How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy.

Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 because of predominant skipping of exon 7 during pre-mRNA splicing. With the recent US Food and Drug Administration approval of nusinersen (Spinraza), the potential for correction of SMN2 exon 7 splicing as an SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here, we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.

Successful extension of assessment and rehabilitation intervention for an adolescent with postcoma multiple disabilities through a learning setup.

Prior to the beginning of this study, the participant (an adolescent with postcoma multiple disabilities) had learned to use a forehead-skin response to access environmental stimuli. These learning data seemed to indicate a minimally conscious state (i.e., awareness of the link between response and stimuli) in spite of 1) a previous diagnosis of postcoma vegetative state; and 2) concomitant electrophysiological measurement showing no evidence of a passive P300 response and of mismatch negativity. The present study was an effort to extend the early learning investigation with two additional responses and related stimuli to broaden learning evidence and ascertain possible choice behavior. Results indicated that the participant learned the new responses and also provided evidence of choice behavior. These data were discussed in terms of the usefulness of the learning paradigm in the assessment and rehabilitation of persons with postcoma multiple disabilities and consciousness disorders.

Promoting step responses of children with multiple disabilities through a walker device and microswitches with contingent stimuli.

Children with severe or profound intellectual and motor disabilities often present problems of balance and locomotion and spend much of their time sitting or lying, with negative consequences for their development and social image. This study provides a replication of recent (pilot) studies using a walker (support) device and microswitches with preferred stimuli to promote locomotion in two children with multiple disabilities. One child used an ABAB design; the other only an AB sequence. Both succeeded in increasing their frequencies of step responses during the B (intervention) phase(s). These findings support the positive evidence already available on the effectiveness of this intervention in motivating and promoting children's locomotion.

Microswitch for vocalization responses: comparing single- versus dual-microphone arrangements for a man with multiple disabilities.

Microswitches are technical devices designed to enable persons with multiple disabilities to control environmental events, generally preferred stimuli such as music and lights, using simple/feasible responses. For example, a sound-detecting microswitch may allow a person to turn on brief periods of preferred stimulation through simple vocal responses. This study compared the accuracy of two versions of a sound-detecting microswitch, i.e., one using a throat microphone and the other both throat and airborne microphones, for a man with multiple disabilities. Analysis showed that the latter microswitch version radically reduced the false activations present with the former microswitch version. Thus, the latter version seemed to have a clear accuracy advantage over the former with important practical implications.

Three persons with multiple disabilities accessing environmental stimuli and asking for social contact through microswitch and VOCA technology.

BACKGROUND: Direct access to environmental stimuli and opportunity to ask for social contact/attention may be considered highly relevant objectives for persons with multiple disabilities. We assessed the possibility of enabling three of these persons (two children and one adolescent) to combine two microswitches (for accessing environmental stimuli) and a Voice Output Communication Aid (VOCA), which allowed them to ask for caregiver's attention. METHODS: Initially, the participants were required to use each of the two microswitches individually and then together. Thereafter, they were taught to use the VOCA. Eventually, the VOCA was available together with the microswitches, and the participants could use any of the three. RESULTS: The results, which support preliminary data on this topic, showed that all participants (1) were able to operate the two microswitches as well as the VOCA; and (2) used all three of them consistently when they were simultaneously available. CONCLUSIONS: Teaching persons with multiple disabilities to combine a VOCA with conventional microswitches may enrich their general input, emphasize their active social role and eventually enhance their social image.

Enabling two adolescents with multiple disabilities to choose among environmental stimuli through different procedural and technological approaches.

Two single-case studies were carried out using different procedural and technological approaches to enable two adolescents with multiple disabilities to choose among environmental stimuli. Study I focused on replicating a recently developed procedure, which relied on samples of the auditory stimuli available as cues for choice responses. Study II assessed a new procedural and technical setup relying on the use of pictorial representations of the stimuli available as cues for choice responses. The auditory samples and the pictorial representations were presented through computer systems. The participants' choice responses relied on microswitches connected to the computer systems. The data of Study I fully supported previous findings with the same procedural approach. The participant learned to choose preferred stimuli and bypass nonpreferred ones. The data of Study II showed that the participant learned to concentrate his choice. responses on a few stimuli, suggesting that these stimuli were actually preferred and that responding was purposeful. Implications of the results were discussed.

Enabling a young man with minimal motor behavior to manage independently his leisure television engagement.

Persons with severe spastic tetraparesis and minimal motor behavior may be confined to a wheelchair or bed and have virtually no chances of constructive engagement with their immediate environment. A possible way to modify this situation may involve the use of technology. The present study (a) assessed specific technology to enable a young adult to manage his leisure television engagement independently and (b) carried out a social validation assessment of the technology-supported performance involving 90 teacher trainees as raters. The intervention period with the new technology included 67 sessions, during which the participant performed independently 392 of the 408 television-management responses, i.e., turning on the television, finding a channel with a preferred program, setting the volume, and turning off the television. He also indicated preference for using the technology as opposed to not using it. The raters provided relatively high (positive) scores for the technology-supported performance compared to the baseline performance. Implications of the findings are discussed.

