Renzhi Han
Indiana University-Purdue University-Indianapolis, IN·Pharmacology
Genetic diseases could in principle be fixed at their source, by repairing the faulty gene or supplying a working copy. Turning that idea into a safe treatment runs into practical walls: the carrier used to deliver the therapy may not reach all the needed tissue, the gene may be too large to fit, the editing machinery may keep working after the job is done and cut in the wrong places, and the immune system may attack both the carrier and the newly made protein.
- Fields
Pharmacology
Genetics
Medicine & Clinical Research
- Topics
Duchenne muscular dystrophy
dystrophin
gene therapy
- Grants
- 3 known grants, through Mar 2030
What they work on
- Develop an improved triple-vector system in next-generation myotropic adeno-associated virus capsids to reconstitute full-length dystrophin by protein trans-splicing across skeletal, diaphragm, and heart muscle in models of Duchenne muscular dystrophy.
- Test the efficacy and safety of full-length dystrophin gene therapy in a newly established DMD rabbit model that recapitulates the muscular dystrophy and cardiomyopathy seen in patients.
- Engineer immune-friendly vectors and immune-modulating strategies to reduce host responses against the viral capsid, the dystrophin-intein fusion products, and the restored full-length dystrophin protein.
- Build a controllable, switchable base editing system that converts single DNA letters without cutting both strands, to limit accumulation of off-target edits and immune exposure to the editing proteins in DMD.
- Deliver the controllable base editor in engineered myotropic AAV capsids reported to transduce muscle with about ten-fold less virus than AAV9, and evaluate correction efficiency and safety in the DMD rabbit model.
- Determine optimal base editing strategies to knock out ASGR1, a liver receptor whose loss lowers cholesterol, first in cultured rabbit cells and then in rabbit hepatocytes using engineered virus-like particles as a non-viral delivery vehicle.
- Test whether a single dose of virus-like-particle-delivered ASGR1 base editing reduces lipids and disease in a rabbit atherosclerosis model, and establish its long-term safety profile.
More about the research
Work here tackles those obstacles for two very different diseases, a fatal muscle-wasting disorder and the lipid problems behind heart disease, using virus-based and particle-based delivery, protein engineering, base editing, and large-animal models that mimic human disease better than mice.
Why it matters
Boys with Duchenne muscular dystrophy currently have gene therapies that deliver only a shortened dystrophin and require large virus doses; delivering the full-length protein, or precisely correcting the mutation with a switchable base editor, could offer better protection of muscle, diaphragm, and heart with fewer immune and toxicity risks. For cardiovascular disease, still the leading cause of death worldwide, a single-dose liver editing therapy against ASGR1 could lower lipids in patients who remain at risk despite statins. Rabbit models that mirror human disease make the safety data more informative for eventual clinical testing.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Arun Srivastava
University of Florida, FL·Medicine & Clinical Research
Develop liver-de-targeted, capsid- and genome-modified next-generation AAV vectors based on AAVrh74 for skeletal muscle and AAV9 for the central nervous system, and demonstrate enhanced expression from AAV-PDHA1 vectors.
Qinglan Ling
University of Massachusetts Chan Medical School, MA·Genetics·Early-career
Develop and optimize a mitochondria-targeting base editor, a tool that changes single DNA letters, to create a truncating mutation in the mouse MTATP6 gene and generate a conditional mouse model.
Michael Lopez
University of Alabama at Birmingham, AL·Genetics·Early-career
Test how over-expressing or knocking down Smad8, a TGF-beta–linked transcription factor elevated in Duchenne muscle, changes muscle cell growth, maturation and regeneration in cell culture and Duchenne mouse models.
The school
Indiana University-Purdue University-Indianapolis: 25 labs on PI Pages, $89M a year on research, 120 research doctorates a year.
More about Indiana University-Purdue University-Indianapolis
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