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2015 International Research Conference
on Tuberous Sclerosis Complex:
From Treatment to Prevention

Presented by The Rothberg Institute For Childhood Diseases.
This program is also made possible with support from Novartis.

CONFERENCE SUMMARY

Download a PDF of this summary.  You can also download a PDF of the Conference Program Book.

Approximately 260 attendees from 30 countries participated in the 2015 International Tuberous Sclerosis Complex Research Conference: From Treatment to Prevention, held September 10-12, 2015, in Windsor, UK. Jointly sponsored by the TS Alliance and the Tuberous Sclerosis Association in the UK, the program featured oral presentations, a poster session, and ancillary meetings including TSC International and TSCure, a working group of clinical researchers tackling issues necessary to plan clinical trials of very early treatments to prevent manifestations of TSC from occurring rather than treating them when they appear. Work and ideas presented at the conference showed clearly that the future of those impacted by TSC has never been brighter.

The keynote address by Professor Michael Hall, discoverer of the protein named “target of rapamycin” (TOR, or mTOR in mammals), highlighted multiple specific examples in which the work of basic and clinical scientists has been repeatedly intertwined over the years to understand the biology and develop treatment for TSC. TOR is a key controller of cell growth in cells, playing an important role in early development, growth, and aging. Because TSC1 and TSC2 regulate the activity of TOR, this helps explain why what we learn about TSC can help us learn about other aspects of human health and disease, as well.

GENETICS

Drs. Julian Sampson and David Kwiatkowski each presented next-generation (NextGen) DNA sequencing data suggesting that nearly all individuals with no mutation identified (NMI) by clinical genetic testing are mosaic for mutations in TSC1 or TSC2. Mosaic simply means that some, but not all, of the cells in their body carry a mutation in one of those genes. Detection of mosaicism by certified genetic testing laboratories will require NextGen sequencing in most cases, and in some cases may require testing biopsies of affected tissue because mosaicism may be undetectable in blood in some individuals.

Dr. Kwiatkowski showed a correlation of heterozygous-mosaic-NMI genotypes with the number of organs involved and number of signs or features experienced. Individuals who are heterozygous for a TSC1 or TSC2 mutation have the highest level of involvement, those who are mosaic tend to have fewer organs involved or fewer manifestations of TSC, and those who remain NMI even after NextGen sequencing have an even fewer number. Dr. Sampson showed that TSC1 or TSC2 genotype does not seem to influence a person’s response to mTOR inhibitors; TSC1, TSC2, and NMI genotypes all respond well to these drugs.

mTOR INHIBITORS

Drs. Sampson, Darcy Krueger, Chris Kingswood, and David Franz all showed data that indicate the response of various tumors in TSC to mTOR inhibition is durable over time, although measurable fluctuations of tumor size up and down may occur from one scan to the next. Dr. Kingwood noted that, five years after the EXIST-1 trial, no instances of renal bleeds have been reported in any of the participants in that early clinical trial. Dr. Frank

McCormack described the recent FDA approval of rapamycin for treatment of lymphangioleiomyomatosis (LAM) based on efficacy observed in clinical trials conducted over the past several years.

Dr. Franz presented data that side effects of mTOR inhibitors don't worsen over time. This could be due to a number of factors, including that healthcare providers might be better at optimizing the dosage level over time to achieve an effective response while minimizing side effects.

Dr. Iris Overwater reported data from the RATE trial, a rapamycin cross-over study of 23 subjects with TSC and epilepsy. The number of subjects increasing and decreasing in seizure frequency was the same whether on or off of rapamycin, but only 14 subjects had reached target blood levels of the drug.

Dr. Michael Wong’s data in both TSC and PTEN mouse models suggest mTOR inhibitors can be anti-epileptogenic, meaning they can prevent the development of epilepsy. But we don't know how early they must be started in humans or whether duration of therapy must be life- long. He also showed that intermittent dosing of mTOR inhibitors can preserve efficacy and minimize loss of weight gain, a common side effect of mTOR inhibitors in mice. This suggests that intermittent dosing might be useful in people affected by TSC who have trouble tolerating side effects.

EARLY INTERVENTION

Dr. Martina Bebin presented data from the TSC Clinical Research Consortium that an abnormal EEG in infants with TSC may be 100% predictive of seizures. However, both Dr. Bebin and Dr. Sergiusz Jóźwiak noted that abnormal EEGs are not always observed prior to the onset of seizures in infants. This could be because EEGs are administered weeks apart, and the EEG might be changing prior to seizure onset but after the previous EEG was completed. Ongoing studies will try to address this.

