Survival of the enterprise and maintaining US competitiveness.

NIGMS has some interesting approaches that help their funding rates. Can any of these approaches be adopted more readily by NHLBI?

With the challenging NIH funding climate, many junior investigators are struggling to obtain their first R series grant. Without better support of our junior investigators, the next generation of investigators in academic medicine is in peril.

Approximately 20% of the population are characterized by elevated circulating levels of lipoprotein(a), regardless of age, gender or blood cholesterol levels. Estimates suggest that up to 90% of the variation in plasma lipoprotein(a) levels could be due to genetic factors, which makes lipoprotein(a) the most prevalent inherited risk factor for cardiovascular diseases (CVD). Large-scale genetic studies have shown that Lipoprotein(a) was the strongest genetic determinant of CVD such as atherosclerosis and aortic stenosis. Lipoprotein(a) is one of the strongest predictors of residual CVD risk and has been shown to improve CVD risk prediction in several population-based studies. Lipoprotein(a) is also one of the strongest known risk factors for spontaneous ischemic stroke in childhood.
A comprehensive research strategy aiming at identifying, evaluating interaction with other risk factors, treating and educating patients with elevated lipoprotein(a) levels would result in substantial reductions of health care costs in the US and around the globe by reducing the burden of CVD while simultaneously improving the quality of life of these patients.

The list of pharmaceutical agents that reduce lipoprotein(a) levels is steadily increasing. There are approximately half a dozen strategies that have been shown to significantly and safely lower lipoprotein(a) levels. One of the challenges of this research strategy will be to determine which of these strategies represent the most efficient, safe, cost-effective and widely applicable approach to lower lipoprotein(a) levels and CVD outcomes.
Increasing awareness on lipoprotein(a) and CVD will also be of utmost importance for this effort as relatively few physicians perform lipoprotein(a) testing and even fewer patients are aware of their lipoprotein(a) level. The first sign of high lipoprotein(a) is often a heart attack or stroke. Our challenge will be to identify patients with high lipoprotein(a) that could be enrolled in trials of risk characterization and lipoprotein(a)-lowering.

As described, we need to move beyond association to intervention. We have developing mobile technologies to assess outcomes in subjects living in their normal circumstances. The issue is what interventions can be applied and be shown to work to address both sleep length and circadian timing of sleep. There is a need to stimulate research to assess different potential interventions to see which are the most effective.

The impact of this will be invaluable. We should be able to improve sleep and circadian health in the US population and thereby modifying this risk factor for development of chronic diseases.

We have the relevant tools to do this. There are millions of Americans with short sleep and millions of Americans who have misplaced sleep in relation to their normal circadian rhythms. Thus, there is no shortage of subjects to recruit for this type of research. There is now a developing body of knowledge about techniques that can be applied to modifying behavior in other areas—weight loss, stopping smoking, etc. These techniques could be the basis of new interventions to improve sleep health.

During the past several decades there have been revolutionary changes in technology that have enabled an unprecedented understanding of basic biologic and pathobiologic phenomena. However, there has not been a concomitant increase in novel technologies to prevent, diagnose, and treat disease. While NHLBI funds thousands of R01 grants that support mechanistic research, only a small percentage moves the basic discoveries into the pre-clinical space, a critical step in fulfilling NHLBI’s mission. An analysis of the Division of Blood Diseases applications for the FY 2012, showed that while 32% (174/541) of the unsolicited applications (RO1, R21, PO1) had at least one early translational component, only 15% went beyond proof of concept and only 3% included early phase clinical trials. Patent filings, a main gateway to translation, are another way to estimate the translation of NHLBI discovery science. A survey of 90 NHLBI investigators, randomly selected across all three Divisions, found 76% of the investigators had no patent activity over a 10 year period and 12% accounted for 82% of all the patent activity. These data suggest that there may be barriers to investigators being able to realize the translational potential of promising discoveries beyond proof of concept. NHLBI needs an overarching, coordinated, and efficient plan to encourage and support investigators in their independent pursuit of translational research.

