New mouse model seen to better mimic survival in juvenile Batten

Model 'may be of value' in testing new treatments for rare disorder

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A trio of mice are pictured in a lab alongside a beaker, a medication bottle, and a rack of test tubes.

Researchers have developed a mouse model of juvenile Batten disease that better reflects the survival outcomes of human patients, according to a new study.

While mice without the gene that carries instructions for the CLN3 protein recapitulate many juvenile Batten features, these mice have milder disease and a much longer lifespan compared with their human patient counterparts.

The new mouse model was created by deleting the CLN3 protein, and one, but not both copies of the gene that encodes for TPP1 — in which mutations cause the late-infantile form of the disorder.

The survival characteristics of this mouse model make it useful for supporting the development of therapies for juvenile Batten, the researchers noted.

The study, “A mouse mutant deficient in both neuronal ceroid lipofuscinosis-associated proteins CLN3 and TPP1,” was published in the Journal of Inherited Metabolic Disease.

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New Model for Classifying Types of Batten Disease Proposed

New mouse model carries mutations in genes for TTP1 and CLN3

Batten disease is a group of genetically distinct conditions characterized by the dysfunction of lysosomes, the compartments within cells that degrade and recycle damaged or unused molecules and proteins.

Mutations that affect lysosomal function lead to the accumulation of storage material, eventually causing cell death — particularly nerve cells. These events trigger the onset of neurological symptoms, including vision loss, seizures, and cognitive impairment.

Common types of Batten include the late-infantile and juvenile forms. Late-infantile Batten is caused by defects in the production of TTP1, an enzyme in lysosomes that normally breaks down proteins. Onset typically occurs around age 2 to 4, with an expected lifespan of up to 15 years. That form is treated with enzyme replacement therapy (ERT), which provides a lab-made source of the TPP1 enzyme.

By contrast, juvenile Batten is caused by mutations in a gene that carries instructions for the CLN3 protein found in the lysosomal membrane. The juvenile form appears later and progresses more slowly than infantile Batten, with vision problems being a first sign around age 8, and patients living into their 20s and 30s.

To date, there are no disease-modifying therapies for juvenile Batten, with treatments mainly consisting of anti-seizure medications and immunosuppressants, as well as physiotherapy and occupational therapy, and speech therapy.

Because CLN3 is located within the fatty lysosomal membrane, ERT is not an option. Also, CLN3 has been associated with numerous cellular activities, but there is no clear evidence of its exact function. Additionally, mouse models of juvenile Batten with CLN3 mutations present a milder disease than humans, especially regarding survival.

To address some of these issues, researchers based at Rutgers University, in New Jersey, created a mouse model that carries mutations in the genes for both TTP1, also called CLN2, and CLN3.

“The phenotype [characteristics] of a double mutant may provide insights into CLN3 protein function and possible functional interactions with TPP1,” the team wrote.

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Study IDs Function of CLN3 Protein, Defects of Which Cause Juvenile Batten

Animal lifespans in mouse model affected by different genes

Double mutant mice were bred, lacking both copies — one from each parent — of the genes for TTP1 and CLN3. These mice are known as homozygous mutants. There also were mice with various mixed TTP1 or CLN3 deletions, known as heterozygous mutants.

Survival assessment found mice lacking both copies of TTP1 and CLN3 lived slightly but significantly shorter than those lacking only TTP1 (120 vs. 124 days). However, the researchers noted substrain variation between homozygous and heterozygous mutants likely reflected these survival differences.

Unexpectedly, in mice lacking both CLN3 copies, those lacking only one TPP1 copy had a significantly shorter lifespan than those with both TPP1 copies. By contrast, in mice with both CLN3 copies intact, deleting one TPP1 copy had no effect.

Although mice lacking both copies of CLN3 (but TPP1 positive) lived significantly shorter than healthy mice, the median survival of 719 days (two years) was similar to that of other juvenile Batten mouse models.

Significant immune activation, a sign of inflammation, and changes in cell structure, a sign of damage, were seen in mice brain tissue lacking just TPP1 or both TTP1 and CLN3. Indicators of inflammation and cell damage were similar, with or without CLN3.

This does potentially provide a mouse model with a clear [juvenile Batten] survival phenotype that may be of value in therapeutic testing.

Overall, a lack of CLN3 did not affect TPP1-related disease, providing further evidence that CLN3 defects do not exacerbate the late-infantile Batten-like illness in these animals, the team noted.

Consistently, in mice lacking both TTP1 copies, similar patterns of protein production were observed regardless of the presence or absence of CLN3.

Similar to previous studies, mice lacking TTP1, regardless of CLN3, had elevated levels of proteins called GPNMB, LYZ2, and SERPINA3, which represent potential biomarkers for late-infantile Batten.

By contrast, mice lacking CLN3, with one or two TTP1 copies, had lower levels of three lysosomal proteins: CTSF, SMPD1, and NPC1, which may serve as biomarkers in juvenile Batten. Finally, the TTP1 activity in mice without CLN3 was about two times higher than in mice with CLN3.

“We find that the lifespan of the [Cln3-lacking] mouse model is shortened in a Tpp1 heterozygous background,” the researchers wrote. “While the physiological implications of this are unclear, this does potentially provide a mouse model with a clear [juvenile Batten] survival phenotype that may be of value in therapeutic testing.”