Anthony Akkari

Background
Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

Methods
We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.

Results
Twenty-six studies (N ranges: 6–485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95 % CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.

Conclusions
The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs’ role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.

Background
Young people often face significant challenges accessing effective mental health support as they navigate through complex healthcare systems, education pathways, and social pressures. Understanding the service-level barriers they encounter is critical to improving mental health system design and delivery. While previous studies have examined individual barriers to mental healthcare access, few have adopted a cross-sectorial, youth-informed approach which captures the interrelated structural, institutional, and socio-cultural factors influencing young people’s mental health experiences.

Methods
Seventeen participants aged 18–24 years with lived experience of depression and/or anxiety participated in nine in-person focus groups and interviews in Perth. Reflexive thematic analysis was used to identify systemic barriers and facilitators to mental healthcare, with a particular focus on access, care coordination, therapeutic engagement, and service responsiveness.

Results
Key themes included fragmented care pathways, inadequate provider follow-up, prolonged wait times, financial constraints, lack of youth-specific mental health training among clinicians, and limited therapeutic rapport. Participants also described inadequate mental health literacy within schools and persistent stigma in social and familial settings. These intersecting barriers hindered access, disrupted continuity of care, and undermined trust in the mental health system.

Conclusions
Findings highlight critical inefficiencies in mental health service delivery for young Australians. Policy responses should prioritise integrated care models, investment in multidisciplinary youth mental health hubs, improved school-based mental health literacy, and culturally inclusive anti-stigma initiatives to promote access, trust, and continuity of care.

Background: The prevalence of depression and mood disorders has been steadily rising in Australian youth, with a concomitant increase in antidepressant pharmacotherapy prescription rates. Yet, the tolerability and efficacy of antidepressant drugs in youth remain poor. Pharmacogenetic (PGx) testing, or the personalised and guided treatment of medication based on genetic data, has been suggested to improve the effectiveness and tolerability of antidepressants. However, limited studies have evaluated the utility of antidepressant PGx-guided treatment in adolescent and young adult populations. Thus, this pilot randomised controlled trial (RCT), the GENE-YD Study, will evaluate the feasibility for a large-scale RCT assessing the effect of PGx-guided antidepressant prescription vs treatment as usual in youth with major depressive disorder (MDD).

Methods and analysis: Eighty young people between 16 and 24 years of age and in the early stages of pharmacotherapy treatment for MDD will be recruited. Following initial screening, participants will be randomised on a 1:1 ratio to either the intervention or control study group. Participants in the intervention condition will have their treatment tailored based on their PGx profile. Participants randomised into the control group will have their prescription based on current best practice recommendations, or treatment as usual. Individuals will be assessed at drug prescription baseline and again 6 and 12 weeks following drug prescription. The primary outcome of the study will be to evaluate the feasibility and acceptability of the GENE-YD protocol. Specifically, this study will explore participation recruitment strategies and attrition to the study protocols to guide the recruitment processes of a large-scale RCT, along with participating satisfaction in overall study protocols. Secondary outcomes will inform the utility and variability of specific measures (eg, depression rating scales, quality of life measures and medication adherence scales) that may be scaled up for use in a future full-scale trial.

Ethics and dissemination: Ethics approval was granted by the Department of Health, Western Australia’s Human Research Ethics Committee (RGS0000006822) and recognised by the University of Western Australia’s Human Research Ethics Committee (2024/ET000685). All participants will be required to provide written informed consent. Results will be published in international peer-reviewed journals.

Trial registration numberACTRN12624000760572.

With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.

Key points
1. Precision medicine means giving the right drug to the right patient at the right time. With the emergence of antisense oligonucleotide technologies, additional gene targeted therapies will soon enter the market for ALS.

2. The improved understanding of the complex genetic architecture of ALS and pathophysiological mechanisms involved in disease has increased the number of validated drug targets for ALS.

3. Long-read sequencing will revolutionise our understanding of ALS genetics through the comprehensive mapping of genetic variation. Long read sequencing has enabled the complete sequence of a human genome and subsequently, the first human global and population-specific pan-genome references, adding hundreds of millions of bases that were not present in the previous human genome reference.

