the cardinal clinical characteristics of sca3 include gait and stance unsteadiness , limb ataxia , dysarthria , oculomotor dysfunction , sensory disorder , pyramidal and extrapyramidal dysfunction , and so on .
sca3 is a slowly progressive and unremitting disease , in which patients generally will become wheelchair - bound and bedridden in the end stage , and the median survival time after disease onset is approximately 21 years .
the resulting loss of working ability and reduced survival confer significant disease burden to the patients , their families , and the society .
thus , it is of vital importance to explore effective therapeutic options in order to alleviate the symptoms or retard the disease progression in sca3
. nerve growth factor ( ngf ) is the founding member of the neurotrophin family , and is essential for the proper development , patterning , and maintenance of the mammalian nervous system .
previous studies have revealed that ngf specifically targets sensory and sympathetic neurons in the peripheral nervous system , as well as basal forebrain cholinergic neurons in the central nervous system . there is also growing evidence to support the role of ngf in the development , differentiation , and maintenance of the human cerebellar connectivity . in this context , ngf and its high - affinity receptor tachykinin receptor antagonist ( tkra )
these data imply that ngf may have neuroprotective effects on cerebellar neurons and hence might serve as a therapeutic candidate of sca3 .
therefore , this clinical pilot study was set forth to examine the efficacy of ngf in patients with sca3 .
this study was an open - label clinical trial assessing the efficacy of ngf in patients with sca3 ; it was conducted at the first affiliated hospital of zhengzhou university from november 2011 to november 2012 .
this study was approved by the ethics committee of first affiliated hospital of zhengzhou university and registered at the chinese clinical trial registry ( www.chictr.org ; chictr - onc-11001954 ) .
all study procedures were in accordance with the declaration of helsinki and all recruited subjects have provided written informed consents .
ataxia patients with family history were screened at the department of neurology , first affiliated hospital of zhengzhou university and referred for genetic testing at the department of genetic diagnosis .
patients who fulfilled the following inclusion criteria : ( 1 ) ataxia patients with family history were checked and diagnosed by two independent doctors , then the genotype sca3 was confirmed by genetic test ; ( 2 ) older than 18 years ; and ( 3 ) willing to give informed consent , will be recruited .
the exclusion criteria were as follows : ( 1 ) allergy to neurotrophin ; ( 2 ) with concomitant severe systematic diseases or psychiatric disorders ; ( 3 ) unable to finish the scale for assessment and rating of ataxia ( sara ) score ; ( 4 ) refuse to attend the study , and ( 5 ) ataxias attributed to secondary causes ( such as alcohol or drug abuse and toxic exposure ) .
all enrolled patients underwent standard neurological , electrophysiological and neuroimaging examinations , and the sca3 subtype was classified according to these clinical findings .
china ) used in this study was extracted and purified from the submandibular gland of the male mouse and has high homology in the amino acid sequence with human ngf .
the mngf has been safely used in a series of clinical studies . , and has been approved by china food and drug administration .
mngf was administered peripherally by intramuscular injection at the dose of 18 g once daily for 4 weeks consecutively .
it has been proven to have good reliability and validity among chinese patients with degenerative cerebellar .
the sara evaluates axial ( gait , stance , sitting ) , speech , and appendicular ( finger chase , nose - finger test , fast alternating hand movements ( fahms ) , and heel - shin slide ) functions .
the sara sum score ranges from 0 to 40 with 0 indicating no ataxia and 40 the most severe ataxia , thus deterioration or improvement of disease severity is , respectively , represented by an increase or decrease of the sara score . for each patient ,
chinese version of sara was performed at the baseline , 2 weeks ( midpoint ) and 4 weeks ( endpoint ) after treatment .
these sara evaluations were all videotaped and reviewed independently by two other investigators who did not attend the original assessment in a random order .
the average of score rated by these two evaluators was denoted as the final sara score .
the primary outcome measure was the change of sara score after treatment compared with that at baseline .
continuous variables were expressed as mean  standard deviation ( sd ) , and categorical variables were expressed as frequencies or proportions where appropriate .
the observed changes of sara score after treatment from baseline were analyzed with nonparametric wilcoxon signed - rank test .
continuous variables were expressed as mean  standard deviation ( sd ) , and categorical variables were expressed as frequencies or proportions where appropriate .
the observed changes of sara score after treatment from baseline were analyzed with nonparametric wilcoxon signed - rank test .
the mean age was 39.14  7.81 years , the mean age of onset was 35.00  6.53 years , the mean disease duration was 4.14  1.90 years , and the mean cag repeats number was 77.57  2.27 .
the mean sara score dropped from 8.48  2.40 to 6.94  2.34 ( p < 0.001 ) and 6.30  1.87 ( p < 0.001 ) after 2 and 4 weeks of treatment , respectively [ table 2 ] .
