There is no standard global definition for what constitutes a rare disease. In fact, nearly 300 definitions exist, as determined by > 1,100 organizations. For the purposes of this manuscript, we will refer to conditions with an estimated prevalence of <1 in 2,000 persons. It is estimated that rare diseases affect up to 30 million people in the United States, and up to 400 million people worldwide. Many of these rare cardiovascular diseases have a genetic etiology, which can be identified more easily and at a younger age with broader access to genetic testing.

The collective economic impact of rare diseases is substantial. In 2019, there were $997 billion in estimated expenditures for a subset of just 379 rare diseases in the US. This included an estimated $139 billion related to lost productivity and absenteeism for rare disease patients and their caregivers. The proportion of these costs that may be attributable to rare cardiovascular diseases specifically is unknown. Models suggest that total costs for rare diseases increase 21.2% per patient per year in the absence of approved therapies, emphasizing the unmet need for rare disease treatments.

The United States Orphan Drug Act of 1983 was created with the goal of stimulating investment in the development of therapies for rare diseases. In its initial form, the act provided a 7-year period of market exclusivity for a drug approved to treat a rare disease (as compared to the 3- to 5-year period typical for drugs approved for other indications), as well as tax credits for up to 50% of research and development expenses. The impact of these changes have been significant, and are partly responsible for the exponential increase in rare and orphan drug designations ( Figure 2 ). The Orphan Regulation (passed in 2000) in the European Union, provides orphan designated medicines with 10 years of European market exclusivity, as well as additional incentives to reduce the costs associated with approval. More recently, the US Inflation Reduction Act (2022), which requires Medicare to negotiate prices for drugs with more than $200 million per year in Medicare spending, exempted drugs approved for treatment of a single rare disease from such price negotations. While these regulatory frameworks have increased incentives to develop therapies for rare cardiovascular diseases, investment into research and development of rare disease therapies remains constrained by the smaller potential market for such treatments. Government agencies including the NIH, larger foundations including the National Organization for Rare Disorders, as well as smaller disease-specific groups, are critical funders of rare cardiovascular disease research.

Orphan drug designations and approvals by decade, 1983-2022. Between 2013 and 2022, the number of orphan drug designations was approximately 7 times greater, and the number of initial orphan drug approvals was approximately 6 times greater, as compared to the first decade after the enactment of the Orphan Drug Act (1983-1992). Reproduced with permission from Fermaglich et al, Orphanet J Rare Dis 2023. Creative Commons License: http://creativecommons.org/licenses/by/4.0/ .

Before discussing the landscape of therapeutic development for rare cardiovascular diseases, it is first useful to reflect on the lived experience of rare cardiovascular disease patients. Such patients often experience a long diagnostic ‘journey’ with associated frustrations, morbidity, and costs. Up to 40% of rare disease patients will receive an incorrect initial diagnosis, and 25% may wait >5 years before the appropriate diagnosis is made. To receive the correct diagnosis or appropriate treatment, many patients need to travel long distances, out of state or even internationally. The frustration of this process may also be compounded by significant financial stress. Other rare cardiovascular diseases occur in the setting of secondary developmental abnormalities, or have symptom onset in childhood or adolescence which may lead to restrictions in independent function from an early age, and necessitate significant caregiver involvement that may be life-long. In addition to high direct costs for care, frequent medical visits may complicate caregiver participation in the workplace, and travel costs are a significant economic burden on patients and their caregivers.

A bright spot for patients has been the growth of patient advocacy and support groups, fueled by the internet and social media which create strong patient communities, as well as partnerships with academia and industry. Such groups have the ability to connect patients and caregivers across the globe. These organizations are an important source of social connectedness, and resource sharing. Frequently, such groups facilitate diagnosis through production of online materials which connect patients to specialists. Additionally, such groups have started to play a larger role in fundraising ( Table ). For example, CureDuchenne® helped fund Sarepta Therapeutics, the first company to have an FDA-approved therapy for Duchenne’s muscular dystrophy (which often has significant cardiovascular morbidity). Cure SMA, a patient organization dedicated to improving care for patients with spinal muscular atrophy (SMA), provided critical early funding which helped enable the eventual approval of first in kind SMA treatments including the genetic therapy zolgensma. Patient groups have also played a direct role in lobbying governmental agencies for increased research funding, as well as collaborating with the scientific community on research priorities and key clinical trial design issues. Patient advocacy groups should ideally be engaged as partners throughout therapeutic development, including trial design, study conduct, interpretation of data, and dissemination and implementation of results. ^,

