The Vector
Volume 9, Issue 7: July 2020
Editorial Team
Edith Pfister, Ph.D. – Editor, The Vector
Karen Bulaklak, Ph.D. – Associate Editor, The Vector
Inside This Issue
Leadership Message
Breaking Through
Society News
Career Center
Public Policy
Industry News
Leadership Message
New Global Outreach Committee Ramps Up International Efforts
ASGCT’s most recent strategic plan, developed last year, includes global outreach as one of the five priority areas for the Society. I am thrilled that ASGCT rose to the call for action raised in the editorial I co-authored for Molecular Therapy, which highlighted the issue of inequitable access to gene therapies in low- and middle-income countries (LMICs), where a majority of patients live who have diseases potentially treated by gene therapies. To begin supporting global access to gene therapy, ASGCT was a sponsor in 2019 for the Foundation for the NIH’s International Summit in Human Genetics and Genomics, which provides a month-long training program at NIH for researchers from LMICs. This year, the Society created a Global Outreach Committee, for which I serve as chairperson.
The committee, with support from ASGCT staff, will be exploring opportunities to foster access globally in various ways. We aim to encourage clinical trial development in middle-income countries, such as Brazil, India, and South Africa, which have burgeoning regulatory frameworks and medical systems that can support gene therapy. By connecting with medical experts and the companies with gene therapy trials in these areas, we will identify trial challenges and potential ways to support development. We will also support low-income countries by increasing awareness of the state of the gene therapy field through partnered online educational programming. Since many of these countries are in the process of improving their medical infrastructure, raising awareness of gene therapy has the potential to impact public health initiatives. Given key targets of gene therapy (i.e., cancer, thalassemia, sickle cell disease, and hemophilia), improving knowledge will be an important component of improved access.
Lastly, the committee plans to foster interactions with gene therapy societies in other countries, as well as other potential partners, to provide research funding and training opportunities for researchers in their home countries.
We will provide information about this issue for attendees to the 2021 Annual Meeting through the committee’s first symposium. The session will highlight challenges and proposed solutions to facilitate access to gene therapy in LMICs, and the status of efforts toward the crucial goal of increasing access to gene and cell therapy around the world.
Ken Cornetta, M.D.
ASGCT Global Outreach Committee Chair
Breaking Through
Pronounced Therapeutic Benefit of a Single Bidirectional AAV Vector Administered Systemically in Sandhoff Mice
Lahey HG, Webber CJ, Golebiowski D, Izzo CM, Horn E, Taghian T, Rodriguez P, Batista AR, Ellis LE, Hwang M, Martin DR, Gray-Edwards H, Sena-Esteves M
DOI: https://doi.org/10.1016/j.ymthe.2020.06.021
Summary by Karen Bulaklak, Ph.D.
Tay-Sachs disease (TSD) and Sandhoff disease (SD) are rare lysosomal storage diseases that are caused by mutations in HEXA and HEXB genes, respectively. These genes encode subunits of the HexA protein that hydrolyzes GM2 ganglioside, and loss of activity leads to GM2 neuronal accumulation, resulting in neuronal death as well as microglial and astroglial activation. TSD and SD patients commonly experience seizures, difficulty swallowing, and failure to meet developmental milestones. Unfortunately, palliative measures can only help to extend lifespan in affected patients to a maximum of five years of age. A number of experimental therapies have been explored, including enzyme replacement therapy, substrate reduction therapy, and dietary changes. At the moment, adeno-associated virus (AAV) gene therapies appear to be the most promising approach for TSD and SD and have shown to improve neuropathology, reduce neuroinflammation, and extend lifespan when delivered intracranially in animal models of the diseases. While a less invasive approach is desired, delivery of both HEXA and HEXB genes in a single AAV is difficult due to the limited packaging capacity of 4.7 kb. A group of researchers from the University of Massachusetts and Auburn University explored the therapeutic potential of bicistronic AAV vectors to co-express both genes in SD mice.
