New Batten Research: NtBuHA and Lysosomal Storage Diseases

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This child has a lysosomal storage disease. Image by Wonderlane

This child has a lysosomal storage disease. Image by Wonderlane

An antioxidant chemical provides a “proof of concept” in lab mice as a therapeutic target for the devastating neuron-killing disease in children.

New research published recently in Nature Neuroscience gives hope for future, to treat children with Batten disease. Led by Dr Anil Mukherjee at the National Institute of Child Health and Human Development at NIH, USA, a group of scientists tested the potential of an antioxidant chemical, called NtBuHA, in mouse model carrying Batten disease.

Blame the Lysosome

Clinically named as Neuronal Ceroid-Lipofuscinoses (NCL), Batten disease is one of the Lysosomal Storage Diseases (LSD). More than 50 LSDs cause a gradual death of neurons; the problem arises during the child’s birth.

Researchers have found eight or more genes behind these diseases. “INCL is a rare disease (worldwide 1 in >100,000 births) but it is one of the most lethal among all NCLs,” Dr Mukherjee told Decoded Science.

The affected children usually lose their vision, or have dementia. “By age 2, they are completely blind and by age 4, they manifest no brain activity. These children remain in a vegetative state for several more years before eventual death,” says Dr Mukherjee. Though there are some treatment processes in clinic, so far there is no promising cure for the disease, and these “grim facts underscore the urgent need for developing an effect therapy,” as Dr. Mukherjee tells us.

At the cellular level, the damage is because of a cell organelle, known as a lysosome that is out of order. Lysosomes are cellular “suicidal bags” where a cell recycles its chemicals for the same previous, or modified new uses. After the cells produce the needy proteins for body to work properly, depending on where they are targeted for function, they get modified with chemical tags – for example, with a sugar or a fat (lipid) molecule. According to Dr. Mukherjee, “This modification is required for the function of these proteins. However, when such proteins have manifested the function, the lipid molecules must be detached from the proteins before they can recycle or get degraded in the lysosome.” Usually an enzyme does this job.

This is the structure of palmitoyl protein tioesterase 1. Image courtesy of the Protein Data Bank, Europe.

This is the structure of palmitoyl protein tioesterase 1. Image courtesy of the Protein Data Bank, Europe.

The Story of NtBuHA

In children without Batten disease, the lysosomal enzyme, known as Palmitoyl-protein thioesterase-1 (PPT1) cleaves off the fatty acid, called Palmitoic Acid, to recycle the proteins. But in patients with the disease, this is the “missing enzyme” that leaves their neurons to “accumulate the lapidated proteins.” So what does this NtBuHA do? And how did the scientists arrive at this potential drug candidate?

The story is interesting. The scientists already knew that hydroxylamine, a natural product, does exactly the same job as the normal enzyme would do. But at very high concentrations, hydroxylamine is poisonous to humans, so, it cannot be a good drug. Hence, they chemically made “derivatives” of hydroxylamine, to make it non- or less toxic.

Out of the 12 derivatives made, they chose NtBuHA – chemically, N-(tert-Butyl)-hydroxylamine as the best candidate. Dr Mukherjee says, “NtBuHA […] cleaves the linkage that connects the lipid with the protein just like PPT1 does. In addition, [it] has antioxidant property, which is beneficial for neurodegenerative diseases like INCL”.

Still, like any other chemical drug, NtBuHA could also have side effects, but only at high concentrations, according to the tests the scientists did in human cells (INCL lymphoblasts) in the lab. However, their study in mice with a mutation of the gene for the PPT1 enzyme showed no toxicity. Moreover, the treated mice lived longer too. Could this compound be an ultimate cure for Batten disease?

Dr Mukherjee says, “For NtBuHA, we are in the process of determining the half-life and other parameters required for gaining approval of this compound as a drug.

NtBuHA’s Future

In their article, the authors speculate NtBuHA’s potential towards treating adult NCLs. However, “the veracity of this speculation can only be proven by conducting careful experiments in the laboratory” says Dr Mukherjee. Nevertheless, the group is “working to collect more data to gain the approval  of NtBuHA as an investigational new drug (IND), which is required for testing this potentially new drug in a clinical trial.” What’s next for NtBuHA and Batten Disease? Only time will tell.

Resources

Sarkar C, Chandra G, Peng S, Zhang Z, Liu A, Mukherjee AB. Neuroprotection and lifespan extension in Ppt1-/- mice by NtBuHA: therapeutic implications for INCL. (2013). Nature Neuroscience. Accessed October 17, 2013.

Ricki Lewis. Battling Batten Disease. (2013). DNA Science Blog (PLoS Blog). Accessed October 17, 2013.

Bee For Battens. About Batten Disease. (2013). Accessed October 17, 2013.

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