in the brain.

Agilis has partnered with Dr. Edwin Weeber and Dr. Kevin Nash at the University of South Florida, two members of the FAST FIRE Team (FAST Integrative Research Environment). There is ongoing research currently being conducted and collaboration with USF to move to a human UBE3A gene-AAV.  FAST is working with Agilis and the University of South Florida to assess innovative targeting vectors to deliver the therapeutic UBE3A DNA or the UBE3A protein to key neurons of the brain. Together, we are exploring safe and effective long-term expression of the gene and/or protein for individuals with Angelman Syndrome.

In 2015, Agilis Biotherapeutics received Orphan Drug Designation by the FDA for their gene therapy program in Angelman Syndrome. This is the first time orphan designation has ever been granted to any product for AS. This designation provides a 7 year market exclusivity for this specific technology, tax incentives for research and development costs, user fee waivers, eligibility for fast tracking through the FDA review process to get drugs approved in an expedited manner and allows Agilis to have more frequent interactions with regulators at the FDA to ensure excellent clinical trial design.   Additionally, Agilis is actively working with the Angelman community in a pre-competitive approach, in order to help establish patient centered outcome measures and biomarkers, which will be needed to assess therapeutic benefit during clinical trials for AS.

During the FAST Summit, Dr. Jodi Cook presented a pre- and post- treatment video on another gene therapy program Agilis Biotherapeutics is developing for aromatic L-amino acid decarboxylase deficiency (AADC), which is caused by a mutation in the DDC gene (dopa decarboxylase). The lack of this gene results in the inability to develop motor strength and control, causing breathing, feeding and swallowing problems.  Many individuals with AADC die within the first decade of life. Recently, Agilis partnered with National Taiwan University to investigate gene therapy using AAV delivery mechanisms with the human AADC gene construct. The patients demonstrated substantial motor function gains, cognitive scale improvements and had reduced morbidity and mortality rates.  The results were astonishing.

The video below demonstrates the effect of a single injection into the brain of a gene therapy product in another patient with AADC and is a great example of how functional AAV gene therapy can change the landscape for a neurogenetic disorder.

FAST is very excited to continue their work with Agilis Biotherapeutics to develop a gene therapy for our children.  As always, FAST is enormously grateful to our community and supporters whose generous contributions make these advancements possible.