The creation of an integrated, facilitative programmatic pathway at NHLBI that would leverage existing NIH resources to ease the major barriers to translation of scientific discovery in the investigator community by:
•Providing skills development training and guidance for investigators wishing to do translational research
•Coordinating the support of all pre-IND phases of translational science
Facilitating reproducible pre-clinical research in animals, including animal and humanized models, medical chemistry, pharmacological toxicology
•Providing support for early phase or adaptive design clinical trials
•Ensuring scientific review that is available and tailored to all phases of investigator-initiated translational science
•Establishing a robust system for ongoing portfolio analysis and program evaluation as well as metrics for evaluating programmatic outcomes

The creation of an integrated, facilitative programmatic pathway at NHLBI that would leverage existing NIH resources to ease the major barriers to translation of scientific discovery in the investigator community by:
•Providing skills development training and guidance for investigators wishing to do translational research
•Coordinating the support of all pre-IND phases of translational science
Facilitating reproducible pre-clinical research in animals, including animal and humanized models, medical chemistry, pharmacological toxicology
•Providing support for early phase or adaptive design clinical trials
•Ensuring scientific review that is available and tailored to all phases of investigator-initiated translational science
•Establishing a robust system for ongoing portfolio analysis and program evaluation as well as metrics for evaluating programmatic outcomes

The overwhelming response to NHLBI translational initiatives suggests a critical mass of investigators willing and able to explore the translational potential of their discoveries. The barriers to the continuous receipt of translational applications outside of the RFA mechanism have been identified and the proposed model for a competitive peer-reviewed process that spans the early translational pipeline has already been successfully implemented in at least one other NIH Institute. Adopting this model, the pipeline, as envisioned, would mostly consist of facilitative PAs and Review would not require a major up front expenditure of NHLBI targeted funding.

The necessary tools have been assembled, and managing implementation will reduce the time required for completion of larger scale projects.

high feasibility; the challenge will be managing communication across groups to maximize impact

Much of the research on the consequences of sleep/circadian disorders has focused on their consequences or behavior. This type of research needs to be continued and there are new opportunities in this area. These behavioral studies need to be established in model systems to parallel studies in humans. In addition, new neurobiological approaches, including optogenetics and use of DREAD, provide new tools for this investigation. Moreover, we now have powerful molecular tools to evaluate effects of sleep/circadian disorders both in humans and animal models. These include microarrays, RNA seq, etc. Moreover, genetic studies, e.g., in restless legs syndrome, have identified gene variants conferring risk for the disorder. We do not know, however, how these particular genes are involved in the pathogenesis of the disorder or whether they represent potentially targets for drug intervention. There is a need for studies both in animal models and in humans to elucidate the function of these genes. Studies in other areas are obtaining stem cells from biopsies in patients and then turning these into relevant target cells such as neurons to elucidate gene function using in vitro approaches.
The impact of this effort will be the following:

a. Taking our understanding of pathogenesis of sleep and circadian disorders to a new level.
b. Understanding the consequences of sleep and circadian disorders on different end organs at a more in-depth molecular level.

The sleep and circadian field have access to all the major cells systems for these studies—C. elegans, aplysia, Drosophila, zebra-fish, mice, etc. Moreover, there are already gene variants identified in human studies which require follow-up functional studies. The field has the expertise in all of the techniques described above. Moreover, there are more validated animal models for many of the common sleep disorders. Thus, this new approach is very feasible. 

The following will be the impact of addressing this critical challenge:

1. Having an assessment that can be used following a crash to assess the level of sleep loss of the driver.
2. Having a method to assess chronic sleep insufficiency as a potential pathogenetic process in patients with cardiovascular disease, hypertension, etc.
3. Having a method to estimate circadian phase so that in patients with chronic insomnia one can identify individuals with delayed sleep phase.
4. Having a technique to establish magnitude of circadian disruption to assess its role in pathogenesis of diseases such as cardiovascular disease.
5. Add a molecular biomarker to other techniques to screen for obstructive sleep apnea in high risk populations such as obese commercial drivers.
6. Utilize a biomarker signature to identify who with obstructive sleep apnea will be particularly at risk for downstream consequences such as cardiovascular disease.
7. Develop the equivalent of HbA1C to assess therapeutic response to CPAP

The first challenge is to identify a signature for each of these use cases. This will require initial studies in a small number of well phenotyped subjects with all the “-omic” techniques. Thereafter, these multiple cohorts, already available with blood samples, etc. and relative phenotype can be used for validation purposes.