Eye- and mouth-opening movements replacing head and hand responses in a microswitch program for an adolescent with deteriorating motor condition.

This study assessed the possibility of replacing head and hand responses (no longer feasible) with minimal movements within the microswitch-based program of an adolescent with deteriorating motor condition and multiple disabilities. The new movements, i.e., eye- and mouth-opening, were introduced individually and then combined through the simultaneous availability of the related microswitches. Data showed the participant acquired the new movements (responses) successfully and retained them at a 2-mo. postintervention check. Mood improvements, i.e., increases in indices of happiness, also occurred through the program. The conclusion was that a person with deteriorating motor conditions may be able to revitalize a microswitch-based occupational program and retain a constructive engagement if new, feasible responses are identified.

Small hand-closure movements used as a response through microswitch technology by persons with multiple disabilities and minimal motor behavior.

This study assessed small hand-closure movements as a potential response for microswitch activation with two participants with profound multiple disabilities of 5.2 and 20.6 yr. of age. The microswitch consisted of a two-membrane thin pad fixed to the palm of the hand and a control system. The outer membrane (the one facing the fingers) was a touch-sensitive layer; the inner membrane was activated if the participant applied a pressure of over 20 gm. The activation of either membrane triggered an electronic control system, which in turn activated one or more preferred stimuli for 6 sec. except in baseline phases. Each participant received an ABAB sequence, in which A represented baseline and B intervention phases, and a 1-mo. postintervention check. Analysis showed both participants increased their responding during the intervention phases and maintained that responding at the postintervention check. Implications of the findings are discussed.

Enabling persons with multiple disabilities to choose among environmental stimuli and request stimulus repetitions through microswitch and computer technology.

This study assessed microswitch and computer technology to enable two participants with multiple disabilities, 32 and 19 years of age, to choose among environmental stimuli and request their repetition whenever they so desired. Within each session, 18 stimuli (12 preferred and 6 nonpreferred) were available. For each stimulus, a computer system provided a sample of 3 sec. duration. During the intervention, participants' vocal responding in relation to a stimulus sample activated a microswitch and a computer system turned on that stimulus for 15-30 sec. When participants did not vocally respond, the computer system paused briefly and then presented the next scheduled stimulus sample. When participants vocally responded at the end of a stimulus presentation, the stimulus was repeated. Intervention data showed that the participants learned to choose preferred stimuli and bypass nonpreferred ones as well as to request repetitions of the preferred stimuli. This performance was maintained at a 1-mo. postintervention check and transferred to sets of stimuli not used in the intervention. The implications of these results were discussed.

Transforming growth factor-beta-regulated expression of genes in macrophages implicated in the control of cholesterol homoeostasis.

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-beta (transforming growth factor-beta), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-beta signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.

Enabling a man with multiple disabilities and limited motor behavior to perform a functional task with help of microswitch technology.

This study evaluated the extent to which two microswitches used as interfaces would enable a man with multiple disabilities and limited motor behavior to operate an electric door opener at the entrance of the day center that he attended. Analysis showed the man (a) learned to use the two microswitches, (b) preferred the microswitch placed at his wheelchair's footrest (which also allowed more effective responding) over the microswitch placed at his wheelchair's armrest, and (c) maintained his positive performance at the 1- and 2-mo. postintervention checks. The results were discussed from a technical and practical standpoint and in terms of implications for the quality of life of persons with disabilities.

Writing program with word prediction for a young man with multiple disabilities: a preliminary assessment.

This study assessed a writing program with word prediction, which completed the writing of a word and spoke it out only when there was certainty that such a word was the correct one. The assessment was carried out with a young man with multiple disabilities, who typically used a word-processing program without word prediction. The two programs were compared on the time required by the participant for writing general sentences, through a social validation assessment, and eventually a check on the participant's preference. Analysis showed the program with word prediction was significantly more effective in terms of the writing time, which was halved, and was deemed preferable by 40 raters (psychology students) involved in the social validation assessment and by the participant himself. Implications of the findings are discussed.

Assessing the effects of stimulation versus microswitch-based programmes on indices of happiness of students with multiple disabilities.

BACKGROUND: Stimulation and microswitch-based programmes are considered main strategies to promote indices of happiness in students with multiple disabilities. However, only limited attempts have been made to assess the relative effects of the two programmes. This study conducted such an assessment with seven students with multiple disabilities. METHODS: The first four phases of the study served to: (1) provide the students with a systematic exposure to each of the programmes; and (2) measure the programmes' effects on indices of happiness by comparing them with baseline levels. The fifth phase served to compare the programmes with each other. RESULTS: The first four phases of the study showed that the microswitch-based programme produced a significant increase in indices of happiness for all seven students, and the stimulation programme produced a significant increase for six students. During the fifth phase of the study (i.e. when the two programmes were alternated), the microswitch-based programme promoted significantly higher indices of happiness than the stimulation programme for four of the seven students. CONCLUSIONS: Microswitch-based programmes might be deemed preferable to stimulation programmes because they can promote higher or comparable indices of happiness while promoting the acquisition of adaptive responses and self-determination.

Multiple microswitches for persons with multiple disabilities: a basic procedure to examine the persons' choice behavior.

