US-12616680-B2 - Combined use of biotin and thiamine in the treatment of huntington's disease

Abstract

The present invention relates to the use of a combination of vitamins, more specifically to the combined use of biotin and thiamine, for the treatment of Huntington's disease. More specifically, the present invention explains that treatment with a combination of biotin and thiamine can improve the neurological, neuroimaging and spectroscopic symptoms associated with Huntington's disease.

Inventors

• José Javier Lucas Lozano
• Sara PICÓ DEL PINO
• Alberto PARRAS RODRÍGUEZ
• María SANTOS GALINDO

Assignees

• CONSEJO SUPERIOR DE INVESTIGACIONES CIENTÍFICAS (CSIC)
• CONSORCIO CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED

Dates

Publication Date

20260505

Application Date

20200923

Priority Date

20190924

Claims (9)

1. 1 . A method for the treatment of Huntington's disease comprising administering to a subject in need thereof an effective amount of a composition comprising biotin and thiamine.
2. 2 . The method according to claim 1 wherein the concentration of biotin is at least 0.40 mg/kg/day, and the concentration of thiamine is at least 2 mg/kg/day.
3. 3 . The method according to claim 1 wherein the composition further comprises at least one excipient and/or pharmacologically acceptable carrier.
4. 4 . The method according to claim 1 wherein the composition further comprises at least one active ingredient.
5. 5 . The method according to claim 4 wherein the active ingredient is selected from the list consisting of: tetrabenazine, haloperidol, chlorpromazine, risperidone, quetiapine, amantadine, levetiracetam, clonazepam, citalopram, escitalopram, fluoxetine, sertraline, olanzapine, valproate, carbamazepine, lamotrigine and/or any of the combinations thereof.
6. 6 . The method according to claim 1 characterized in that the composition is administered by any of the following routes: oral, sublingual, parenteral, intravenous, intraperitoneal and/or intramuscular route.
7. 7 . The method according to claim 6 wherein the route of administration is the oral route.
8. 8 . The method according to claim 1 wherein the compounds of said composition are formulated or administered together, separately or sequentially.
9. 9 . The method according to claim 1 wherein said composition is repeatedly administered to a subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS AND PRIORITY This patent application claims priority from PCT Application No. PCT/ES2020/070570 filed Sep. 23, 2020, which claims priority from Spanish Patent Application No. P201930825 filed Sep. 24, 2019. Each of these patent applications are herein incorporated by reference in their entirety. FIELD OF INVENTION The present invention belongs to the field of medicine and pharmacy and relates to the use of a combination of vitamins, more specifically to the combined use of biotin and thiamine in the prevention and/or treatment of Huntington's disease (HD). REFERENCE MATERIALS Various sequence listings and variant listings are provided herein and attached in a separate sequence listing .txt file. The provided listings are incorporated herein by reference. BACKGROUND OF THE INVENTION Huntington's disease is an inherited neurodegenerative disorder characterised by marked atrophy of the striatum (St) and prominent motor symptoms caused by a CAG trinucleotide repeat in the exon 1 coding region of the Huntingtin gene (Htt) on human chromosome 4, giving rise to a self-aggregating polyglutamine (polyQ) segment in the N-terminal region of the Huntingtin protein, which leads to an accumulation of said structurally changed and modified protein and fragments thereof in the brain and other organs or cells over time. In addition to the toxicity of PolyQ, there is also evidence of toxicity induced by the Htt mRNA molecule with CAG expansion. Clinical symptoms of Huntington's disease progress in a predictable manner, beginning with mood swings or cognitive problems followed by unsteady gait and motor problems which occur as a result of progressive neuronal death in different areas of the brain. This manifests itself with more virulence in the medium spiny neurons of the striatum and determines the onset of impaired motor coordination and typical “chorea” movements. Over time, physical abilities further deteriorate, with evident movement coordination problems in combination with a greater decline in mental abilities and psychiatric and behavioural problems. Symptoms can vary significantly and it is well documented that age at onset is inversely correlated with the number of CAG repeats in the modified htt gene, corroborating the causative role of modified Huntingtin. There is no cure or prevention for HD nor is there any known way to stop the disease from getting worse. The average life expectancy is approximately twenty years after the first clinical manifestation. The aim of treatment is to delay and reduce symptoms and to help people with the disease care for themselves for as long as possible. Studies in genetically modified mouse models of HD have shown that HD-like phenotypes can be resolved by knocking out the expression of the mutant huntingtin gene, even in advanced stages of the disease (Yamamoto et al. Cell. 2000, 101: 57-66; Díaz-Hernández et al. J. Neurosci., 2005, 25:9773-9781). In this sense, gene therapy is an important approach in the search for a possible treatment of the disease. Thus, introducing different gene constructs at the cellular level to inhibit the transcription or translation of the mutated protein, even to replace the defective gene with a new one, through gene therapy has given good results in mouse animal models of the pathology, but unfortunately these trials do not provide the same results in humans since said therapy is not effective in them. This strategy is therefore still far from being an effective strategy for its application in humans (Tabrizi S J. at al. N Engl J Med. 2019; 380(24):2307-2316). Pharmacological therapy is the most used therapy to relieve the symptoms of subjects suffering from Huntington's disease. In this sense, tetrabenazine is used for the symptomatic treatment of hyperkinetic movement disorders, such as Huntington's disease, hemiballismus, senile chorea, tics, tardive dyskinesia and Tourette's syndrome. The main pharmacological effect of tetrabenazine is to reduce the supply of monoamines (e.g., dopamine, serotonin and norepinephrine) in the central nervous system by inhibiting isoform 2 of the human vesicular monoamine transporter (hVMAT2). The drug also blocks postsynaptic dopamine receptors. Tetrabenazine is an effective and safe drug for the treatment of various hyperkinetic movement disorders and, unlike typical neuroleptic agents, it has not been shown to cause tardive dyskinesia. Nevertheless, tetrabenazine does show a number of dose-related side effects, including depression, Parkinson's disease, drowsiness, nervousness or anxiety, insomnia and, in exceptional cases, neuroleptic malignant syndrome. The international patent application WO2006053067 describes the use of a combination of amantadine and tetrabenazine for the treatment of hyperkinetic disorders and, in particular, of Huntington's disease. There is a serious side effect of this tetrabenazine drug that triggers or worsens depression and other psychiatric