significant decrease in subsections sara scores was also observed in stance ( p = 0.008 and 0.003 ) , speech ( p = 0.046 and 0.023 ) , finger - chase ( p = 0.026 and 0.015 ) , fahms ( 0.015 and 0.009 ) , and heel - shin slide ( p = 0.006 and 0.001 ) at 2 and 4 weeks after therapy , respectively .
the mean improvement in total sara score was 2.18  1.30 ( ranging from 0 to 5.75 ) in our study .
scores of sara and its subsections at baseline , 2 and 4 weeks after ngf therapy * comparisons between midpoint of therapy and baseline ; comparisons between endpoint of therapy and baseline .
sara : scale of the assessment of rating of ataxia ; fahm : fast alternating hand movements ; ngf : nerve growth factor .
one previous study has shown that insulin - like growth factor-1 , one of the neurotrophic factors , may be effective in reducing the disease progression of sca3 .
previous studies have reported that ngf can improve cognitive decline in patients with alzheimer 's disease and may also have potential therapeutic roles in other neurodegenerative diseases .
postmortem histopathological study in patients with sca3 has revealed considerable neuronal loss at the cerebellar purkinje cell layer and the four deep cerebellar nuclei .
ngf can prevent neuronal death or age - related atrophy in the adult brain by inhibiting apoptosis of cholinergic neurons in the basal forebrain , and it would be reasonable to postulate that it may also inhibit the apoptosis in the cerebellum neurons expressing tyrosine kinase a ( trka ) and serve as a potential therapy for sca3 .
such treatment effect is observed as early as 2 weeks after therapy and sustained after 4 weeks . to our knowledge , this study is the first to investigate the efficacy of ngf in sca3 .
postmortem study has shown that ngf and its high - affinity receptor tkra are distributed in the neurons of the human cerebellum cortex and its deep nuclei throughout life .
these findings support the involvement of ngf in the development , differentiation and maintenance of the cerebellar connectivity .
although the blood - brain barrier ( bbb ) has low permeability to large proteins , some autoradiography studies suggested ed that blood - borne ngf and its subunit -ngf can cross the bbb of mice and arrive at the brain parenchyma by direct permeation .
second , the therapeutic effect of ngf might also be mediated via the proprioceptive sensation system .
it has been reported that most ( 87% ) of the sca3 patients had somatosensory evoked potential abnormalities , especially in the lower limbs , which was due to degenerative lesions in the dorsal column of the spinal cord .
hence , ngf therapy may improve stance and heel - knee - shin slide due to improved proprioception .
these two proposed mechanisms may explain the observed improvement after therapy and substantiate the use ngf to treat a patient with sca3 .
first , it was an open - label study , in which the observed therapeutic efficacy might be contributed by placebo effects . however , in one randomized , double - blind , and placebo - controlled study to evaluate the efficacy of varenicline in sca3 patients , the mean improvements of sara score in the therapeutic group , and the placebo group were 1.97 and 0.86 , respectively .
the sara score improvement of 2.18 in our current study is unlikely to be accounted for by placebo effect alone .
furthermore , sara is a reliable and valid scale to linearly assess the ataxia symptoms , and changes of sara scores exceeding 1.1 points are considered clinically relevant .
nevertheless , our pilot data suggest that ngf may be a promising treatment for patients with sca3 . a large - scale randomized
, double - blind placebo - controlled trial would be worthwhile to evaluate the efficacy and tolerability of ngf in sca3 patients .
 background : spinocerebellar ataxia type 3 ( sca3 ) is the most common subtype of sca worldwide , and runs a slowly progressive and unremitting disease course . 
 there is currently no curable treatment available . 
 growing evidence has suggested that nerve growth factor ( ngf ) may have therapeutic effects in neurodegenerative diseases , and possibly also in sca3 . 
 the objective of this study was to test the efficacy of ngf in sca3 patients.methods:we performed an open - label prospective study in genetically confirmed adult ( > 18 years old ) sca3 patients . 
 ngf was administered by intramuscular injection ( 18 g once daily ) for 28 days consecutively . 
 all the patients were evaluated at baseline and 2 and 4 weeks after treatment using the chinese version of the scale for assessment and rating of ataxia ( sara).results : twenty - one sca3 patients ( 10 men and 11 women , mean age 39.14  7.81 years , mean disease duration 4.14  1.90 years , mean cag repeats number 77.57  2.27 ) were enrolled . 
 after 28 days of ngf treatment , the mean total sara score decreased significantly from a baseline of 8.48  2.40 to 6.30  1.87 ( p < 0.001 ) . 
 subsections sara scores also showed significant improvements in stance ( p = 0.003 ) , speech ( p = 0.023 ) , finger chase ( p = 0.015 ) , fast alternating hand movements ( p = 0.009 ) , and heel - shin slide ( p = 0.001).conclusions : our preliminary data suggest that ngf may be effective in treating patients with sca3 . 
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