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Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
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4

Moving Forward

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
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Understanding sex differences in the brain is one of the major challenges to be addressed as neuroscience moves forward, said Eric Nestler. This will require integrating genomic, transcriptomic, epigenetic, cellular, and circuitry data in order to understand how genome sequence influences function and how it interacts with the environment throughout life, he said. Stevin Zorn, president and chief executive officer of MindImmune Therapeutics, Inc., added that technological innovation alone will not enable achievement of this goal but will need to be coupled with policy changes and consideration of ethical implications (e.g., reducing barriers to clinical trial participation for underrepresented groups).

TECHNOLOGICAL INNOVATION TO DRIVE PROGRESS

Technological innovation has fueled an increased understanding of the underlying genetic and molecular mechanisms that contribute to sex-specific differences in health and disease, said John Ngai, director of the National Institutes of Health’s (NIH’s) Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. The BRAIN Initiative was launched in 2014 to develop and apply new tools for understanding how neural circuits underlie complex behaviors. As an example of how new technologies have been applied to the study of sex differences, Ngai pointed

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×

to a study by Nirao Shah and colleagues at Stanford University that used bulk RNA profiling to identify a handful of genes that showed sexually dimorphic expression in mouse amygdala and hypothalamus. Interestingly, knocking out these genes affected specific sex-typical behaviors, providing evidence that sex-specific innate behaviors are governed by discrete genetic programs (Xu et al., 2012).

More recently, Science published several papers from the NIH Common Fund’s Genome-Tissue Expression (GTEx) project, including one focused on the role of sex in gene expression. For example, Barbara Stranger, associate professor of pharmacology at Northwestern University Feinberg School of Medicine, and colleagues showed that about one-third of all genes showed sex differences in expression (Oliva et al., 2020). These differences were subtle and usually restricted to one or two tissues, but in aggregate could have biologically significant effects, said Ngai.

Genes showing sex-specific differences were enriched for a wide spectrum of functions, including drug and hormone responses, epigenetic patterning, embryonic development, tissue morphogenesis, immune response, and cancer, said Stranger. The pattern of sex-differentiated gene expression was highly tissue specific. Stranger said her lab and others have also used expression quantitative trait loci (eQTL) mapping to see if single-nucleotide polymorphisms may have different effects in males versus females. This technique enables identification of genetic loci and candidate genes correlated with traits (Wang et al., 2016). In 44 tissues, they found 366 genes with a sex-biased eQTL signal. These sex-biased eQTLs are present across human tissues and in most cases are driven by a single sex. They could provide clues to understand how sex-biased genetic regulation explains the associations among disease genetics, genes, and mechanisms, said Stranger.

Recognizing that there is much more to learn about sex differences at the genetic and transcriptomic level, Stranger said studies need to be specifically designed to evaluate sex differences in healthy and diseased individuals in longitudinal cohorts across developmental time points, as well as in cell lines.

BRAIN Initiative Cell Census Project

One of the BRAIN Initiative’s major coordinated projects, the Cell Census Project, offers opportunities to advance understanding of sex differences in the brain and how they contribute to both health and disease, said Ngai. The concept underlying the project is to build an integrated, multi-modal brain cell atlas, he said (see Figure 4-1). Through the use of several advanced single-cell sequencing technologies and spatial transcriptomics techniques, the atlas aims to provide a foundation for obtaining other

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Image
FIGURE 4-1 The BRAIN Initiative Cell Census Project. The Cell Census Project will enable building multiple atlases integrating data on the molecular, anatomical, and functional characteristics of various cell types and the neural circuits that comprise them.
NOTE: ATAC = assay for transposase-accessible chromatin; FISH = fluorescence in situ hybridization; mC = methyl-capture; RNA = ribonucleic acid; seq = sequencing.
SOURCE: Presented by John Ngai, September 23, 2020.

information about the anatomy, morphology, connectivity, and function of cells that constitute neural circuits, said Ngai.

One of the newer technologies that has emerged in recent years—single-cell RNA sequencing—enables investigators to identify the contribution of constituent cell types that constitute a tissue despite their relatively small effect sizes, said Ngai. For example, one of the studies funded by the BRAIN Initiative used this approach to identify genes, neurons, and circuits that contribute to sexually dimorphic neuronal function in the hypothalamic preoptic region (Moffitt et al., 2018). More recently, again with BRAIN Initiative funding, David Anderson and colleagues used deep sequencing single cell profiling to identify 17 transcriptionally distinct cell clusters, several of which were male or female specific (Kim et al., 2019).