This study examined a basic choice-analysis procedure to clarify choice between two responses and related stimuli by five persons with multiple disabilities ages 17.1 to 50.2 yr. The procedure was based on reversing the links between responses and stimuli to assess whether the stimuli accounted for differences in response levels. When this was not the case, the procedure added extra stimuli for the less preferred response to judge whether such an increase would compensate for the apparent disadvantage of that response, e.g., its higher physical cost. Analysis showed that the choice of three of the five participants seemed motivated by the stimuli following the responses. The choice of the other two persons seemed related to a preference for one of the responses which was partially or largely modified when extra stimuli were added.

Micro-switch programmes for students with multiple disabilities and minimal motor behaviour: assessing response acquisition and choice.

This study assessed (a) whether three girls with multiple disabilities and minimal motor behaviour could acquire pairs of responses taught through micro-switch-based programmes and (b) how the girls would eventually choose between those responses. In relation to the choice issue, a response-choice analysis was conducted to find out whether possible differences in performance rates for the two responses were due to the stimuli linked to them and/or to potential response preferences. Results indicated that all three girls succeeded in the acquisition of the two responses programmed for them and showed clear response choices. The choices seemed to be largely motivated by the stimuli linked to the responses. Implications of these findings were discussed, including the need to assess their generality and extend the scope of the work in this area.

An optic micro-switch for an eyelid response to foster environmental control in children with minimal motor behaviour.

This study assessed whether two children (11.9- and 9.7-years-old) with profound multiple disabilities and minimal motor behaviour could learn to control environmental stimulation using an eyelid response with a newly developed micro-switch. The response consisted of raising the eyelid markedly (i.e. by looking upward or opening the eyes widely). The micro-switch developed for this target response consisted of an electronically regulated optic sensor mounted on an eyeglasses' frame. Data showed that the children learned the target eyelid response to activate the micro-switch and to increase their level of environmental stimulation. Responding was largely maintained at a 2-month post-intervention check. These results indicate that continued work in this area has positive implications for the rehabilitation of children with most serious disabilities.

Evaluating the applicability of optic microswitches for eyelid responses in students with profound multiple disabilities.

PURPOSE: The two studies reported here served as replication and extension of preliminary research on the use of optic microswitches for eyelid responses with students with profound multiple disabilities. METHOD: In Study I, a young boy was taught to use the same combination of upward eyelid movement and optic microswitch utilized before. In Study II, an adolescent was taught to use a new combination of single blink response and optic microswitch. Study I included an ABAB sequence (in which A represented baseline and B intervention phases) and post-intervention checks. Study II included four phases assessing the effects of baseline, intervention, and non-contingent stimulation conditions. RESULTS: The results of Study I showed that the boy displayed high frequencies of the upward eyelid response during the intervention phases and post-intervention checks (suggesting learning effects). The results of Study II showed that the adolescent performed the single blink response at a significantly higher frequency during intervention as opposed to the other conditions (again suggesting learning effects). CONCLUSIONS: The results of Study I and Study II provide encouraging new evidence, with potentially important practical implications, about the applicability of eyelid responses and optic microswitches for students with profound multiple disabilities and minimal motor behaviour.

A microswitch-based programme to enable a boy with multiple disabilities and minimal motor behaviour to choose among environmental stimuli.

PURPOSE: The present study assessed a microswitch-based programme designed to enable a nine-year-old boy with multiple disabilities and minimal motor behaviour to choose among environmental stimuli. METHOD: The programme relied on the boy's eyebrow movements, a microswitch to detect such movements, and a computer system to handle sets of allegedly preferred and non-preferred stimuli. For each of the 30 stimuli available in every session, the computer system provided a sample/preview of 2-3 seconds. During intervention, the boy's responding to a stimulus sample (i.e., moving the eyebrow and activating the microswitch) led the computer system to turn on that stimulus for 25 seconds. The boy's lack of responding led the computer system to present the next stimulus sample. RESULTS: Intervention data showed that the boy's choice making (i.e., responding to a stimulus sample or avoiding to do so) was largely consistent with the alleged preference value of the stimuli, that is, he tended to choose the stimuli that were considered preferred and to bypass those considered non-preferred for him. The same performance was maintained during post-intervention checks, occurring 6 and 10 weeks after the end of the intervention, and over sets of stimuli not used during the intervention. CONCLUSIONS: The present microswitch-based programme may be considered useful to allow students with multiple disabilities an active choice (control) role in a stimulation-enriched environment.

Assessing a microswitch-based stimulation procedure for eye-blinking responses in a young woman with profound multiple disabilities.

We applied a new microswitch-based stimulation procedure for eye-blinking responses with a young woman with profound multiple disabilities, and compared effects of this procedure on the eye-blinking responses and smiling with the effects of a caregiver-based stimulation condition. Analysis showed that the microswitch-based stimulation procedure, with stimulation occurring contingent on eye-blinking responses, increased the frequencies of these responses significantly above the levels recorded in baseline and caregiver-based stimulation conditions. No changes in smiling frequencies occurred. Implications of the findings in terms of alertness, learning, and quality of life are discussed.