4. Leveraging omics data and machine learning methodologies will improve our understanding of both ALS phenotype and the underlying molecular heterogeneity between ALS patients, enhancing patient stratification through the detection of specific sub-groups of patients.

5. Comprehensive patient profiling through the collection of full omics data will be critical to define responder populations. A patient profiling workflow is proposed to conduct in vitro trials alongside early clinical studies as more antisense therapies begin entering the clinic.

6. Ethical strategies to consider for population targeted therapeutic development include tiered pricing models, public-private partnerships, and global distribution initiatives, all of which may be valuable for facilitating access to genetic therapies, thereby reducing inequalities in ALS care.

Background
Pharmacogenetics (PGx) is the study of how interindividual genetic variation can alter drug metabolism and the response to medication. By evaluating common genetic markers in genes encoding drug-metabolising enzymes, PGx testing has demonstrated the potential to individualise pharmacotherapy, offering a more personalised treatment plan to improve drug efficacy and tolerability. In clinical use, PGx testing has been shown to reduce the process of medication trial-and-error. However, in Australian psychiatric care, PGx testing is seldom used to personalise antidepressant treatment plans for people with depression and/or anxiety. With the rising prevalence of depression and anxiety in young Australians, coupled with the limitations of conventional antidepressant treatment, PGx testing has shown promise in optimising medication selection. Given the drive for further clinical integration of PGx testing in youth psychiatric care, it is essential to first understand the perspectives and concerns of key stakeholders regarding its implementation.

Aims & Objectives
This study aimed to assess the attitudes of young adults towards PGx testing for guiding antidepressant treatment, focusing on their perceived advantages, concerns, and anticipated barriers to its clinical adoption.

Method
Semi-structured focus groups and interviews were employed, engaging with participants aged 18–24 years who had prior or current antidepressant experience. Sessions were recorded and transcribed verbatim. Reflexive thematic analysis was conducted to code, refine, and identify prevalent themes, encompassing perspectives on current treatment, views on PGx, and clinical integration barriers.

Results
Saturation was reached after nine sessions with a total of 17 participants. Three primary themes emerged from the analysis: (1) attitudes towards current antidepressant prescription practices, (2) perspectives and concerns towards PGx testing, and (3) perceived barriers to PGx implementation. Participants appreciated PGx’s potential to reduce the trial-and-error approach, improve medication selection, and potentially minimise medication-related side effects. However, concerns included the high perceived cost of PGx testing, anticipated delays in treatment initiation, and scepticism regarding the efficacy of such genetically guided treatment. Furthermore, participants believed that GPs’ awareness, willingness, and knowledge to incorporate PGx results in treatment plans would act as a key barrier to PGx implementation.

Discussion & Conclusions
This study highlights significant gaps in youth mental health treatment, including the limited involvement of youth patients in medication decision-making. Participants viewed PGx testing as a promising step toward personalised treatment, provided concerns around cost, accessibility, and testing accuracy are addressed. Furthermore, education and awareness campaigns around PGx testing were viewed as necessary for both patients and healthcare providers to facilitate integration into clinical use. The findings from this study highlight the importance of recognising patient perspectives when integrating medical practices into healthcare, ensuring that the implementation of PGx testing in Australian psychiatric practices remains patient-focused, upholding the needs and expectations of those receiving care. Furthermore, these findings have helped to inform the design and outcomes of an ongoing pilot randomised controlled trial aimed at evaluating the efficacy and tolerability of PGx-guided antidepressant pharmacotherapy in youth. This trial, conducted at the Perron Institute for Neurological and Translational Science, aims to address the youth concerns expressed in this qualitative study.

Introduction: The field of pharmacogenetics (PGx) is experiencing significant growth, with increasing evidence to support its application in psychiatric care, suggesting its potential to personalize treatment plans, optimize medication efficacy, and reduce adverse drug reactions. However, the perceived utility and practicability of PGx for psychiatric treatment in youth remains underexplored. This study investigated perceived barriers and attitudes in Australian young adults towards the implementation of PGx testing to guide antidepressant treatment in primary care.

Methods: Semi-structured focus groups and interviews were conducted with 17 participants aged between 18 and 24 years. These sessions were recorded and transcribed before thematic analysis was used to identify collective themes.

