Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct;31(19-20):1034-1042.
doi: 10.1089/hum.2020.259.

The Platform Vector Gene Therapies Project: Increasing the Efficiency of Adeno-Associated Virus Gene Therapy Clinical Trial Startup

Philip J Brooks  1 , Elizabeth A Ottinger  2 , Deanna Portero  1 , Richa Madan Lomash  2 , Asaf Alimardanov  2 , Pramod Terse  2 , Xin Xu  2 , Randy J Chandler  3 , Janelle Geist Hauserman  4 , Eric Esposito  4 , Carsten G Bönnemann  4 , Charles P Venditti  3 , Christopher P Austin  5 , Anne Pariser  1 , Donald C Lo  2
Affiliations

The Platform Vector Gene Therapies Project: Increasing the Efficiency of Adeno-Associated Virus Gene Therapy Clinical Trial Startup

Philip J Brooks et al. Hum Gene Ther. 2020 Oct.
No abstract available

PubMed Disclaimer

Conflict of interest statement

No competing financial interests exist.

Figures

Figure 1.
Figure 1.
PaVe-GT development process overview. (a) Traditional one-disease-at-a-time approach: The development process for the four diseases/genes under study would proceed from bottom to top through each of the CMC, preclinical, and clinical phases separately with no leveraging of resources from one disease-program to another, and resulting in separate clinical trials. No resource savings would be expected from this approach. (b) PaVe-GT many-diseases-at-a-time approach: PaVe-GT seeks to leverage available information from each of the four related programs to others with the hypothesis that time and resources can be saved in the CMC, preclinical, and clinical phases. From bottom to top, expected resource savings (indicated by progressively smaller text boxes) beginning in vector product characterization, biodistribution, and toxicology phases. In the clinical phase, each of the two therapeutic-disease areas for the organic acidemias and NMJ diseases can be grouped into master protocols rather than being performed as separate trials. CMC, chemistry, manufacturing, and controls; NMJ, neuromuscular junction; PaVe-GT, Platform Vector Gene Therapy.
Figure 2.
Figure 2.
Propionate and cobalamin metabolism. The organic acidemias under study in PaVe-GT are PA caused by mitochondrial-localized PCCA deficiency, an enzyme responsible for conversion of propionyl-CoA to d-methylmalonyl-CoA, and isolated MMA MMAB caused by cobalamin B deficiency (PCCA and MMAB indicated by red asterisks). PCC deficiency (caused by PCCA or PCCB deficiency, both of which occur with equal frequencies) results in elevated levels of toxic propionyl-CoA derived from metabolism of some amino acids (isoleucine, valine, threonine, and methionine), propionate from gut flora, cholesterol and odd-chain fatty acids, which contribute to the production of propionyl-CoA. MMAB is one of several enzymes involved in the conversion of vitamin B12 to 5′-deoxyadenosylcobalamin, the active cofactor required by the mitochondrial enzyme MMUT to function in the conversion of l-methylmalonyl-CoA to succinyl-CoA. Isolated MMA due to enzyme or cofactor deficiencies lead to elevations in methylmalonic acid. Similar to PA, patients with MMA are unable to metabolize certain amino acids and lipids. MMA, methylmalonic acidemia; MMAB, cobalamin type B MMA; MMUT, methylmalonyl-CoA mutase; PA, propionic acidemia; PCC, propionyl-CoA carboxylase; PCCA, propionyl-CoA carboxylase A; PCCB, propionyl-CoA carboxylase B.
Figure 3.
Figure 3.
Molecular components of the NMJ affected in CMS. CMS are a collection of diseases caused by pathogenic genetic variants in the molecular components of the NMJ (adapted from and ). Defects in all areas of the NMJ—including the presynaptic cell (nerve), synaptic cleft and postsynaptic cell (muscle)—have been causatively linked to the development of CMS, with several of these genes indicated in the figure (within black boxes; distribution of genes causatively linked to CMS within box). The two forms of CMS chosen for the PaVe-GT initiative are DOK7 and COLQ deficiencies (appear in red text within black boxes). DOK7 functions primarily to activate MuSK, which allows for the subsequent clustering of acetylcholine receptors in postsynaptic muscle cells. COLQ is a specific nonfibrillar collagen, which anchors AChE in the basal lamina of the mammalian NMJ. Without proper function these proteins in patients with CMS, NMJ signaling is altered. AChE, acetylcholine esterase; CMS, congenital myasthenic syndromes; COLQ, collagen Q; DOK7, downstream of tyrosine kinase 7; MuSK, muscle-specific tyrosine kinase.
See this image and copyright information in PMC

References

    1. Haendel M, Vasilevsky N, Unni D, et al. . How many rare diseases are there? Nat Rev Drug Discov 2020;19:77–78 - PMC - PubMed
    1. Online Mendelian Inheritance in Man®: An Online Catalog of Human Genes and Genetic Disorders. https://www.omim.org/ (accessed October12, 2020)
    1. Ciulla TA, Hussain RM, Berrocal AM, et al. . Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development. Expert Opin Biol Ther 2020;20:565–578 - PubMed
    1. Hoy SM. Onasemnogene Abeparvovec: first Global Approval. Drugs 2019;79:1255–1262 - PubMed
    1. Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov 2019;18:358–378 - PMC - PubMed

Publication types

MeSH terms