Full-Field Electroretinogram Responses in Rodent Models of Ganglion Cell Injury.

Preclinical studies of optic nerve injury models have led to significant insight into the mechanism underlying retinal ganglion cell neurodegeneration. During the process of ganglion cell injury, morphological changes can occur prior to gross structural changes and cell death. Similarly, following injury, functional changes can occur in the absence of substantive structural changes. These more subtle effects can often be detected using functional tools such as the electroretinogram. Moreover, the electroretinogram is a sensitive and complementary means to quantify treatment efficacy. Here, we describe in vivo electroretinography for assessing ganglion cell injury in rodent models.

A New Augmentation Strategy against Depression Combining SSRIs and the N-terminal Fragment of Galanin (1-15).

Depression is one of the most disabling mental disorders, with the second highest social burden; its prevalence has grown by more than 27% in recent years, affecting 246 million in 2021. Despite the wide range of antidepressants available, more than 50% of patients show treatment-resistant depression. In this review, we summarized the progress in developing a new augmentation strategy based on combining the N-terminal fragment of Galanin (1-15) and SSRI-type antidepressants in animal models.

Morphological phenotyping of the aging cochlea in inbred C57BL/6N and outbred CD1 mouse strains.

Morphological mouse phenotyping plays a pivotal role in the translational setting and even more in the area of auditory research, where mouse is a central model organism due to the evolutionary genetic relationship and morpho-functional analogies with the human auditory system. However, some results obtained in murine models cannot be translated to humans due to the inadequate description of experimental conditions underlying poor reproducibility. We approach the characterization of the aging process of the mouse cochlea in animals up to 18 months of age belonging to two of the most used outbred (CD1) and inbred (C57BL/6N) strains. Striving to reduce any environmental variable we performed our study compliantly to the ARRIVE guidelines. We integrated instrumental data (auditory brainstem response test), with morphological analyses to correlate functional discrepancies to morphological changes and track the differences in the evolution of sensorineural hearing loss in the two strains. We featured the localization of Gipc3, Myosin VIIa, and TMC1 in hair cells of the Corti organ as well as NF 200 and the density of type I neuron in the spiral ganglion. We outlined age-related hearing loss (ARHL) in both strains, and a clear drop in the selected marker localization. However, in CD1 we detected a different trend allowing the identification of potential strain-specific mechanisms, namely an increase in myosin VIIa in 6 months aging mice in comparison to 2 months old animals. Our findings represent an asset to investigate the strain-dependent physiological trigger of ARHL providing new insights in the translational area.

Rat shoulder contracture models: Techniques, evaluation, pathophysiology, and applications in developing treatment interventions.

Studies on the pathophysiology of shoulder contracture and development of interventions have greatly benefited from the use of animal models. This narrative review comprehensively analyzes research on established rat model of shoulder contracture and new treatment approaches. This review evaluated existing literature on the available techniques for inducing contracture models, assessed these models, conducted pathological analyses, and explored their application in developing new treatment interventions. Our review highlights the usefulness of different rat shoulder contracture models, including external immobilization, internal immobilization, and intra-articular injection models, each with varying levels of success. Pathological analyses have demonstrated similarities to the human condition. The effective models have been instrumental in developing new treatment interventions, including recombinant human relaxin-2, platelet-rich plasma, collagenase clostridium histolyticum, and peroxisome proliferator-activated receptor-γ agonists. Therefore, rat shoulder contracture models serve as valuable tools for researchers to establish an effective animal model foundation for investigating the etiology and potential treatment.

Disease models of Leigh syndrome: From yeast to organoids.

Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.

Maternal loss of 24-hydroxylase causes increased intestinal calcium absorption and hypercalcemia during pregnancy but reduced skeletal resorption during lactation in mice.

