Developing gene therapies for rare diseases: an interview with Geoff MacKay

Regenerative Medicine ◽

10.2217/rme-2021-0126 ◽

2021 ◽

Author(s):

Geoff MacKay

Keyword(s):

Gene Therapy ◽

Clinical Stage ◽

Senior Leadership ◽

Leadership Positions ◽

Gene Therapies ◽

Track Record ◽

Lysosomal Disorders ◽

Successful Leadership ◽

Lentiviral Gene Therapy ◽

Cell And Gene Therapy

Geoff MacKay is a pioneer in cell and gene therapy with a track record of successful leadership at innovative biotechs. He is currently the president and CEO of AVROBIO, a clinical-stage lentiviral gene therapy company that treats lysosomal disorders, and a board member of Talaris Therapeutics and Satellos Bioscience. He is also the founding CEO of eGenesis, a biotech that applies CRISPR-Cas9 gene editing to xenotransplantation and the former president and CEO of Organogenesis, a world-leading cell therapy company. Earlier in his career, MacKay spent 11 years at Novartis in senior leadership positions within the global transplantation and immunology franchise.

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Critical Aspects of Clinical Trial Design for Novel Cell and Gene Therapies

Parkinson s Disease ◽

10.4061/2011/804041 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Zinovia Kefalopoulou ◽

Iciar Aviles-Olmos ◽

Thomas Foltynie

Keyword(s):

Gene Therapy ◽

Viral Vector ◽

Safety Data ◽

Clinical Trial Design ◽

Open Label ◽

Double Blind ◽

Gene Therapies ◽

Technological Advances ◽

Vector Gene Transfer ◽

Cell And Gene Therapy

Neural cell transplantation and gene therapy have attracted considerable interest as promising therapeutic alternatives for patients with Parkinson's disease (PD). Preclinical and open-label studies have suggested that grafted fetal neural tissue or viral vector gene transfer can achieve considerable biochemical and clinical improvements, whereas subsequent double-blind, placebo-controlled protocols have produced rather more modest and variable results. Detailed evaluation of these discordant findings has highlighted several crucial issues such as patient selection criteria, details surrounding transplantation or gene therapy methodologies, as well as the study designs themselves that ought to be carefully considered in the planning phases of future clinical trials. Beyond the provision of symptomatic efficacy and safety data, it also remains to be identified whether the possibilities offered by stem cell and gene therapy technological advances might translate to meaningful neuroprotection and/or disease-modifying effects or alleviate the nonmotor aspects of PD and thus offer additional benefits beyond those achieved through conventional pharmacotherapy or deep brain stimulation (DBS).

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The role of small molecules in cell and gene therapy

RSC Medicinal Chemistry ◽

10.1039/d0md00221f ◽

2021 ◽

Author(s):

Lewis L. Brayshaw ◽

Carlos Martinez-Fleites ◽

Takis Athanasopoulos ◽

Thomas Southgate ◽

Laurent Jespers ◽

...

Keyword(s):

Gene Therapy ◽

Small Molecules ◽

Gene Therapies ◽

Cell And Gene Therapy

Current and future uses of small molecules to improve the safety, efficacy and manufacturing of cell and gene therapies.

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Automation in cell and gene therapy manufacturing: from past to future

Biotechnology Letters ◽

10.1007/s10529-019-02732-z ◽

2019 ◽

Vol 41 (11) ◽

pp. 1245-1253 ◽

Cited By ~ 15

Author(s):

P. Moutsatsou ◽

J. Ochs ◽

R. H. Schmitt ◽

C. J. Hewitt ◽

M. P. Hanga

Keyword(s):

Gene Therapy ◽

Mass Production ◽

Large Scale ◽

Process Efficiency ◽

Manufacturing Processes ◽

Regulatory Requirements ◽

Translation Process ◽

Gene Therapies ◽

Cell And Gene Therapy ◽

Insight Into

Abstract As more and more cell and gene therapies are being developed and with the increasing number of regulatory approvals being obtained, there is an emerging and pressing need for industrial translation. Process efficiency, associated cost drivers and regulatory requirements are issues that need to be addressed before industrialisation of cell and gene therapies can be established. Automation has the potential to address these issues and pave the way towards commercialisation and mass production as it has been the case for ‘classical’ production industries. This review provides an insight into how automation can help address the manufacturing issues arising from the development of large-scale manufacturing processes for modern cell and gene therapy. The existing automated technologies with applicability in cell and gene therapy manufacturing are summarized and evaluated here.

