The Vector

Volume 9, Issue 1: January 2020


Editorial Team

Melvin Rincon, M.D., Ph.D. – Editor, The Vector
Edith Pfister, Ph.D. – Associate Editor, The Vector
Karen Bulaklak, Ph.D. – Junior Editor, The Vector

Inside This Issue

Leadership Message
Breaking Through
Society News
Career Center
Public Policy
Industry News

Leadership Message

Gearing Up for 2020

Happy New Year, ASGCT Members! I hope you all had a happy and restful holiday, and that you’re ready for an exciting year ahead. I’m looking forward to finding out what this year will bring for the field of gene and cell therapy, and I’m positive that it will be another groundbreaking year for our Society.

One of the highlights of 2020 will be the ASGCT 23rd Annual Meeting, May 12-15 in Boston, the first held in a convention center since 2013. As a citizen of Massachusetts, I hope it does not sound too biased for me to say that Boston is the hottest place on the planet for gene therapy! It certainly will be this May! If you haven’t submitted an abstract for the meeting, please submit your research soon, as abstract submission closes on January 29. Submitting an abstract gives you the opportunity to present your work to thousands of peers at the meeting, and you may also be eligible for awards, travel grants, and free registration. In addition to the incentives, make sure you read up on submission and presentation information and the abstract topic categories. We look forward to reading and learning about all of your fantastic research. If you’ve already submitted an abstract, notifications will be sent on April 6.

With the commotion that surrounds the holidays, I know it can be difficult to check off everything on your to-do list. That’s why I also want to remind you to renew your ASGCT membership if you haven’t already. You’ll receive a discount on annual meeting registration (in addition to the discount if you register by April 10), journal subscriptions, and more. Your membership is so important to the work we do to advance the field of gene and cell therapy; we can’t do it without you. Thank you for your support, and get ready for an exhilarating year.

Best,
Terence R. Flotte, M.D.
ASGCT Secretary

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Breaking Through

biAb Mediated Restoration of the Linkage between Dystroglycan and Laminin-211 as a Therapeutic Approach for α-Dystroglycanopathies

Gumlaw N, Sevigny L, Zhao H, Luo Z, Bangari D, Masterjohn E, Chen Y, McDonald B, Magnay M, Travaline T, Yoshida-Moriguchi T, Fan W, Reczek D, Stefano J, Qiu H, Beil C, Lange C, Rao E, Lukason M, Barry E, Brondyk W, Zhu Y, Cheng S

DOI: https://doi.org/10.1016/j.ymthe.2019.11.023

Summary by Karen Bulaklak, Ph.D.

For patients with α-dystroglycanopathies, a group of rare congenital muscular dystrophies, treatment options are vastly limited. Patient symptoms are largely heterogeneous and can range from congenital-onset weakness and severe structural brain abnormalities, as with Walker-Warburg syndrome or muscle-eye-brain disease, to late-onset muscle weakness without brain involvement, such as with limb girdle muscular dystrophy type 2I. Thus far, α-dystroglycanopathies have been linked to mutations in one of 18 genes, which lead to reduced or absent O-linked glycosylation on α-dystroglycan. α-dystroglycan (αDG) is a vital component of the dystrophin-associated glycoprotein complex (DGC), which is located at the cellular membrane and serves to link the extracellular matrix and intracellular cytoskeleton, providing structural stability. Without proper O-glycosylation, αDG is unable to efficiently bind ligands in the extracellular matrix, such as laminin-211, agrin and perlecan, resulting in contraction-induced damage. Because α-dystroglycanopathies vary in their presentation, severity, and genetic cause, designing effective therapies to address all subtypes is challenging. Furthermore, previous attempts to provide O-glycosylated αDG in mouse models were unsuccessful. In the current study, Gumlaw et al sought to overcome these obstacles by creating a bispecific antibody (biAb) to link the DGC to the extracellular matrix, effectively compensating for αDG’s function in stabilizing the membrane. By focusing on the structural role of αDG rather than tackle a single genetic mutation, this approach would be applicable to many patients with various forms of α-dystroglycanopathy.