Inactivation of 24-hydroxylase (CYP24A1) causes mild hypercalcemia in humans that becomes severe and life-threatening during pregnancy through unclear mechanisms. We studied Cyp24a1 null mice during pregnancy, lactation, and post-weaning. We hypothesized that Cyp24a1 nulls have a much greater increase in calcitriol during pregnancy and lactation, leading to markedly increased intestinal calcium absorption and reduced lactational bone loss. WT and Cyp24a1 null sisters were mated to Cyp24a1+/- males. Timepoints included baseline (BL), late pregnancy (LP), mid-lactation (ML), late lactation (LL), and weekly x4 weeks of post-weaning recovery (R1-4). Assessments included intestinal calcium absorption (IntCaAbs) by gavage of 45Ca, bone mineral content (BMC) by DXA, microCT of femurs, 3-point bending tests of tibias, serum hormones, serum and urine minerals, milk analysis, and intestinal gene expression. At LP, whole body BMC increased equally by ~12% in null and WT. Calcitriol was 2.5-fold higher in nulls vs WT, accompanied by 3-fold increased IntCaAbs, hypercalcemia, hypercalciuria, and 6.5-fold higher FGF23. PTH was suppressed in both. Twenty percent of null dams died during delivery but their serum calcium at LP did not differ from Cyp24a1 nulls that survived. At ML, calcitriol, IntCaAbs, and FGF23 declined in both genotypes but remained higher than BL values in Cyp24a1 nulls. By LL, nulls were still hypercalcemic vs WT, and had lost less mean whole body BMC (11% vs. 21%, P<.02), but by micro-CT there were no differences from WT in cortical or trabecular bone mass. Lactational losses in BMC, cortical thickness, and trabecular number were restored by R4 in both genotypes. In summary, ablation of Cyp24a1 increased IntCaAbs and caused hypercalcemia during pregnancy and lactation, late gestational mortality in some nulls, and reduced lactational BMC loss. Treating women with gestational hypercalcemia from CYP24A1 mutations should focus on reducing calcitriol or IntCaAbs, since increased bone resorption is not the cause.

24-hydroxylase breaks down calcitriol, the hormonal form of vitamin D. Genetic deficiency of 24-hydroxylase causes mildly increased blood calcium (hypercalcemia) in adult humans, which can become life-threateningly high during pregnancy. We used a genetically engineered mouse model to determine the cause of this severe hypercalcemia. Calcitriol increased 10-fold during pregnancy in 24-hydroxylase deficient mice versus 4-fold in normal pregnant mice. High calcitriol in turn caused a marked increase in intestinal calcium absorption, which explained the hypercalcemia. Some 24-hydroxylase deficient mice died in late pregnancy. Our findings indicate that affected pregnant women need treatments that specifically reduce intestinal calcium absorption.

Hepatitis E virus infection during pregnancy: Advances in animal models.

Hepatitis E virus (HEV) is one of the major pathogens causing acute viral hepatitis worldwide, which usually causes acute self-limited diseases in general individuals. However, it can lead to high mortality and adverse pregnancy outcomes in pregnant women. Due to the lack of effective and stable cell culture models for HEV, the establishment of suitable animal models for HEV infection during pregnancy is necessary. An electronic search of the relevant database was conducted to identify eligible articles. Main animal models for the study of HEV infection during pregnancy include rabbits, swine, nonhuman primates and Mongolian gerbils. These animal models have been used to study the prevention, treatment and possible mechanisms of HEV infection during pregnancy. Studies using these animal models have investigated the potential pathogenesis of HEV infection during pregnancy. It has been found that immune mechanism (changes in the CD4/CD8 ratio and cytokines), hormonal changes (increase in pregnancy-related hormones) and viral factors (different genotypes and genome structures) can lead to HEV-related adverse pregnancy outcomes in animal models. In this review, we aimed to comprehensively present the characteristics of different animal models and the pathogenesis of HEV-related adverse pregnancy outcomes.

How life events may confer vulnerability to addiction: the role of epigenetics.

Substance use disorder (SUD) represents a large and growing global health problem. Despite the strong addictive potency of drugs of abuse, only a minority of those exposed develop SUDs. While certain life experiences (e.g., childhood trauma) may increase subsequent vulnerability to SUDs, mechanisms underlying these effects are not yet well understood. Given the chronic and relapsing nature of SUDs, and the length of time that can elapse between prior life events and subsequent drug exposure, changes in SUD vulnerability almost certainly involve long-term epigenetic dysregulation. To validate this idea, functional effects of specific epigenetic modifications in brain regions mediating reinforcement learning (e.g., nucleus accumbens, prefrontal cortex) have been investigated in a variety of animal models of SUDs. In addition, the effects of epigenetic modifications produced by prior life experiences on subsequent SUD vulnerability have been studied, but mostly in a correlational manner. Here, we review how epigenetic mechanisms impact SUD-related behavior in animal models and summarize our understanding of the relationships among life experiences, epigenetic regulation, and future vulnerability to SUDs. Despite variations in study design, epigenetic modifications that most consistently affect SUD-related behavior are those that produce predominantly unidirectional effects on gene regulation, such as DNA methylation and histone phosphorylation. Evidence explicitly linking environmentally induced epigenetic modifications to subsequent SUD-related behavior is surprisingly sparse. We conclude by offering several directions for future research to begin to address this critical research gap.

Development of a Preclinical Double Model of Mandibular Irradiated Bone and Osteoradionecrosis in New Zealand Rabbits.