Ngai argued that these and other discoveries supported by the BRAIN Initiative lay the foundation for unraveling the molecular and cellular underpinnings of sex-specific behaviors and for identifying sex-specific differences in circuits that are affected in neurological and neuropsychiatric diseases. These discoveries, he said, may guide the development of new, effective, specific, and rational therapies.

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×

ACCOUNTING FOR SEX DIFFERENCES IN THERAPEUTIC DEVELOPMENT

Developing therapies for brain disorders that account for sex differences in disease presentation or response to treatment will be a long process, said Zorn. The challenge in a resource-limited world is to determine when the time is right to invest limited resources so that the data on sex differences can be translated into actions that are based on data-driven hypotheses, he said (IOM, 2011).

The Industry Perspective

In the context of drug development, David Michelson, chief medical officer at Regenacy Pharmaceuticals, said consideration of sex differences must fit into the overall drug development framework, which focuses on pharmacology and predictions about pharmacokinetics, efficacy, and safety. In addition to sex differences, he said, developers must also consider other subpopulations such as children, the elderly, and people with specific comorbidities, among others.

Two categories of information need to be collected, said Michelson. First is understanding how a drug in development works differently in men and women, whether it has a different safety profile, and whether there will be differences between the way men and women will use the drug. The information provided by these studies is limited by the size of the sample and distribution of men and women, he said. He added that the types of studies required may differ depending on the drug and the intended indication, and that some drugs may not require studies on sex-specific differences. If there is empirical support coming out of the laboratory for some sort of sex difference, study designs can be better tailored to either confirm or refute what was predicted, said Michelson.

The second set of studies are more exploratory and tend to be more hypothesis driven as they assess potential sex differences at the mechanistic level, said Michelson. These studies are informed by predictions emerging from preclinical studies, what is known about the mechanism, and what is known about the differential impact of the compound in men and women. Then the developer must determine how much more deeply to study the effects of sex and what essential questions to ask. He noted that the process is challenging given resource limitations. Michelson added that post-approval data may provide additional information that was not uncovered during the core development process.

Melissa Laitner, director of public policy and government affairs at the Society for Women’s Health Research, added that patient demographics could help identify who should be included in trials to ensure representa-

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×

tion that is proportional to disease prevalence. Laitner also highlighted the barriers to trial participation. For example, she said, women and certain underserved groups face more caregiving, transportation, and financial barriers. Decentralizing clinical trials or adopting digital technologies for data collection could potentially mitigate some of these barriers, said Laitner.

POLICY IMPLICATIONS OF INCORPORATING SEX AS A BIOLOGICAL VARIABLE INTO RESEARCH AND DRUG DEVELOPMENT

In 2014, NIH announced that as part of its efforts to ensure rigor and transparency in taxpayer-funded research, the agency would require investigators to account for sex as a biological variable (SABV) in all funded research, said Janine Clayton, associate director for research on women’s health and director of the NIH Office of Research on Women’s Health (ORWH) (Clayton, 2016). The policy applies to research designs, analysis, and reporting for vertebrate animal and human studies, and requires scientific justification for single-sex studies. For basic and hypothesis-generating research, it may be sufficient to observe and report sex-based data, she said. However, for preclinical research where the intent is to go to the clinic, the research design itself must incorporate SABV, whether that means employing factorial designs or other strategies. In the clinical space, research designs should lead to increased understanding of the differences in how a disease manifests in men and women; how interventions, diagnostics, or other perturbations affect men and women differently; and what is the clinical meaningfulness of those differences, said Clayton. Finally, sex differences should inform the delivery of care, she added.

The 2016 NIH policy was not the first initiative designed to ensure consideration of sex differences in research. The NIH Revitalization Act of 1993 required NIH-funded clinical trials to include women and minorities as participants and to assess outcomes according to sex, race, and ethnicity (NIH, 1994). Clayton said some progress has been made. NIH data indicate women represent at least 50 percent of NIH-supported clinical research and trials, yet Geller and colleagues (2018) have shown that compliance with sex-specific reporting remains low, she added. As shown in Figure 4-2, only about one-quarter of randomized controlled trials in 2015 analyzed data by sex, and in most of those cases no justification was given for those that did not (Geller et al., 2018). Inadequate reporting means that the return on investment is not being realized for these trials, said Clayton, noting that better SABV reporting would allow other investigators to conduct additional analyses, including meta-analyses of data.

