The Safety and Tolerability of Kinetin, in Patients With Familial Dysautonomia
| Status: | Recruiting |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 16 - Any |
| Updated: | 12/26/2018 |
| Start Date: | November 2009 |
| End Date: | May 2019 |
| Contact: | Horacio Kaufmann, MD |
| Email: | horacio.kaufmann@nyumc.org |
| Phone: | 212 263 7225 |
The Safety and Tolerability of Kinetin, a Nutritional Supplement That Corrects the Splicing Defect, in Patients With Familial Dysautonomia
This is a study of kinetin, a nutritional supplement that corrects the mRNA splicing defect
in patients with familial dysautonomia (FD, also known as Riley Day syndrome or hereditary
sensory and autonomic neuropathy type III). FD is a rare fatal autosomal recessive disease in
which the growth and development of selective neuronal populations is impaired. The disease
is the result of a point mutation in the gene sequence that encodes for kinase complex
associated protein (IKAP) in chromosome 9q31. The mutation, at the start of the non-encoding
intron 20, weakens the splice site, causing the spliceosome to wrongly join together exons 19
and 21 when transcribing the mRNA strand and miss out exon 20. The mutated mRNA produces a
short unstable IKAP protein that is quickly degraded. Interestingly, the mutation does not
lead to a complete loss of function. Instead, it results in a tissue specific deficiency in
splicing efficiency with both normal (wild type) and mutant IKAP mRNA being expressed in
different ratios in different tissues. Some cells, like fibroblasts, produce mostly normal
mRNA and protein, where as others, like neurons, produce mostly mutant mRNA and almost no
functional protein product.
in patients with familial dysautonomia (FD, also known as Riley Day syndrome or hereditary
sensory and autonomic neuropathy type III). FD is a rare fatal autosomal recessive disease in
which the growth and development of selective neuronal populations is impaired. The disease
is the result of a point mutation in the gene sequence that encodes for kinase complex
associated protein (IKAP) in chromosome 9q31. The mutation, at the start of the non-encoding
intron 20, weakens the splice site, causing the spliceosome to wrongly join together exons 19
and 21 when transcribing the mRNA strand and miss out exon 20. The mutated mRNA produces a
short unstable IKAP protein that is quickly degraded. Interestingly, the mutation does not
lead to a complete loss of function. Instead, it results in a tissue specific deficiency in
splicing efficiency with both normal (wild type) and mutant IKAP mRNA being expressed in
different ratios in different tissues. Some cells, like fibroblasts, produce mostly normal
mRNA and protein, where as others, like neurons, produce mostly mutant mRNA and almost no
functional protein product.
Familial dysautonomia (FD, also called Riley Day syndrome or hereditary sensory and autonomic
neuropathy type III) is an autosomal recessive disease caused by a point mutation in the
kinase complex associated protein (IKAP) gene sequence (1, 2). This leads to a tissue
specific splicing defect with variable "skipping" of exon 20 (1, 3, 4). The consequence is a
devastating congenital sensory neuropathy, affecting pain and temperature perception (5) as
well as afferent information from the viscera (6). As a result, patients suffer recurrent
aspiration pneumonias, respiratory insufficiency, proprioceptive ataxia, scoliosis and the
long-term consequences of volatile blood pressure including renal failure (7) and left
ventricular hypertrophy (8).
In-vitro studies have shown that the plant hormone kinetin corrects the splicing defect and
increases the production of normal IKAP protein levels in FD derived cell lines (9, 10).
Preliminary studies in heterozygous carriers of the IKAP mutation showed that dietary
supplementation with kinetin increased the production of correctly spliced IKAP mRNA, in
white blood cells (11). Preliminary studies in patients with FD have demonstrated that
kinetin also increases the expression of correctly spliced IKAP mRNA extracted from white
blood cells. However, the effect of kinetin on mRNA levels in neuronal tissue is unknown.
The overall objective of this study is to assess the safety and tolerability of administering
kinetin in patients with FD. The specific aim of this proposal is to determine the safety of
a once daily dose of kinetin in patients with FD using a dose ascending titration and to
determine the long-term safety and tolerability during 3-years of receiving a maximum
tolerated steady state dose of kinetin. The investigators hope to also demonstrate early
proof of concept that kinetin enhances the ability of neuronal tissue to correctly splice
IKAP mRNA.
neuropathy type III) is an autosomal recessive disease caused by a point mutation in the
kinase complex associated protein (IKAP) gene sequence (1, 2). This leads to a tissue
specific splicing defect with variable "skipping" of exon 20 (1, 3, 4). The consequence is a
devastating congenital sensory neuropathy, affecting pain and temperature perception (5) as
well as afferent information from the viscera (6). As a result, patients suffer recurrent
aspiration pneumonias, respiratory insufficiency, proprioceptive ataxia, scoliosis and the
long-term consequences of volatile blood pressure including renal failure (7) and left
ventricular hypertrophy (8).
In-vitro studies have shown that the plant hormone kinetin corrects the splicing defect and
increases the production of normal IKAP protein levels in FD derived cell lines (9, 10).
Preliminary studies in heterozygous carriers of the IKAP mutation showed that dietary
supplementation with kinetin increased the production of correctly spliced IKAP mRNA, in
white blood cells (11). Preliminary studies in patients with FD have demonstrated that
kinetin also increases the expression of correctly spliced IKAP mRNA extracted from white
blood cells. However, the effect of kinetin on mRNA levels in neuronal tissue is unknown.
The overall objective of this study is to assess the safety and tolerability of administering
kinetin in patients with FD. The specific aim of this proposal is to determine the safety of
a once daily dose of kinetin in patients with FD using a dose ascending titration and to
determine the long-term safety and tolerability during 3-years of receiving a maximum
tolerated steady state dose of kinetin. The investigators hope to also demonstrate early
proof of concept that kinetin enhances the ability of neuronal tissue to correctly splice
IKAP mRNA.
Inclusion Criteria:
1. Male of female patients aged 16 and older
2. Confirmed diagnosis of familial dysautonomia by genetic testing
3. Written informed consent to participate in the trial and understanding that they can
withdraw consent at anytime without affecting their future care.
4. Ability to comply with the requirements of the study procedures.
Exclusion Criteria:
1. Patients who have taken other nutritional supplements that may affect IKAP mRNA
splicing within the last 30 days
2. Patients with a known hypersensitivity to any component of the nutritional supplement
kinetin
3. Patients with atrial fibrillation, angina or an electrocardiogram documenting
significant abnormality that may jeopardize the patient's health.
4. Patients with significant pulmonary, liver, renal (creatinine >2.5 mg/ml) or cardiac
illness
5. Women who are pregnant or lactating
6. Women of childbearing potential who are not using medically accepted methods of
contraception.
7. Patients who have a significant abnormality on clinical examination that may, in the
investigator's opinion, jeopardize their healthy participating in this pilot trial.
8. Patients taking allopurinol, other xanthine oxidase inhibitors or other compounds that
may interfere with the metabolism of kinetin including oral calcium supplements.
We found this trial at
1
site
New York, New York 10016
Principal Investigator: Horacio Kaufmann, MD
Phone: 212-263-2775
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