# In vivo efficacy of a kinase inhibitor, roscovitine, in HD mouse model

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $450,313

## Abstract

Project Summary (Abstract):
Huntington’s disease (HD) is caused by a mutation in the huntingtin gene (HTT). Expanded CAG trinucleotide
repeats in exon 1 encode polyglutamine in the mutant huntingtin protein (mHTT), causing preferential
neurodegeneration in striatum, cortex and other regions. No disease-modifying treatment is available. Mutant
HTT lowing approaches are very promising; However, the delivery agents are mostly large molecules with limited
brain penetration, requiring invasive procedures. Small molecule RNA-directed therapies are also emerging, but
they are generally non-allele specific and may have off target effects on other mRNAs.
Huntingtin protein (HTT) has many sites of post-translational modification (PTM). As part of a long-standing
program to study PTMs of HTT, we have identified a small number of PTM sites can modify mHTT toxicity,
especially those sites with serine and targeting by phosphorylation. Using in vitro kinase screens, we have found
that one of those serines, S1181, is actively phosphorylated by CDKs, including CDK1, CDK2 and CDK5, etc. A
CDK inhibitor, roscovitine (also known as seliciclib, CYC202), is highly neuroprotective against mHTT toxicity
in our HD cell model. As a proof of principle for this strategy, we now propose to determine whether roscovitine
can be therapeutically efficacious in an HD mouse model in vivo.
Roscovitine is a well-known CDKs inhibitor and has been in several human phase II clinical trials. One previous
study in an HD mouse model showed that roscovitine can ameliorate depressive-like behavior in HD mice.
However, this study used intracerebral infusion to deliver roscovitine into the brain for a short period of time.
Other studies have found that a single oral administration of roscovitine can penetrate brain. We hypothesize
that chronic peripheral administration of roscovitine can achieve adequate brain concentrations to
inhibit overactivated CDK5, which involves in HD pathogenesis. Thus, it will have beneficial effect in HD
mouse model.
We have confirmed that single injection of roscovitine can penetrate brain. Three weeks of daily injection is well
tolerable in zQ175 HD mice, which is a knock-in mouse express full length human exon1 HTT under mouse
huntingtin gene with approximate of 175 CAG repeats. We will inject roscovitine in manifested zQ175 HD mice
for long term (6 months). Body weight, behavioral task and MRI scan will be used to compare HD mice treated
with or without roscovitine. Brain samples will be collected and brain pathology, molecular biological changes
will be examined in HD mice. We expect that roscovitine protect HD mice and can be further translate into HD
clinic.

## Key facts

- **NIH application ID:** 10586210
- **Project number:** 1R21NS125063-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jing Jin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $450,313
- **Award type:** 1
- **Project period:** 2022-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586210

## Citation

> US National Institutes of Health, RePORTER application 10586210, In vivo efficacy of a kinase inhibitor, roscovitine, in HD mouse model (1R21NS125063-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10586210. Licensed CC0.

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