The trans-NIH strategic plan for women’s health research, published in 2018, established five goals to advance women’s health research

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Image
FIGURE 4-2 Sex-specific results reporting in clinical trials. While enrollment of women in randomized controlled trials has increased over time, sex-stratified reporting of data remains low, often with no justification provided.
NOTE: RCT = randomized controlled trial; SABV = sex as a biological variable.
SOURCES: Presented by Janine Clayton, September 23, 2020; adapted from a subset of data presented by Geller et al., 2018.

(NIH, 2018). Clayton provided an overview for three of these goals and described several NIH programs designed to reach the first goal—advancing rigorous research relevant to the health of women, including research on biological differences between females and males, sex differences in health and disease, effects of exposure on disease outcomes, and the mind–body connection as it pertains to sex and gender. These programs include the following:

  • Specialized Centers of Research Excellence (SCORE)1—Funded through U54 grants, these disease-agnostic centers support basic, clinical, and translational research; provide career development awards for pilot studies often to junior faculty (distinct from the Building Interdisciplinary Research Careers in Women’s Health [BIRCWH] program2); and support educational opportunities.

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1 For more information, see https://orwh.od.nih.gov/womens-health-research/interdisciplinaryresearch/specialized-centers-research-excellence-sex (accessed November 27, 2020).

2 For more information, see https://orwh.od.nih.gov/career-development-education/building-interdisciplinary-research-careers-womens-health-bircwh (accessed February 3, 2021).

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
  • First ever trans-NIH R01 (RFA-OD-19-029)—The Intersection of Sex and Gender Influences on Health and Disease, a partnership between ORWH and 11 institutes and centers across NIH.
  • Funding for sex and gender administrative supplements, for example, to add subjects or do additional analyses.

The second goal focuses on methods and the leveraging of data sources to examine sex and gender influences. To achieve this goal, ORWH is developing checklists and tools for large-scale analysis of grant applications, and is deploying an inclusion outreach toolkit to engage, recruit, and retain diverse women in clinical studies. Clayton noted that the 21st Century Cures Act reaffirmed NIH’s commitment to inclusion across sex, age, race, and ethnicity. The Act also established a task force to increase coordination of research pertaining to pregnant and lactating women, she said. This extends to preclinical research as well, where it is crucial to not only include female animals, but females across the reproductive cycle and life span, added Laitner.

Progress in women’s health research can only be achieved through a well-trained, robust, and diverse workforce, which is the focus of the fourth strategic goal, said Clayton. She noted that women are underrepresented in science, technology, engineering, and mathematics (STEM) careers, particularly at higher career levels. Additionally, she said, fewer than 40 percent of medical schools include sex and gender studies in their curricula, and the numbers are even lower for dental and pharmacy schools.

The Food and Drug Administration’s (FDA’s) Office of Women’s Health (OWH) advances a women’s health agenda through scientific programs, research funding, training, consultation, and consumer education, said Kaveeta Vasisht, associate commissioner for women’s health and director of OWH at FDA. OWH also serves as a principal advisor to the FDA commissioner on scientific, ethical, and policy issues as they pertain to the health of women, she said.

FDA guidance3 recommends that preclinical studies include animals of both sexes. In 1998, the agency issued a regulation that required new drug applications to present safety and efficacy data by age, race, and gender; another 1998 regulation4 required annual reports for investigational new drug data to be presented by age, race, and gender. The agency published a Women’s Health Research Roadmap in 20155 to optimize OWH research

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3 For more information, see https://www.fda.gov/media/71542/download (accessed February 3, 2021) and https://www.fda.gov/media/82725/download (accessed February 3, 2021).

4 For more information, see https://www.fda.gov/science-research/clinical-trials-and-humansubject-protection/investigational-new-drug-applications-and-new-drug-applications-2111998 (accessed February 3, 2021).

5 For more information, see https://www.fda.gov/science-research/womens-health-research/womens-health-research-roadmap (accessed November 6, 2020).

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×

funding initiatives across FDA and to inform the agency’s regulatory work and optimize the health of women, said Vasisht. The roadmap outlined seven priority areas, including advancing safety and efficacy, advancing biomarker science, evaluating new modeling and simulation approaches, and identifying sex differences via emerging technologies, and others.

Vasisht described some of the recent research undertaken by FDA in the area of sex differences. For example, FDA OWH–funded researchers have used exome and RNA sequencing data to evaluate sex differences in Alzheimer’s disease and have evaluated transcriptomics- and epigenetics-based predictions of sex- and age-related susceptibilities to treatment-induced adverse effects.

Working in collaboration with NIH ORWH, Vasisht said NIH ORWH and FDA have also created a set of career development educational models, including online courses on integrating sex and gender across the bench to bedside continuum to improve human health.6 OWH also sponsors a scientific speaker series on topics related to sex and gender differences in health, disease, and response to treatments, she said. The intent of these lectures is to educate staff across FDA’s multiple offices and centers and federal partners about the cutting-edge science that advances understanding of sex and gender considerations.