Dr. Bebin noted that partial seizures or partial seizures occurring along with infantile spasms are as common as infantile spasms alone. Similarly, focal or multifocal discharges are just as common as hypsarrhythmia.

Early recognition and diagnosis of TSC depends upon educating neonatal cardiologists and nurse practitioners in nursery. Multiple features of TSC may be observed before the onset of seizures, such as cardiac rhabdomyomas or hypomelanotic macules (ash leaf spots). If TSC is suspected very early, parents and physicians can be alert for the appearance of signs of seizures or could consider enrolling in a clinical study. Education of parents about TSC and clinical studies encourages study participation because studies involve active monitoring— which is empowering to parents.

Early intervention is not only for infants. Dr. McCormack described an upcoming clinical trial called MILED to test long-term, low-dose mTOR inhibitors to prevent progression of LAM in those who still have good lung function. The idea is that very early treatment might preserve strong lung function much longer rather than waiting until a great deal of function is lost

before starting treatment. In the MILES trial, very high VEGF-D levels were predictive of more rapid decline and better rapamycin response. We still need to understand better if VEGF-D levels can be used to determine optimal timing of treatment and dose.

TSC-ASSOCIATED NEUROPSYCHIATRIC DISORDERS (TAND)

Dr. Kandice Varcin reported data from a recently completed clinical study that the best predictor of an infant with TSC developing autism spectrum disorder (ASD) at age 3 years was decrease in non-verbal IQ during the interval from 12-36 months of age. She emphasized that it is important to get attention and services for these children early; parents often notice changes in their children, but none of the children in the study had gotten services by age three.

Dr. Varcin also stated that standardized autism assessments show a striking similarity between ASD in the general population and ASD associated with TSC, especially in non- verbal skills, suggesting that what we learn about TSC-ASD should be applicable to ASD in the general population.

Dr. Petrus de Vries showed data on burden of TAND on individuals, and data that burden on caregivers causes increased stress and decreased health. Dr. Anna Jansen stated that healthcare utilization studies are largely in the US and involving white individuals; there is no data from low-resource countries. More documentation of the burden of TAND might improve the availability of resources to measure and treat TAND.

Dr. Patrick Bolton reported data from the TS2000 study showing that better treatment of infantile spasms in TSC is starting to eliminate the profound intellectual disability around an IQ of 20. The longer infantile spasms persist in an individual, the worse the cognitive impairment as measured by IQ; interestingly, this is specific for infantile spasms and does not apply to other types of seizures.

PRECLINICAL RESEARCH

A number of new TSC animal models are under development. Dr. Rebecca Ihrie is developing a model of subependymal nodules or tumors. Her goal is to use her model to find ways to make such tumors more responsive to drugs. Dr. Jadwiga Schreiber developed an inducible TSC1 mouse that develops seizures 8-12 days after gene deletion and dies at 12-18 days after deletion. Inhibitors of mTOR can prevent this effect, but so far other anti- seizure drugs decrease frequency but don't rescue lethality. Dr. Wei Shi described his new model of LAM in which knockout of TSC2 in mice at age 30 days specifically in lung cells leads to alveolar destruction only in females. Although more work is required on all of these models to evaluate how well they do or do not reflect TSC in humans, these approaches illustrate the creativity of researchers to keep pushing the boundaries of what we know. All three scientists are funded by the TS Alliance or TS Association.

At the cellular level, Dr. Brendan Manning discussed data on potential new targets for therapies involving pyrimidine and purine synthesis, which is increased by mTOR to support

increased cell growth. Dr. Andrew Tee discussed nelfinavir, which targets stress inside the cell, in combination with chloroquine as a potential therapeutic approach for TSC2-null tumors, but this is not yet ready to be tested in humans. Dr. John Blenis reported data on other combinations of potential drugs that may affect a complex of proteins increased in cancer cells with increased mTOR activity, suggesting that they might be useful in TSC, also.

ACKNOWLEDGEMENTS

This conference was supported by a grant from Novartis, while The Rothberg Institute for Childhood Diseases was a presenting sponsor. Support was also provided by the Brian O’Brien Family, GW Pharmaceuticals, Bcureful, and the Castle Hotel Windsor. We would also like to recognize the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Nation Center for Advancing Translational Sciences, which provided grant support for this year’s research conference.


 
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