PURPOSE: Radiotherapy (RT) plays a crucial role in head and neck (HN) cancer treatment. Nevertheless, it can lead to serious and challenging adverse events such as osteoradionecrosis (ORN). A preclinical rabbit model of irradiated bone and ORN is herein proposed, with the aim to develop a viable model to be exploited for investigating new therapeutic approaches. METHODS: Nine New Zealand white rabbits were irradiated using a single beam positioned to the left of the mandible and directed perpendicular to the left mandible. A 10 × 10 mm2 region of interest (ROI) located below the first molar tooth on the left side was identified and irradiated with 7 Gy each fraction, once every 2 days, for five fractions. Dose distributions demonstrated that the corresponding ROI on the contralateral (right) mandibular side received approximately 5 Gy each fraction, thus bilateral irradiation of the mandible was achieved. ROIs were categorized as ROIH on the left side receiving the high dose and ROIL on the right side receiving the low dose. Rabbits were followed up clinically and imaged monthly. After 4 months, the irradiated bone was excised, and histological examination of ROIs was performed. RESULTS: Radiological signs suggestive for ORN were detected in the entire population (100%) 16 weeks after irradiation on ROIH, which consisted of cortical erosion and loss of trabeculae. ROIL did not show any radiological evidence of bone damage. Histologically, both sides showed comparable signs of injury, with marked reduction in osteocyte count and increase in empty lacunae count. CONCLUSIONS: A preclinical double model was successfully developed. The side receiving the higher dose showed radiological and histological signs of bone damage, resulting in an ORN model. Whereas the contralateral side, receiving the lower dose, presented with histological damage only and a normal radiological appearance. This work describes the creation of a double model, an ORN and irradiated bone model, for further study using this animal species.

Non-rodent Models of Atherosclerosis: Repurposing of Existing Drugs and Search for Novel Treatment Strategies.

Atherosclerosis and associated cardiovascular diseases are the leading causes of illness and mortality worldwide. The development of atherosclerosis is a complex process involving oxidative stress, surplus lipid deposition and retention, endothelial dysfunction, and chronic inflammation. Developing novel anti-atherogenic and repurposing existing drugs requires the use of suitable animal models to characterise the fundamental mechanisms underlying atherosclerosis initiation and progression and to evaluate potential therapeutic effects. Commonly used rodent models, however, are not always appropriate, and other models may be required to translate these discoveries into valuable preventive and treatment agents for human applications. Recent advances in gene-editing tools for large animals have allowed the creation of animals that develop atherosclerosis faster and more similarly to humans in terms of lesion localisation and histopathology. In this review, we discuss the major advantages and drawbacks of the main non-rodent animal models of atherosclerosis, particularly rabbits, pigs, zebrafish, and non-human primates. Moreover, we review the application of recently invented novel therapeutic methods and agents, and repurposed existing drugs (such as antidiabetic and anticancer) for atherosclerosis treatment, the efficacy of which is verified on non-rodent animal models of atherosclerosis. In total, the proper selection of a suitable animal model of atherosclerosis facilitates reproducible and rigorous translational research in repurposing of existing drugs, discovering new therapeutic strategies, and validating novel anti-atherosclerotic drugs.

Antibiotic tolerance among clinical isolates: mechanisms, detection, prevalence, and significance.

SUMMARYAntibiotic treatment failures in the absence of resistance are not uncommon. Recently, attention has grown around the phenomenon of antibiotic tolerance, an underappreciated contributor to recalcitrant infections first detected in the 1970s. Tolerance describes the ability of a bacterial population to survive transient exposure to an otherwise lethal concentration of antibiotic without exhibiting resistance. With advances in genomics, we are gaining a better understanding of the molecular mechanisms behind tolerance, and several studies have sought to examine the clinical prevalence of tolerance. Attempts have also been made to assess the clinical significance of tolerance through in vivo infection models and prospective/retrospective clinical studies. Here, we review the data available on the molecular mechanisms, detection, prevalence, and clinical significance of genotypic tolerance that span ~50 years. We discuss the need for standardized methodology and interpretation criteria for tolerance detection and the impact that methodological inconsistencies have on our ability to accurately assess the scale of the problem. In terms of the clinical significance of tolerance, studies suggest that tolerance contributes to worse outcomes for patients (e.g., higher mortality, prolonged hospitalization), but historical data from animal models are varied. Furthermore, we lack the necessary information to effectively treat tolerant infections. Overall, while the tolerance field is gaining much-needed traction, the underlying clinical significance of tolerance that underpins all tolerance research is still far from clear and requires attention.