There are several ways to engage and collaborate with FDA, said Vasisht. They can fund research through competitive mechanisms, such as contracts awarded under the FDA Broad Agency Announcement7 and cooperative agreements with academic institutions, known as Centers of Excellence in Regulatory Science and Innovation.8 In addition, Cooperative Research and Development Agreements9 and Memoranda of Understanding,10 both unfunded, are other ways to collaborate with FDA.

In addition to funding, FDA provides many other opportunities for stakeholders to engage with the agency. FDA’s Center for Drug Evalua-

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6 For more information, see https://orwh.od.nih.gov/career-development-education/e-learning/bench-bedside (accessed November 6, 2020).

7 For more information, see https://www.fda.gov/science-research/advancing-regulatoryscience/regulatory-science-extramural-research-and-development-projects (accessed November 8, 2020).

8 For more information, see https://www.fda.gov/science-research/advancing-regulatoryscience/centers-excellence-regulatory-science-and-innovation-cersis (accessed November 8, 2020).

9 For more information, see https://www.fda.gov/science-research/fda-technology-transferprogram/cooperative-research-and-development-agreements-cradas (accessed November 8, 2020).

10 For more information, see https://www.fda.gov/about-fda/partnerships-enhancing-sciencethrough-collaborations-fda/fda-memoranda-understanding (accessed November 8, 2020).

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×

tion and Research convenes Critical Path Innovation Meetings (CPIMs).11 CPIM is a forum for FDA and stakeholders to discuss potential scientific advancements in drug development. FDA’s Center for Biological Evaluation and Research (CBER) convenes Initial Targeted Engagement for Regulatory Advice on CBER Products meetings12 to provide informal and non-binding consultation opportunities for sponsors regarding innovative investigational products. A relatively new program at FDA, the Advancing Alternative Methods Working Group,13 enables stakeholders to engage with regulatory authorities in discussions about novel, innovative technologies and methods, said Vasisht.

Stakeholders also include nonprofit and advocacy groups, such as the Society for Women’s Health Research, as well as scientific societies and associations and journal editors and publishers. Laitner highlighted, in particular, the ability of these groups to act as conveners, bringing together interdisciplinary groups of experts to discuss areas of need in women’s health research and to strategize about how to move the field forward through collaboration. There is a particular need for stronger policies in the area of therapeutic development, she said, because women are prescribed more drugs than men and report more diverse drug reactions even when data are adjusted for drug dosing issues based on body weight. She cited recent data showing that women are overmedicated and suffer excess side effects because drug dosages are calculated based on studies done overwhelmingly in male subjects (Zucker and Prendergast, 2020). Although FDA regulations passed in 1993 require inclusion of women in drug studies, Laitner noted that many drugs on the market were approved before the regulations were changed. In addition, she noted, many studies still fail to analyze data for sex differences (Woitowich et al., 2020).

Laitner suggested other policy changes that could accelerate research on sex differences, including incorporating sex and gender issues into basic research and design courses; educating grant reviewers, institutional review boards, and institutional animal care review committees about appropriate ways to consider sex and gender in research designs; and overseeing the publication of research findings to ensure that sex and gender are appropriately addressed. In terms of clinical trials and drug approvals, Laitner also suggested better integration of real-world evidence and data on patient experiences.

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11 For more information, see https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecularentities-and-new-therapeutic-biological-products/critical-path-innovation-meetings-cpim (accessed November 8, 2020).

12 For more information, see https://www.fda.gov/vaccines-blood-biologics/industrybiologics/interact-meetings (accessed November 8, 2020).

13 To learn more, see https://www.fda.gov/science-research/about-science-research-fda/advancing-alternative-methods-fda (accessed November 8, 2020).

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×

ADDITIONAL AREAS FOR FUTURE RESEARCH

Although the workshop focused on sex differences in various brain disorders, Donna Werling, Marianne Seney, and others noted that a better understanding of sex differences in healthy brains could provide insight into the path to disease. Indeed, said Werling, when comparing males and females, neither one is the prototypical human. Baseline for males and females may be fundamentally different, making it necessary to understand baseline for both sexes at a detailed molecular level, at different stages in development, and in specific brain regions, she said. Farah Lubin added that understanding how gene networks are differentially established and regulated by epigenetic mechanisms in males and females might elucidate commonalities as well as subtle differences that could impact the development of cognitive and other disorders.