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Faculty Opinions recommendation of Correction of murine Rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.722644269.793515036 ◽

2016 ◽

Author(s):

Fabio Candotti

Keyword(s):

Gene Therapy ◽

Severe Combined Immunodeficiency ◽

Combined Immunodeficiency ◽

Lentiviral Gene Therapy

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Attenuating Muscle Wasting: Cell and Gene Therapy Approaches

Current Genomics ◽

10.2174/1389202033490222 ◽

2003 ◽

Vol 4 (7) ◽

pp. 575-585 ◽

Cited By ~ 2

Author(s):

A. Musaro ◽

N. Rosenthal

Keyword(s):

Gene Therapy ◽

Muscle Wasting ◽

Cell And Gene Therapy

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The Ocular Gene Delivery Landscape

Biomolecules ◽

10.3390/biom11081135 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1135

Author(s):

Bhubanananda Sahu ◽

Isha Chug ◽

Hemant Khanna

Keyword(s):

Gene Therapy ◽

Genetic Diseases ◽

Gene Therapies ◽

Advantages And Disadvantages ◽

Fda Approval ◽

New Information ◽

Efficient Delivery ◽

Delivery Routes ◽

History Of ◽

Different Parts

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These examinations have revealed new information about the benefits as well as restrictions to using drug-delivery routes to the different parts of the eye. In this article, we will discuss a brief history of gene therapy and its importance to the eye and ocular delivery landscape that is currently being investigated, and provide insights into their advantages and disadvantages. Efficient delivery routes and vehicle are crucial for an effective, safe, and longer-lasting therapy.

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Characterization of Recombinant Adeno-Associated Viruses (rAAVs) for Gene Therapy Using Orthogonal Techniques

Pharmaceutics ◽

10.3390/pharmaceutics13040586 ◽

2021 ◽

Vol 13 (4) ◽

pp. 586

Author(s):

Liam Cole ◽

Diogo Fernandes ◽

Maryam T. Hussain ◽

Michael Kaszuba ◽

John Stenson ◽

...

Keyword(s):

Gene Therapy ◽

Light Scattering ◽

Dynamic Light Scattering ◽

Viral Vector ◽

Structural Characteristics ◽

Genetic Material ◽

Label Free ◽

Gene Therapies ◽

Multiple Challenges

Viruses are increasingly used as vectors for delivery of genetic material for gene therapy and vaccine applications. Recombinant adeno-associated viruses (rAAVs) are a class of viral vector that is being investigated intensively in the development of gene therapies. To develop efficient rAAV therapies produced through controlled and economical manufacturing processes, multiple challenges need to be addressed starting from viral capsid design through identification of optimal process and formulation conditions to comprehensive quality control. Addressing these challenges requires fit-for-purpose analytics for extensive characterization of rAAV samples including measurements of capsid or particle titer, percentage of full rAAV particles, particle size, aggregate formation, thermal stability, genome release, and capsid charge, all of which may impact critical quality attributes of the final product. Importantly, there is a need for rapid analytical solutions not relying on the use of dedicated reagents and costly reference standards. In this study, we evaluate the capabilities of dynamic light scattering, multiangle dynamic light scattering, and SEC–MALS for analyses of rAAV5 samples in a broad range of viral concentrations (titers) at different levels of genome loading, sample heterogeneity, and sample conditions. The study shows that DLS and MADLS® can be used to determine the size of full and empty rAAV5 (27 ± 0.3 and 33 ± 0.4 nm, respectively). A linear range for rAAV5 size and titer determination with MADLS was established to be 4.4 × 1011–8.7 × 1013 cp/mL for the nominally full rAAV5 samples and 3.4 × 1011–7 × 1013 cp/mL for the nominally empty rAAV5 samples with 3–8% and 10–37% CV for the full and empty rAAV5 samples, respectively. The structural stability and viral load release were also inferred from a combination of DLS, SEC–MALS, and DSC. The structural characteristics of the rAAV5 start to change from 40 °C onward, with increasing aggregation observed. With this study, we explored and demonstrated the applicability and value of orthogonal and complementary label-free technologies for enhanced serotype-independent characterization of key properties and stability profiles of rAAV5 samples.

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