Extracellular vesicles release from protozoa parasite and animal model.

Diseases caused by protozoan parasites, such as leishmaniasis, trypanosomiasis, and malaria, are highly complex and together continue to cause high annual morbidity and mortality. The search for new compounds in environmental biodiversity, repositioning known drugs, and developing vaccines using old and innovative technologies have been employed to discover vaccines and new and alternative treatments. Extracellular vesicles (EVs) can carry parasite antigens, creating a new possibility to develop an effective and affordable platform for treatment, vaccines, and drug delivery. Thus, the evaluation of EVs in animal models can and should be explored among the countless biomedical applications. Herein, we will address the concept of EVs, their acquisition and characterization in protozoan parasite models, and the primary studies using these vesicles in therapeutic applications.

An overview of major depression disorder: The endocannabinoid system as a potential target for therapy.

Major depressive disorder is the psychiatric disease with the highest global prevalence, impacting social functioning and decreasing the quality of life. The partial pathophysiological knowledge of the disease, the economic burden and the low remission rates are sufficient justification to carry out an update on the subject in the search for new therapeutic approaches and targets. The endocannabinoid system has been linked to the development of depression, and its stimulation or antagonism is a promising approach in the treatment of major depressive disorder. Cannabidiol (CBD) and its properties have been widely studied recently; its analgesic, anti-inflammatory, antineoplastic and neuroprotective roles have even been reported in animal models and clinical trials, achieving its approved use for certain neurodegenerative pathologies. The use of CBD in depression biomodels and clinical trials has not been the exception, and here we contrast the current evidence of its administration and pharmacology against the pathological mechanisms of major depressive disorder.

Hookworm vaccines: current and future directions.

INTRODUCTION: Hookworms infect about half a billion people worldwide and are responsible for the loss of more than two billion disability-adjusted life years. Mass drug administration (MDA) is the most popular preventive approach, but it does not prevent reinfection. An effective vaccine would be a major public health tool in hookworm-endemic areas. AREAS COVERED: We highlight recent human studies where vaccination with irradiated larvae and repeated rounds of infection-treatment have induced partial protection. These studies have emphasized the importance of targeting the infective larvae to generate immunity to prevent adult worms from maturing in the gut. We summarize the current status of human and animal model vaccine trials. EXPERT OPINION: Hookworm infection is endemic in resource-poor developing regions where polyparasitism is common, and vaccine cold chain logistics are complex. Humans do not develop sterile immunity to hookworms, and the elderly are frequently overlooked in MDA campaigns. For all these reasons, a vaccine is essential to create long-lasting protection. The lack of a robust animal model to mimic human hookworm infections is a barrier to the discovery and development of a vaccine, however, there have been major recent advances in human challenge studies which will accelerate the process.

Nephroprotective and hepatoprotective effects of lemongrass essential oil and citral on diclofenac-induced toxicity in mice.

The present study was carried out to evaluate and compare the protective potential of two well-known antioxidants of herbal origin in a mouse model of acute DIC-induced nephro- and hepatotoxicity. The tested antioxidants included lemongrass essential oil (LO) and its predominant bioactive constituent citral (CIT). A third herbal product, silymarin (SILY), was used as a reference hepato-renal protective agent. DIC administration led to elevated serum urea and creatinine levels, and prompted oxidative stress along with histopathological changes in the kidney tissue. In parallel, DIC administration increased serum liver enzyme activity, decreased total protein, albumin, and globulin levels, and caused oxidative stress with associated histopathological changes in the liver tissue. Pre-treatment with LO or CIT mitigated DIC-induced alterations in all serum biochemical markers of kidney and liver health (except albumin). High-dose LO, like SILY, within kidney and liver tissues, counteracted DIC-induced oxidative stress and histomorphological alterations. By contrast, CIT failed to mitigate DIC-induced oxidative stress in the kidneys and provided only partial control of DIC-induced oxidative stress in the liver, resulting in less efficient preservation of kidney function and liver structural integrity than LO. Besides confirming the efficacy of SILY at protecting kidneys and liver against the toxicity of DIC in a rodent species different from the one tested so far (rat), this study demonstrated the preventive properties of LO and, to a lesser extent, of CIT against DIC-induced hepato-renal toxicity in mice, supporting their developmental potential as therapeutics.

Quantification of porcine lower thoracic spinal cord morphology with intact dura mater using high-resolution µCT.

