# Developing Synthetic Enzymes to Treat Inborn Errors of Metabolism

> **NIH NIH R21** · TUFTS UNIVERSITY MEDFORD · 2022 · $190,711

## Abstract

Project Summary.
The severe, acute, and chronic developmental and neurological impacts seen in branched chain ketoacid
dehydrogenase deficient Maple Syrup Urine Disease (BCKD-deficient MSUD) and isovaleryl‐CoA
dehydrogenase deficient Isovaleric Acidemia (IVD-deficient IVA) seen in newborns are due to the presence of
high concentrations of leucine, isoleucine, and valine in their system. Patients with these disorders are limited
to manage their condition though a low-protein diet and nutrient supplementation, which is often inadequate,
difficult to adhere to, and can still lead to metabolic decompensation. Management strategies include reduction
and restriction of toxic metabolites and substrates, promotion of anabolism and stimulation of residual enzyme
activity along with activation of amino acid and ketoacid scavenging pathways. Even then, the quality of life of
patients is poor, as is for their caregivers since patients need to be monitored closely to avoid metabolic crisis
precipitated either by infection, diet, or other reasons. Thus, there is significant need for new medications that
can benefit infants, children, adolescents, and adults. This work is based on the hypothesis that high systemic
concentrations of offending amino acid(s) in patients can be reduced using high activity enzymes, in a manner
like how Pegvaliase reduces phenylalanine concentrations in phenylketonuria (PKU) patients. Core to this work
is implementation of a twofold approach that combines experimental directed evolution techniques and
computations enzyme design.

## Key facts

- **NIH application ID:** 10281241
- **Project number:** 1R21HD105934-01
- **Recipient organization:** TUFTS UNIVERSITY MEDFORD
- **Principal Investigator:** Nikhil Unni Nair
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $190,711
- **Award type:** 1
- **Project period:** 2021-12-13 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10281241

## Citation

> US National Institutes of Health, RePORTER application 10281241, Developing Synthetic Enzymes to Treat Inborn Errors of Metabolism (1R21HD105934-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10281241. Licensed CC0.

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