Another conundrum facing the field is why syndromes often appear clinically similar and respond to some drugs similarly in men and women even though the underlying biology differs substantially, said Nestler. Seney suggested that drugs might be working on downstream targets that converge across the sexes. Clayton added that some drugs have very broad effects, which could explain common outcomes despite different underlying biology.

A number of therapeutics that appear to affect males and females differently are working their way through the drug development pipeline, and these sex differences could have dramatic impacts on therapeutic development, said Zorn. For example, in the area of neurodegenerative diseases, Nilüfer Ertekin-Taner noted that sex differences have been observed in environmental and genetic factors, transcriptomic changes, biological pathways, comorbidities, and outcomes that include cognition and neuropathology. The evidence for sex differences in incidence, environmental risk factors, symptomatology, neuropathology, and biomarkers is strong, she said, yet there are many knowledge gaps that need to be addressed in the search for new therapies. For example, how do environmental factors affect the epigenome, transcriptome, and disease pathways differently in men versus women; what is the impact of lifelong changes in hormonal status; are there different longitudinal changes in the peripheral transcriptome of men and women and how do they affect disease progression and outcomes; and what sex differences are seen across multiethnic populations?

To understand how these changes occur through a person’s lifetime, Ertekin-Taner advocated leveraging peripheral tissue collections and longitudinal cohorts to conduct multi-omics studies, focusing on the transcriptome as well as other omics and integrating other genetic, outcome, and biomarker data. Integrative analyses should also incorporate demographic, socioeconomic, educational, and other lifestyle data, she said. Finally, new

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×

model systems are needed to investigate the role of chromosomal sex, hormone influences, and transcriptional and epigenetic changes in brain tissue and cell models.

Nestler emphasized that although the workshop focused on transcriptional differences, further research is also needed on sex differences in the interaction between transcriptomics and genomics. These interactions include translational modifications that are mediated through non-transcriptional mechanisms, cellular and synaptic mechanisms at both the structural and functional levels, and brain circuitry. He suggested that brain circuitry differences between males and females might reflect transcriptomic mechanisms that are modified by the environment from the earliest stages of development through old age.

While there remains an open discussion in the field on areas of future research, other questions also needing to be addressed, said Nestler, include how sex differences may impact functional changes reflected in the genome sequence; interactions between the genome and environment throughout life at transcriptional, translational, post-translational, cellular, synaptic, and circuit levels; and ultimately, how these impact behavior. In addition, it would be crucial to develop resources to gain access to post-mortem human brain tissue of people who do not fall along the male/female binary, for example, transgender individuals, those who have transitioned sex, and intersex individuals, to include in this type of research, he added.

CLOSING THOUGHTS

The workshop clarified and confirmed the fact that the underlying biology of many brain disorders is fundamentally different between men and women, said Nestler. Thus, he said, research programs need to consider sex differences at the earliest stage of planning and study design. Indeed, said Clayton, “until the biomedical research enterprise collectively realizes that this is important enough for us to do in a coordinated manner, we are not going to get the progress that we need.” Learning about the effects of sex on response to a therapeutic intervention during phase 3 clinical trials is far too late, she said, advocating instead for sex to be considered in an integrated fashion along the biomedical research continuum at every step, from basic research to marketing approval.

Clayton suggested that convening stakeholders across sectors to reach convergence on how to tackle a problem is essential. Bringing the ecosystem together to think about sex differences in terms of identifying new targets, understanding disease pathogenesis, and designing preclinical and clinical studies is needed, said Zorn, because no one can do this alone.

Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
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Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
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Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
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Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
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Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
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Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Page 34
Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Page 35
Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Page 36
Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Page 37
Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Page 38
Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Page 39
Suggested Citation:"4 Moving Forward." National Academies of Sciences, Engineering, and Medicine. 2021. Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26058.
×
Page 40
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Accumulating evidence gathered over the past three decades has demonstrated a biological basis for differences between men and women with respect to clinical features and treatment responses to several neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. Dramatic sex differences have also been identified in the brain transcriptomes of individuals with multiple brain disorders, including depression, posttraumatic stress disorder, and autism. The brain transcriptome includes all of the messenger RNA as well as the non-protein-coding RNA molecules expressed in brain tissue and thus represents gene activity. To explore these sex-based transcriptomic differences further, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders hosted a workshop on September 23, 2020, titled Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence and Implications for Therapeutic Development. The workshop brought together a broad spectrum of stakeholders to share cutting-edge emerging evidence, discuss challenges, and identify future opportunities and potential directions. This publication summarizes the presentation and discussion of the workshop.

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