Armen Asatryan joined Myrtelle in 2021, shortly after its inception, and has over 20 years of combined experience in pharma/biotech, public health, and clini- cal medicine. Prior to joining the com- pany, Armen held positions of increasing responsibility at Abbott/AbbVie, AveXis/ Novartis, and most recently at AVROBIO, where he was Vice President of Clinical

Development leading Fabry, Cystinosis, Hunter, and Pompe gene therapy programs as well as the company’s Drug Safety and Pharmacovigilance function. Armen’s passion is to bring novel transformational treatments to patients with rare diseases through

Q: Can you describe what rAAV- Olig001-ASPA is and why Canavan disease is a great target?

A: Like most gene therapies, rAAV-Olig001-ASPA is a gene therapy product that consists of 2 parts: “gene construct” – a working copy of the ASPA gene (the gene that is affected in Canavan disease), and “viral vector” – a vehicle by which the “gene construct” is delivered into the patient and ultimately reaches the organ of interest, which is the brain in Canavan disease. Gene construct is made specifically to enable production of Aspartoacylase (ASPA) enzyme – the enzyme that is missing in patients with Canavan disease due to a defect (mutation) in ASPA gene. The viral vector is based on adeno-associated viruses (AAV), and is made via recombinant technology (this is denoted by the letter “r” as the first letter in the name of the drug), meaning that the vector is “man-made” using various parts of the AAVs.

Q: This proprietary gene-therapy has over 25 years of research behind it including earlier Canavan clinical trials. All have used direct delivery into the brain. Can you explain why this method continues to be used in your program?

A: Based on our understanding of the research in animal models of Canavan disease showed that efficacy of gene therapy delivered into the brain space has showed better results compared to other methods. Hence, Myrtelle is focusing its efforts on the intracerebroventricular (ICV), i.e., into the lateral ventricles of the brain, method of delivery of gene therapy.

Q: Canavan disease is a brain-based disease caused by a mutation in the ASPA gene. However, we know the ASPA enzyme also exists in other organs. Can your gene therapy possibly reach other organs, and is it necessary?

A: While ASPA gene may exist in various cells/tissues/organs, the main organ of interest in Canavan disease is the brain – this is the organ that is the most affected in Canavan disease, and damage to the brain is the main source of morbidity and mortality in the patients with Canavan disease. The ability of any gene therapy to reach a given cell/tissue/organ largely depends on the type of the vector used (AAV vectors have many types) and the route of gene therapy administration. For example, AAV9-based vectors are known to traverse the blood brain barrier (BBB) when administered intravenously. Conversely, when these vectors are administered into cerebrospinal spinal fluid space intrathecally or ICV, they are also able to pass through the BBB and distribute systemically into various peripheral organs. However, more vector is retained in the original compartment of gene therapy delivery than the other compartments where the vector may reach after traversing the BBB. For example, with intravenous AAV9 vector-based gene therapy, in our assessment of the data, a substantial amount of vector gets “trapped” in the liver because that is the first major organ through which the vector “travels”, and hence, less amount of vector is available for delivery into the brain.

Q: Do you envision re-dosing? If so, is it possible once a patient has already received treatment?

A: The goal of any gene therapy is to provide life-long therapeutic effect in a safe manner with a single administration of the drug. In certain cells and tissues, where rapid cell turn turnover is a norm, over time, the efficacy of AAV vector-based gene therapies may, theoretically, decrease. However, the cells in the brain targeted by our gene therapy for Canavan disease, namely, oligodendrocytes, have a stable population, and hence, it is not expected that there will be a significant turnover of these cells. Thus, the efficacy of our gene therapy should be preserved over the long period of time. The patients treated in the clinical trials will be followed for many years to assess long-term efficacy and safety of gene therapy.

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