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
. 2017 Jan 1;195(1):23-31.
doi: 10.1164/rccm.201605-0905PP.

Translational Advances in the Field of Pulmonary Hypertension Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing

Eric D Austin  1 , James West  2 , James E Loyd  2 , Anna R Hemnes  2
Affiliations

Translational Advances in the Field of Pulmonary Hypertension Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing

Eric D Austin et al. Am J Respir Crit Care Med. .
No abstract available

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Whole-exome sequencing to identify rare variants relevant to pulmonary arterial hypertension (PAH) pathogenesis. A representative pedigree, similar to that employed for the discovery of a CAV1 mutation in a family with heritable PAH, is represented, with four patients with PAH in the modified family pedigree. Whole-exome sequencing is performed, which involves a number of complicated laboratory and bioanalytical steps, to determine the variants of interest for confirmation. Ultimately, confirmed candidate genes and variants require biological studies to determine the true functional impact of the changes discovered. Finally (data not shown), additional case subjects and control subjects should be genotyped for mutations in the candidate genes of interest.
Figure 2.
Figure 2.
The identification of genes, pathways, and molecules relevant to pulmonary arterial hypertension (PAH) can be used for multiple purposes, including the improvement of clinical trial design. Subjects exposed to a given therapeutic could be compared in a number of different ways, including according to therapeutic response. Comprehensive approaches to explore the shared variations among those who respond and those who do not respond may support the determination of a predictive signature of response to help refine patient selection for a given therapeutic.
Figure 3.
Figure 3.
Schematic of the use of gene-editing techniques to repair a known gene mutation as a therapeutic approach, in this case demonstrating the manipulation of a patient’s own stem cells. (1) CRISPR–Cas9 can be used with homologous recombination to repair a bone morphogenetic protein receptor type 2 (BMPR2) mutation for autologous transplant in patient bone marrow. (2) Bone marrow is extracted from the patient and sorted for stem cells. Stem cells are transfected with CRISPR–Cas9 guided to the mutation site, with homologous recombination DNA containing corrected sequences. (3) Small-molecule nonhomologous end-joining blockers can be used to increase the efficiency of homologous recombination. (4) Molecular probes that fluoresce only when bound to the corrected RNA can be used to sort for cells that have had their mutations corrected. Corrected stem cells are reintroduced into the patient. This process is still a hypothetical approach to correct stem cells with a BMPR2 mutation that may promote pulmonary arterial hypertension; there are a number of technical barriers that must be overcome as described in text. Cas9 = CRISPR-associated protein 9; CRISPR = clustered regularly interspaced short palindromic repeats; gRNA = guide RNA.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991;115:343–349. - PubMed
    1. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier JF, Chabot F, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156–163. - PubMed
    1. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137:376–387. - PubMed
    1. Maron BA, Leopold JA. Emerging concepts in the molecular basis of pulmonary arterial hypertension. II. Neurohormonal signaling contributes to the pulmonary vascular and right ventricular pathophenotype of pulmonary arterial hypertension. Circulation. 2015;131:2079–2091. - PMC - PubMed
    1. Ryan JJ, Archer SL. Emerging concepts in the molecular basis of pulmonary arterial hypertension. I. Metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation. 2015;131:1691–1702. - PMC - PubMed

Publication types