# Treatment of CBS deficiency with proteostasis modulators

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $467,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of cellular
metabolism. Homocysteine is an intermediary metabolite derived from methionine that can either be recycled
back to methionine, or shunted down the transsulfuration pathway by the action of cystathionine beta-synthase
(CBS), an enzyme primarily expressed in the liver and kidney. Individuals with mutations in CBS have CBS
deficiency, characterized by extreme elevations in plasma total homocysteine (tHcy) and phenotypes including
increased incidence of thrombosis, osteoporosis, dislocated lenses, and mental retardation. In healthy adults,
tHcy concentration in plasma ranges from 5 to 15 M, but untreated patients with CBS deficiency often have
tHcy in excess of 200 M. Current treatment strategies involve dietary restriction and vitamin therapy, but
these are only partially effective and do not work in all patients.
 Over 85% of the described mutations in CBS deficient patients are missense mutations in which a single
incorrect amino acid is substituted into the CBS polypeptide. Over the past decade, our lab has developed six
different humanized mouse models that each express a different patient-derived mutant human CBS protein
using an inducible promoter expressed at high levels in the liver. In all of these models, liver CBS activity is
greatly diminished (<5% of wild-type), and serum tHcy is elevated by at least 20-fold. However, the behavior
of each mutant CBS protein is not identical, with mutations affecting protein stability, protein aggregation,
enzymatic function, or a combination of all three. The decreased protein stability effects of the mutations are
mediated via the ubiquitin/proteasome system. Amazingly, treatment of mutant-expressing mice with
proteasome inhibitors (PIs) can functionally reverse the effects of a majority of the missense mutations,
resulting in large increases in CBS activity in the liver, and in some cases lowering of tHcy to near wild-type
levels. PIs are FDA approved drugs for the treatments of certain types of cancer, but have never been studied
in the context of inborn errors of metabolism. Our data suggests that low-dose PI treatment may be able to
restore sufficient CBS enzyme activity to be phenotypically beneficial, but not have the toxicities associated
with the high levels used in cancer therapy. In addition, we have preliminary data that suggests the
combination of PIs with other drugs that modulate the cellular proteostasis network, may be useful in
increasing the effectiveness of PIs. Thus, the overall goal of the current proposal is to extend these studies
and determine if PIs and proteostasis modulators are effective in restoring function to patient-derived CBS
alleles. If successful, the experiments described here could lead to novel treatments of CBS deficiency and
potentially other genetic diseases associated with missense mutations.

## Key facts

- **NIH application ID:** 10004513
- **Project number:** 5R01DK101404-07
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** WARREN D KRUGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,500
- **Award type:** 5
- **Project period:** 2014-05-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004513

## Citation

> US National Institutes of Health, RePORTER application 10004513, Treatment of CBS deficiency with proteostasis modulators (5R01DK101404-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004513. Licensed CC0.

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