Results: Three key themes were identified, including attitudes towards the medication prescription process, concerns and attitudes towards PGx testing, and perceived barriers to its clinical implementation. Although PGx testing was positively perceived by most participants, all participants shared concerns about PGx testing. Participants voiced concerns about the financial impact of PGx testing, the potential for treatment delays, and the accuracy of PGx testing in guiding antidepressant treatment. Additionally, participants noted that the low awareness and willingness of general practitioners to incorporate PGx testing into routine practice could hinder successful clinical implementation.

Discussion: Prior to the implementation of PGx testing into Australian primary practices, it is essential to acknowledge patient perspectives and ensure that clinical practices remain patient-focused. This study highlights important considerations for integrating PGx testing into antidepressant pharmacotherapy and emphasizes the need for future research to address and mitigate the perceived barriers of young adults.

Background
Anorexia nervosa (AN) is a polygenic, severe metabopsychiatric disorder with poorly understood aetiology. Eight significant loci have been identified by genome-wide association studies (GWAS) and single nucleotide polymorphism (SNP)-based heritability was estimated to be ~ 11–17, yet causal variants remain elusive. It is therefore important to define the full spectrum of genetic variants in the wider regions surrounding these significantly associated loci. The hypothesis we evaluate here is that unrecognised or relatively unexplored variants in these regions exist and are promising targets for future functional analyses. To test this hypothesis, we implemented a novel approach with targeted nanopore sequencing (Oxford Nanopore Technologies) for 200 kb regions centred on each of the eight AN-associated loci in 10 AN case samples. Our bioinformatics pipeline entailed base-calling and alignment with Dorado and minimap2 software, followed by variant calling with four separate tools, Sniffles2, Clair3, Straglr, and NanoVar. We then leveraged publicly available databases to characterise these loci in putative functional context and prioritise a subset of potentially relevant variants.

Results
Targeted nanopore sequencing effectively enriched the target regions (average coverage 14.64x). To test our hypothesis, we curated a list of 20 prioritised variants in non-coding regions, poorly represented in the current human reference genome but that may have functional consequences in AN pathology. Notably, we identified a polymorphic SINE-VNTR-Alu like sub-family D element (SVA-D), intergenic with IP6K2 and PRKAR2A, and a poly-T short tandem repeat (STR) in the 3ʹUTR of FOXP1.

Conclusions
Our results highlight the potential of targeted nanopore sequencing for characterising poorly resolved or complex variation, which may be initially obscured in risk-associated regions detected by GWAS. Some of the variants identified in this way, such as the polymorphic SVA-D and poly-T STR, could contribute to mechanisms of phenotypic risk, through regulation of several neighbouring genes implicated in AN biology, and affect post-transcriptional processing of FOXP1, respectively. This exploratory investigation was not powered to detect functional effects, however, the variants we observed using this method are poorly represented in the current human reference genome and accompanying databases, and further examination of these may provide new opportunities for improved understanding of genetic risk mechanisms of AN.

Pathogenic variations in the fused in sarcoma (FUS) gene are associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS). As FUS-ALS is a dominant disease, a targeted, allele-selective approach to FUS knockdown is most suitable. Antisense oligonucleotides (AOs) are a promising therapeutic platform for treating such diseases. In this study, we have explored the potential for allele-selective knockdown of FUS. Gapmer-type AOs targeted to two common neutral polymorphisms in FUS were designed and evaluated in human fibroblasts. AOs had either methoxyethyl (MOE) or thiomorpholino (TMO) modifications. We found that the TMO modification improved allele selectivity and efficacy for the lead sequences when compared to the MOE counterparts. After TMO-modified gapmer knockdown of the target allele, up to 93% of FUS transcripts detected were from the non-target allele. Compared to MOE-modified AOs, the TMO-modified AOs also demonstrated reduced formation of structured nuclear inclusions and SFPQ aggregation that can be triggered by phosphorothioate-containing AOs. How overall length and gap length of the TMO-modified AOs affected allele selectivity, efficiency and off-target gene knockdown was also evaluated. We have shown that allele-selective knockdown of FUS may be a viable therapeutic strategy for treating FUS-ALS and demonstrated the benefits of the TMO modification for allele-selective applications.