There is no doubt that insufficient sleep and circadian disruption are very common in our society. There are also compelling epidemiological data that they are associated with multiple adverse consequences, including increased cardiovascular disease, increase in metabolic abnormalities such as insulin resistance and for shift work an increased incidence of specific concern. Animal studies based on microarrays are showing that inadequate sleep and circadian rhythm alter gene expression not only in brain but also in peripheral tissues. These studies are hypothesis-generating and there are many opportunities for hypothesis-driven research in this area to assess mechanisms. Identifying mechanisms will allow investigators to begin to assess mechanisms of individual differences and to identify new pathways for intervention.

Sleep and circadian research is in a very strong position. Sleep and clock function has now been identified in all the major model systems—C. elegans, Aphysia, Drosophila, zebra-fish, mice, etc. Thus, there is a strong platform to assess conserved pathways for effect of sleep loss and circadian disruption. Moreover, microarray studies have identified likely pathways thereby setting up hypothesis-driven research. There are major opportunities in this area.

There is a strong rationale for application of a personalized approach to sleep disorders. This requires approaching this question using multiple domains as in other areas of medicine—clinical features, physiological factors, application of the –omic approaches, genetics. The impact of this will be several:

a. A new way to classify sleep disorders.
b. Identification of subgroups of patients with apparently the same disorder who will have different outcomes of therapy.
c. Identification of subgroups of patients who will have different approaches to diagnosis.
d. Identification of subgroups of patients with apparently the same disorder who will have different therapeutic approaches.

These sleep and circadian disorders are extremely common. There is a risk infrastructure for this type of research based on the large number of accredited sleep centers in the United States that could be used for subject recruitment and who can adopt similar techniques. There is also a rich set of data obtained from sleep studies that could be used to identify new patterns that reflect different subgroups of subjects. These studies need to be based on clinical populations of patients who present with the different disorders rather than on population-based cohorts.

The ability of allogeneic blood or marrow transplantation (BMT) to cure diverse non-malignant diseases is well-documented. However, widespread use in diseases such as sickle cell anemia that cause substantial morbidity and shorten life but are not immediately life-threatening, has been limited by transplant-related toxicity and mortality especially in the majority of these patients who lack HLA-matched donors. Several new therapeutic approaches now exist that are promising strategies, separately or in combination, for addressing issues of donor availability, graft rejection, organ toxicity and acute and chronic graft-versus-host disease more effectively. Evaluation and refinement of these therapeutic strategies in both preclinical and Phase I-III clinical trials now offers a real possibility that allogeneic BMT could be applied early in the course of these diseases, allowing normal growth, development, quality of life and lifespan. If successful, allogeneic BMT offers a major advantage over gene therapy approaches even if such approaches become possible in the future; i.e., allogeneic BMT can be done with low-dose, non-toxic conditioning while gene therapy requires high-dose myeloablative therapy which not only can be toxic/fatal to these patients who often have end-organ dysfunction but also universally induces infertility, a major concern of patient groups who usually survive beyond child-bearing years.

