Dr. Steven Gray from UT Southwestern
We are working with Dr. Steven Gray from UT Southwestern to develop a gene therapy for DHPS Deficiency. Dr. Gray has developed several previous gene therapies that are currently in clinical trials in patients with other neurogenetic conditions. The DHPS gene therapy is currently being evaluated in mice to determine safety and efficacy. We hope to advance this gene therapy to clinical trials to supply patients with DHPS Deficiency with a healthy copy of the gene.
Center for the Development of Therapeutics from the Broad Institute of MIT and Harvard
We are working with the Center for the Development of Therapeutics from the Broad Institute of MIT and Harvard to identify small molecule drugs that could increase DHPS enzyme activity in patients by enhancing activity of the hypomorph DHPS N173S variant. This program is at an early stage, in assay development.
Dr. Yetrib Hathout
To be able to measure the activity of DHPS in patients, and confirm the efficacy of treatments in future clinical trials, we have established a collaboration with Binghamton University and NYU to develop a non-invasive biomarker for DHPS activity. This biomarker consists of measuring free hypusine in clinical urine samples by using LC-MS. Because hypusine can only be produced in the body through a two-step enzymatic process by DHPS and DOOH, levels of hypusine are direct reporters of DHPS activity. Dr. Yetrib Hathout, from the School of Pharmacy & Pharmaceutical Sciences at Binghamton University, is the leading investigator developing the analytical method for clinical urine hypusine measure. Dr. Orrin Devinsky, from NYU Langone Medical Center, is the clinical lead for this program. We hope to get clinical confirmation of this biomarker, including samples from patients and carriers, by end of 2024.
Dr. Przemysław Grudnik
We are also collaborating with Dr. Przemysław Grudnik from the Jagiellonian University in Kraków to test in our in vitro models the small molecule DHPS activators that his group is developing by combining cryo-EM analysis of DHPS enzyme and a fragment-to-drug screen (see previous publication). This program is also at an early stage, in hit identification.
JAX lab
Mice carrying the N173S conserved variant are also directly available from Jax as a cryopreserved line. The DHPS Foundation also keeps a living colony of this line at Jax, and we will be happy to share it with you to speed up the process. Just reach out to us.
Another strain that you might find useful is a conditional DHPS mouse line also available from Jax as a cryopreserved line, donated by Dr. Mirmira. This strain has been used in several publications:
- Levasseur et al 2019. Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis. Sci Signal. Dec 3;12(610):eaax0715.
- Padgett LR, et al 2021. Deoxyhypusine synthase, an essential enzyme for hypusine biosynthesis, is required for proper exocrine pancreas development. FASEB J. May;35(5):e21473.
- Anderson-Baucum et al 2021. Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype. Cell Metab. Sep 7;33(9):1883-1893.e7.
- Connors CT, et al 2024. Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates β-Cell Identity and Function. Diabetes. Mar 1;73(3):461-473.
Dr. Alysson Muotri from UCSD
Dr. Alysson Muotri from UCSD has generated organoids from patient-derived iPSC and isogenic controls and these organoids display growth and survival phenotypes, as well as a deficiency in production of hypusine. This model is useful for compound and gene therapy evaluation.
Dr. Alexander Crawford from the IODD
Dr. Alexander Crawford from the IODD has generated zebrafish deficient in DHPS using a morpholino approach. These zebrafish have disease-related phenotypes and are useful for biological research as well as for compound and gene therapy evaluation.
Dr. Teresa Mastracci
Several unpublished mouse lines carrying DHPS disease variants are in the process of being deposited at Jax as cryopreserved lines. These lines have been generated by Dr. Wendy Chung and Dr. Teresa Mastracci, and are available for interested scientists upon request to Dr. Mastracci at IU.
Dr. Mastracci’s collection includes three lines carrying patient mutations in the DHPS mouse gene as well as a humanized strain and the corresponding mutant likes over the humanized DHPS gene:
- DHPS-mouse missense N173S
- DHPS-mouse splice 1014+1G>A
- DHPS-mouse deletion Ile306del
- DHPS-humanized WT
- DHPS-humanized missense N173S
- DHPS-humanized splice 1014+1G>A
- DHPS-humanized deletion Ile306del
Dr. Chengzu Long from NYU
Dr. Chengzu Long from NYU has generated patient-derived iPSC lines as well as isogenic controls for the two most common mutations: c.1014+1G>A and p.N173S. These likes are useful for biological research into DHPS function and dysfunction.