BACKGROUND AND PURPOSE: Spinal cord stimulation (SCS) is approved by the Food and Drug Administration for treating chronic intractable pain in the back, trunk, or limbs through stimulation of the dorsal column. Numerous studies have used swine as an analog of the human spinal cord to better understand SCS and further improve its efficacy. We performed high-resolution imaging of the porcine spinal cord with intact dura mater using micro-computed tomography (µCT) to construct detailed 3-dimensional (3D) visualizations of the spinal cord and characterize the morphology of the dorsal and ventral rootlets. METHODS: We obtained spinal cords from Yorkshire/Landrace crossbred swine (N = 7), stained samples with osmium tetroxide, and performed µCT imaging of the T12-T15 levels at isotropic voxel resolutions ranging from 3.3 to 50 µm. We measured the anatomical morphology using the 3D volumes and compared our results to measurements previously collected from swine and human spinal cords via microdissection techniques in prior literature. RESULTS: While the porcine thoracic-lumbar spinal cord is a popular model for SCS, we highlight multiple notable differences compared to previously published T8-T12 human measurements including rootlet counts (porcine dorsal/ventral: 12.2 ± 2.6, 26.6 ± 3.4; human dorsal/ventral: 5.3 ± 1.3, 4.4 ± 2.4), rootlet angles (porcine ventral-rostral: 161 ± 1°, ventral-caudal: 155 ± 6°, dorsal-rostral: 148 ± 9°, dorsal-caudal: 142 ± 6°; human ventral-rostral: 170 ± 3°, ventral-caudal: 22 ± 10°, dorsal-rostral: 171 ± 3°, dorsal-caudal: 15 ± 7°), and the presence and count of dorsal rootlet bundles. CONCLUSIONS: Detailed measurements and highlighted differences between human and porcine spinal cords can inform variations in modeling and electrophysiological experiments between the two species. In contrast to other approaches for measuring the spinal cord and rootlet morphology, our method keeps the dura intact, reducing potential artifacts from dissection.

Classics in Chemical Neuroscience: Deliriant Antihistaminic Drugs.

Antihistaminic drugs are widely used clinically and have long been primarily known for their use to treat severe allergic conditions caused by histamine release. Antihistaminic drugs also exert central nervous system (CNS) effects, acting as anxiolytics, hypnotics, and neuroleptics. However, these drugs also have multiple serious neuropharmacological side-effects, inducing delirium, hyperarousal, disorganized behavior, and hallucinations. Due to their robust CNS effects, antihistamines are also increasingly abused, with occasional overdoses and life-threatening toxicity. Here, we discuss chemical and neuropharmacological aspects of antihistaminic drugs in both human and animal (experimental) models and outline their current societal and mental health importance as neuroactive substances.

Biochemistry, pharmacology and in vivo function of arginases.

Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. Significance Statement The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer.

Evaluation of A Non-Nucleoside Inhibitor of the RSV RNA-Dependent RNA Polymerase in Translatable Animals Models.

Respiratory Syncytial Virus (RSV) causes severe respiratory infections and concomitant disease resulting in significant morbidity and mortality in infants, elderly, and immunocompromised adults. Vaccines, monoclonal antibodies, and small molecule antivirals are now either available, or in development, to prevent and treat RSV infections. Although, rodent and non-rodent preclinical animal models have been used to evaluate these emerging agents there is still a need to improve our understanding of the pharmacokinetic (PK)-pharmacodynamic (PD) relationships, within and between animal models to enable better design of human challenge studies and clinical trials. Herein, we report a PKPD evaluation of MRK-1, a novel small molecule non-nucleoside inhibitor of the RSV L polymerase protein, in the semi-permissive cotton rat and African green monkey models of RSV infection. These studies demonstrate a strong relationship between in vitro activity, in vivo drug exposure, and pharmacodynamic efficacy as well as revealing limitations of the cotton rat RSV model. Additionally, we report unexpected horizontal transmission of human RSV between co-housed African green monkeys, as well as a lack of drug specific resistant mutant generation. Taken together these studies further our understanding of these semi-permissive animal models and offer the potential for expansion of their preclinical utility in evaluating novel RSV therapeutic agents.

Preclinical research (on rare diseases): we need to talk about health equity.

There is a thriving, worldwide, biomedical research community working to understand the molecular bases of diseases of all types, continuously driving improved diagnostics and therapies. Developments in genetics and experimental medicine are yielding novel genetic therapies that were hardly dreamt of 40 years ago. But along with these scientific achievements, there exist challenges in ensuring that 21st century medical interventions are accessible to all who need them. This perspective will discuss how preclinical research, with a focus on rare diseases, can better contribute to healthcare ecosystems that are oriented towards greater health equity. This contribution may require changes to the prevailing scientific research culture that will need support from relevant institutions and the wider community.