In designing their therapeutic, the research group aimed to create a biAb that bound DGC-associated β-dystroglycan (βDG) to laminin-211 in the basal lamina, circumventing the issue of low levels of αDG interfering with linkage restoration. After screening monoclonal antibodies that bound mouse and human βDG and laminin-211 with the desired specificity and affinity in their native state, they engineered a biAb containing the VH and VL sequences of each mAb. The resulting biAb was used to treat the LARGEmyd-3J mouse model of α-dystroglycanopathy, which are deficient in the LARGE protein that O-glycosylates αDG. After intramuscular injection with the biAb, treated LARGEmyd-3J mice showed decreased muscle membrane damage after forced treadmill exercise compared to treatment with the parental mAbs. Next, the group treated mice systemically and observed muscle-specific accumulation of the biAb and levels maintained in the blood for up to 14 days post injection. Moreover, biAb treatment improved strength and endurance of LARGEmyd-3J mice and appeared to reduce exercise-induced damage of the tibialis anterior muscle. While the results are encouraging, the authors did not see a reduction of damage in other muscles or improvements in other biochemical markers. The authors pointed to steric hindrance, monovalent biAb binding (versus normal multivalent a-DG binding), as well as suboptimal biAb dose as possible reasons. To this end, they created a biAb in a Duobody format, “biAb-2,” to improve target affinity and reduce steric hindrance. They found that biAb-2 treatment improved grip strength of LARGEmyd-3J mice, albeit to a lesser degree than AAV-mediated Large overexpression.

In its current state, the biAb-based therapy has some drawbacks that may contribute to its performance in vivo.  Inefficient binding and the inability to bind other extracellular matrix ligands, such as agrin, also prevent the therapy from addressing neuromuscular deficits associated with α-dystrophinopathies. However, this approach is a step in the right direction in creating more accessible therapies benefitting a larger patient population affected by rare diseases.

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Society News


Abstract Submission is Open Through January 29

We need your research for the 23rd Annual Meeting. Submit your abstracts by Jan. 29 for the opportunity to present your work in Boston to colleagues and leaders in the field of gene and cell therapy. Visit the annual meeting website for more information about abstract categories, award incentives, and submission information.

Maintain Benefits by Renewing Your Membership

If you haven't renewed your ASGCT membership, now is the perfect time to do so. Make sure you don't lose access to your membership benefits, like Annual Meeting travel grants, registration discounts, poster and publication opportunities. Your membership is critical to helping the Society's efforts in 2020!

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Career Center


Are you looking for a job in the field of gene and cell therapy? Check out the ASGCT Job Bank and sign up to receive alerts for open jobs in your area.

If you're from a recruiting institution, advertise in the Featured Jobs section to target the 3,000+ audience of The Vector.

Featured Jobs

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Public Policy


USP Invites ASGCT to Join as a Voting Member

The United States Pharmacopeial (USP) Convention has invited ASGCT to join their organization as a voting member. Through membership in the USP Convention, ASGCT will have the opportunity to contribute its expertise to support the development of global health standards.

USP is an international organization with a mission to improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods. USP Convention members include more than 450 scientific, academic, patient, and industry associations, in addition to government agencies in the US and abroad. At the USP Convention meeting, which occurs every five years, delegates from voting members discuss USP’s next strategic plan and elect leadership and expert committees.

The chair of ASGCT’s Regulatory Affairs Committee, Adora Ndu, PharmD, J.D. will serve as the ASGCT delegate to the USP Convention for the five-year cycle. Dr. Ndu is the vice president of Regulatory Affairs; Policy, Research, Engagement (PRE) & International at BioMarin.

ASGCT Supports Treatment Access in Cures 2.0 Comments

As part of ASGCT’s priority to ensure patient access to approved gene therapies, the Society responded last month to a request for information from Representatives Fred Upton (R-MI) and Diana DeGette (D-CO). These representatives are working on a proposed update to the 21st Century Cures Act of 2016, known as Cures 2.0. The original Cures Act, passed with broad bipartisan support, provided $5.3 billion to the National Institutes of Health and the Food and Drug Administration to help accelerate medical development and increase safe, efficient patient access to innovative new treatments, including gene and cell therapies.

ASGCT submitted comments supporting the following recommendations:

  • Eliminating coverage barriers for newly approved therapies
  • Reforming the new technology add-on payment system
  • Clarifying the pathway to MS-DRGs for new technologies
  • Paving the way for alternative payment models

ASGCT Signs on to Newborn Screening Letter

In December ASGCT signed on to a letter led by the March of Dimes urging HHS Secretary Alex Azar to resume the activities of the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). The Committee provides systematic evidence-based and peer-reviewed recommendations for adding conditions to the Recommended Uniform Screening Panel, which serves as the model for state newborn screening programs. The ACHDNC had a lapse in functioning since reauthorization of the Newborn Screening Saves Lives Act has not yet occurred. ASGCT supports robust newborn screening programs, which allow for early diagnosis and access to approved treatments for genetic diseases.

Industry News


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2020

23rd Annual Meeting

May 12-15 | Boston