There are now single institution and registry (CIBMTR) data showing that related haploidentical allogeneic BMT using post-transplantation cyclophosphamide (PTCy) produces results similar to those seen with HLA-matched sibling donors. Accordingly, every patient in need of allogeneic BMT now can safely undergo the procedure, including those ethnic groups (such as African-Americans and Hispanics) who are unlikely to find a donor in unrelated registries. Combining PTCy with other approaches for preventing graft-versus-host disease (GVHD) can even eliminate GVHD and transplant-related mortality. Although recurrence of malignant diseases remains an issue, especially as GVHD is eliminated, relapse is not a concern for non-malignant diseases after successful allogeneic engraftment. Moreover, the average cost of allogeneic BMT, about $150K, is a cost-savings over the long-term management of many of these diseases. The NHLBI-funded BMT Clinical Trials Network (CTN) has developed the infrastructure to rapidly and efficiently carry out large multi-institutional BMT trials. Over the last 15 year, thousands of patients have been entered on BMT CTN trials. Of note, African-Americans and Hispanics remarkably represent 30% of the accruals on one such trial, CTN1101, studying unrelated umbilical cord and related haploidentical allogeneic BMT. However, funding for the infrastructure for continuing this work remains problematic, since BMT trials generally lack corporate funding.

There is a developing evidence from both basic research and clinical research on the role of insufficient sleep in different co-morbidities. These include cardiovascular disease, hypertension and metabolic disorders. The Centers for Disease Control (CDC) has appreciated the importance of this that adequate sleep is one of the pillars of health. As part of the CDC-supported program on sleep health, a consensus statement has been issued on normal sleep duration. The group doing this on behalf of the American Academic of Sleep Medicine and Sleep Research Society realized that our evidence base is inadequate at this time. Thus, there is a need to focus on this critical challenge. Sleep duration varies across the lifespan and there is some evidence that it is different in different ethnic groups. Thus, there is a need for comprehensive efforts to address this question and to obtain normative data for sleep duration that is age-, gender-specific and with respect to different ethnic groups.

There are now recent cohorts at NIH assessing sleep duration using not only self-report but also actigraphy. These could be used as an initial approach to address this question. This will require some degree of coordination between NIH Institutes. In the future a cohort that is specific to addressing questions about sleep duration and other sleep problems would be optimal. There are major prevalent public health issues. This would be facilitated by development of new mobile approaches to assessing these behaviors in an objective way.

This question will have considerable impact. Sleep apnea is an independent risk factor for insulin resistance. Moreover, observational studies show that treatment of OSA reduces the rate of future diabetes compared to that which occurs in untreated OSA. Therefore, identifying OSA and treating this could have a profound impact on reducing the rate of diabetes, i.e., a preventative strategy.

Both sleep loss and obstructive sleep apnea have also been shown to be risk factors for subsequent development of Alzheimer’s disease. This has been shown in mouse models and in epidemiological studies to address whether insufficient sleep and sleep apnea are independent risk factors for development of Alzheimer’s disease, in particular accelerating their onset. Determining whether this is so and whether interventions to treat these sleep disorders delay onset of diabetes and Alzheimer’s disease would have profound public health significance.

These disorders are extremely common so that recruitment of subjects is not challenging. Moreover, new technology reduces protocol burden to assess individuals. All studies can be done in the patients’ home. There are existing cohort studies focused on diabetes and the Alzheimer’s Center program that could be used for these studies. Thus, the studies are extremely feasible in the near term.

There are major individual differences in response to sleep loss (both acute and chronic) and to circadian disruption. This has major impact both in terms of health consequences and in safety. Some individuals are particularly vulnerable to sleep loss and hence are more likely to have adverse consequences of losing sleep—increased risk of crashes, errors by physicians, etc. They are also more likely to be affected by metabolic and other consequences if they have chronic insufficient sleep.

Identifying the basis of these individual differences will have several impacts:

1. It will provide likely targets for development of biomarkers to assess effect of sleep loss and circadian disruption.
2. It will provide tools to risk stratify individuals and to employ preventative strategies to reduce risk of major adverse consequences.
3. It will identify novel pathways that could be the target for future intervention studies.

These studies are highly feasible. Phenotyping and recruitment strategies to study this question have been established in many laboratories. Moreover, more laboratories are utilizing genetic, -omic approaches and epigenetic approaches that could be applied to this question. There is also a developing repertoire of neuroimaging studies that can be applied to address this question.