Health In Focus
Histone Deacetylase Inhibitors for Treatment of Niemann-Pick Disease Type C
  • Niemann-Pick disease is a rare genetic disorder
  • It is also called "Children's Alzheimer's"
  • FDA approved histone deacetylase inhibitors provided treatment in experimental mice
Niemann-Pick is a rare genetic disorder that is characterized by mental and physical degeneration of children, noticeable by the time they reach adolescence. It occurs in one in 150000 children and is also called "Children's Alzheimer's" though the disease has nothing in common with the neurodegenerative disorder like Alzheimer's.

Niemann-Pick Type C Disease

This rare autosomal genetic disease leads to the unusual accumulation of non-esterified cholesterol in the lysosomal compartments of cells. This accumulation of cholesterol occurs in the spleen, liver as well as the brain. The symptoms may begin within a few months after birth or may even set in during adulthood.

  • Ataxia (loss of control of bodily movements)
  • Seizure
  • Dementia
  • Vertical gaze palsy ( The eyes cannot be moved up and down)
  • Enlarged spleen
  • Jaundice
  • Enlarged liver
Initially, only one or two symptoms arise during the start of the disease with the progression of the disease leading to further complications. The disease is always fatal and children with this type of Niemann-Pick disease die by the time they reach their 20s.

When the disease begins to show symptoms later in life, the progression is slower, but no individual with this type of disease has lived for longer than 40 years of age.

The fatality associated with this disease, the trauma endured by parents of children affected with Niemann-Pick type C disease and the problems faced by the affected children encourage studies on a prospective cure for this disease.

Researchers Mohammed Suhail Alam and colleagues studied the markers for Niemann-Pick type C disease in the plasma in a quest to identify the disease early to slow the progression of the disease. The article titled " Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C" was published in The Journal of Chemical Biology in 2014.

These researchers working on mice found that the Purkinje cells present in the cerebellum were affected in Niemann-Pick type C due to over-expression of lysozyme leading to symptoms of ataxia.

The affected mice, in this study, were treated with hydroxypropyl-β-cyclodextrin (HPβCD) also called cyclodextrin.
  • This was found to control the inflammatory process in the liver but not in the brain.
  • Moreover, it did not affect transcripts of 24 hydroxylase which is specific to neurons, its product 24 hydroxycholesterol is not a marker for the disease.
The researchers continued to study treatment solutions for Niemann-Pick type C. Their work on the effect of histone deacetylase inhibitor has raised hopes of a possible cure for the disease. The article titled "Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model" published in the journal Science Translational Medicine.

About the Study

Histone deacetylase inhibitors (HDACi) are approved for the treatment of certain types of cancers.

The researchers used a triple combination of -
  • (HDACi) Vorinostat
  • Hydroxypropyl β-cyclodextrin (which was found to be effective in controlling inflammation in the liver of Niemann-Pick disease in their earlier study)
  • Polyethylene glycol (PEG)
The use of Vorinostat (HDACi) in the treatment of Niemann-Pick Type C disease was studied previously by researchers Paul Helquist and colleagues who found that Vorinostat increased the level of NPC1 protein, which is found lacking in Niemann-Pick type C patients. The researchers concluded that vorinostat is a promising drug but that further study and clinical trials need to be carried out.

The current study by researchers Mohammed Suhail Alam and colleagues examined the effect of Vorinostat alone on mice with Niemann-Pick type C disease as well as the effect of the triple combination. This helps in identifying the most effective treatment measure.

Animals Under Study

The study was conducted on mouse models with Niemann-Pick disease type C.

Administration of Vorinostat (Histone deacetylase inhibitors (HDACi))

The administration of vorinostat alone ( single agent administration) had an effect on Niemann-Pick Type C mouse cell lines, but it did not aid in increasing the period of survival of the mouse.

Administration of the Triple Combination

The administration of the triple combination in low doses ( once a week) intra-peritoneally lead to:
  • Preservation of Purkinje cells as well as neuritis
  • A delay in the neurodegenerative disorders
  • The increase in the lifespan of the mouse by nearly 5 months
The neurodegeneration observed in Niemann-Pick Type C disease patients is a difficult symptom to adjust to, as most patients are young and have their whole life to lead. It is also very disturbing for parents and other relatives to cope with the changes.

This study provides a ray of hope to such patients and could possibly delay the symptoms and prolong their life. Advancements in medical therapy like gene therapy have also been utilized to identify a cure for this disease.


3. Helquist P, Maxfield FR, Wiech NL, Wiest O., "Treatment of Niemann--pick type C disease by histone deacetylase inhibitors.", Neurotherapeutics. 2013 Oct
4. Md. Suhail Alam, Michelle Getz, Sue Yi, Jeffrey Kurkewich, Innocent Safeukui, and Kasturi Haldar, "Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C", J Biol Chem. 2014 Mar 21
5. Alam MS, Getz M, Haldar K. " Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model.", Sci Transl Med. 2016 Feb 17;8
Source: Medindia

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