In this study, the researchers designed two bicistronic AAV vectors, which they called AAV-Bic and AAV-P2I. AAV-Bic consisted of a bidirectional mini CBA promoter between the HEXA and HEXB genes, driving expression in opposite directions, while AAV-P2I contained a small P2 promoter and intron cassette beside each ITR to drive expression of each gene towards the center of the vector genome. These constructs were packaged into both AAV9 and AAV-PHP.B and injected systemically in four to six week old SD mice. Lifespan increased significantly for all treated mice compared to untreated mice. The greatest effect was seen with the AAV-PHP.B-Bic, which increased median survival up to 656 days. Motor function was also assessed via rotarod and inverted screen testing, which showed that all treatments stabilized strength and coordination in mice with SD. Hex enzymatic activity was measured, revealing a significant increase in both total and HexA activity in various brain regions after AAV9-Bic, AAV-PHP.B-Bic and AAV-PHP.B-P2I treatment. Liver enzymatic activity increased only with injection of AAV9-Bic. Furthermore, GM2 levels were assessed in the same brain regions and were markedly reduced in all treatment groups compared to the untreated cohort. Again, the most drastic reductions were observed with AAV9-Bic, AAV-PHP.B-Bic and AAV-PHP.B-P2I treatment, demonstrating a correlation between Hex activity and decreases in GM2. To measure neuroinflammation, immunofluorescent staining was performed to detect and quantify expression of microglial activation marker CD68. A significant reduction in microglial activity was observed in the brainstem and spinal cord after AAV9-Bic treatment, with levels similar to WT mice. Finally, the maximum age and minimal dose at which AAV9-Bic provide therapeutic effect was explored by looking at survival of treated SD mice. They observed that the treatment could still provide significant benefit when mice were treated up to 12 weeks of age and at a dose of 3e11 vg, which was roughly 1/3 of the maximum dose tested in the experiment. Taken together, these results show that an AAV-based bicistronic vector coexpressing HEX genes can ameliorate biochemical and functional aspects of disease, as well as extend survival close to a normal life expectancy of about two years in mice.
While the results of this study are promising, additional work is necessary prior to application in humans. For example, the greatest induction of enzymatic activity was observed via systemic injection with AAV-PHP.B. This recombinant capsid has shown exceptional neurotropism in mice on the C57BL/6J background, but low transduction efficiency after IV injection in NHPs. In the current study, AAV9 improved biochemical aspects and neuroinflammation; however, this was to a lesser degree and in lower brain regions. Mice also have an alternative metabolic pathway to catabolize GM2, which may work to enhance the improvements seen in this study. Still, the current work is the first to demonstrate therapeutic benefit with such an approach and seeks to overcome obstacles that hinder AAV gene therapies for TSD and SD. With continued effort, there may one day be an effective, minimally invasive treatment for these patients.
Society News
Submit an Abstract for COVID-19 Symposium Through July 31
Are you conducting research related to COVID-19? Submit an abstract through July 31! ASGCT is hosting a complementary two-day virtual scientific symposium September 15-16 that will highlight the advances in understanding SARS-Cov2 and treating COVID-19. More information will be available in the coming weeks.
Check Out Upgrades to Our Online Member Services
A new era for ASGCT calls for updated, easier to use online member services. We've built some new tools to handle many of the ways you interact with the Society online.Upgraded services include dues renewals, new member applications, Membership Directory, profile updates, committee listings, and Molecular Therapy access via the Members Only area of ASGCT.org. We hope you enjoy the updates!
Career Center
Are you looking for a job in the field of gene and cell therapy? Check out the new ASGCT Career Center and sign up to receive alerts for open jobs in your area.
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Featured Jobs
Public Policy
The 2020 Policy Summit is Going Virtual
ASGCT is putting together an exciting agenda for the 2020 Policy Summit, September 23-25. From the comfort and safety of your home, you can virtually participate in discussions on regulatory, government relations, market access, and ethical issues related to gene and cell therapy. Registration will open later this month.
Access Under Proposed Medicaid Project Concerns ASGCT
Last month ASGCT submitted a letter to the Centers for Medicare & Medicaid Services (CMS) expressing concern that a proposed Oklahoma Medicaid demonstration project could restrict patient access to gene and cell therapies. The proposal is the first application from a state Medicaid program for the Healthy Adult Opportunity (HAO) program, which CMS announced in January. The HAO program allows states to create demonstration projects that differ from standard Medicaid program requirements in certain key ways. Major issues with the proposed project include the introduction of patient cost-sharing, which can depress enrollment. Beneficiary failure to meet cost-sharing requirements can also lead to termination under the proposal. The elimination of retroactive coverage eligibility, the switch from per-patient reimbursement to a defined capped budget approach, and the potential to introduce a closed drug formulary are additional provisions that could restrict access to gene and cell therapies. HAO demonstration programs only apply to patients in states’ “Medicare expansion” populations—adults under age 65 who are not eligible for Medicaid on the basis of disability or their need for long-term care services and supports (“healthy adults”).
Industry News
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