A key example of the role for patient groups is the partnership of the Cystic Fibrosis Foundation with Vertex Pharmaceuticals, resulting in the FDA approval of ivacaftor (a cystic fibrosis transmembrane conductance regulator potentiator). The Cystic Fibrosis Foundation utilized venture philanthropy, a process of, amongst other actions, providing early-stage funding to industry partners to offset initial drug development costs and attract investment into treatments of this orphan disease. The organization simultaneously established clinical trial networks across the US and Europe, as well as patient advisory boards to foster input on therapy development. Such partnership and network creation facilitated the completion of a phase 3 trial of ivacaftor in <2 years, and culminated in its FDA approval in just 4 years. In addition to the therapeutic success of ivacaftor, the royalties paid to the Cystic Fibrosis Foundation for their role in its development generated billions of dollars in additional funding for the foundation’s work to support further therapeutic discovery.

The advent of advanced diagnostic technologies, including genetic testing and advanced cardiovascular imaging modalities, has enabled a surge in the diagnosis of rare and inherited cardiovascular diseases. Most notably, clinical genetic testing, in which targeted (phenotype-specific) genetic panels or whole genome sequencing can be sent directly from the cardiology clinic, has increased significantly over the past decade. Such testing has enabled cardiovascular clinicians to understand the genetic basis of rare phenotypes, and to distinguish rare genetic causes of common phenotypes (such as identifying hereditary transthyretin amyloidosis (ATTR), Fabry’s disease, or sarcomeric hypertrophic cardiomyopathy (HCM) as a patient’s cause of heart failure with preserved ejection fraction). Providing a correct diagnosis in such instances can have important therapeutic consequences.

Guideline documents across cardiovascular medicine have recommendations for genetic testing in rare and inherited cardiovascular diseases, including arrhythmia syndromes (such as Brugada syndrome, long QT syndrome, and catecholaminergic polymorphic ventricular tachycardia) as well as cardiomyopathies (HCM, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy). ^, Cost and systems challenges, including a need for prior authorization from payors to obtain genetic testing and a low rate of insurance coverage for such testing (despite evidence of its cost-effectiveness), have likely hindered the equitable spread of genetic diagnostics. ^, Nevertheless, though the costs of genetic testing have become progressively lower, there is a still a tremendous underutilization of genetic testing in clinical practice. ^,, A recent analysis across 35,000 US outpatient practices found that only 0.32% (71/22,254) of individuals with newly diagnosed HCM, and only 0.38% (264/69,331) patients with newly diagnosed dilated cardiomyopathy, received guideline-recommended genetic testing. In Europe, despite the widespread availability of nationalized healthcare systems, the majority of patients with HCM, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy similarly do not undergo genetic testing. Another analysis using US claims data from 35 million unique outpatient records found that only 2.5% (604/87,231) of the patients with newly diagnosed long QT syndrome, and 1.9% (316/16,310) of patients with newly diagnosed familial hypercholesterolemia, received guideline recommended genetic testing Additional barriers to the use of cardiovascular genetic testing may include patient concerns over the privacy of testing results and their impact on insurance and employment, a shortage of genetic counselors, and a lack of knowledge about genetic testing among cardiovascular clinicians. ^,

As there is a critical synergy between the use of advanced diagnostics, and therapeutic development for rare cardiovascular diseases, increasing utilization of genetic testing has potentially significant consequences on the entire pipeline of therapies ( Table ). To begin, genetic therapy trials rely on identifying sufficient numbers of individuals with the genetic variants of interest to generate an adequate cohort size. Genetic testing also enables the personalized delivery of existing, nontargeted therapies. For example, individuals with Lamin A/C mutations may benefit from earlier implantation of cardioverter-defibrillators than other individuals with dilated cardiomyopathy. Similarly, patients with inherited aortopathy (such as Marfan Syndrome) may benefit from earlier surgical repair of aortic aneurysms than patients without such conditions. Expanding training of cardiovascular genetic counselors, as well as expanding reimbursement for genetic testing, have been proposed as critical steps to increase the uptake of guideline recommended genetic testing ( Table ).

Diagnostic advances in cardiac imaging modalities, including cardiac magnetic resonance imaging (MRI) and Positron Emission Tomography (PET), have also driven the development of rare disease therapeutics. Cardiac MRI is recommended in the diagnosis of cardiomyopathy. Cardiac MRI allows for characterization of subtle myocardial tissue changes not appreciable on standard imaging modalities such as echo, which can enable earlier diagnosis of rare cardiovascular diseases before late-phenotypic expression occurs. MRI can also aid in distinguishing among rare diseases that share a common phenotype—for example, facilitating the diagnosis of LAMP2-related or ATTR-associated cardiomyopathy in patients initially labeled as having HCM. In a recent single center analysis, the addition of cardiac MRI plus genetic testing to the background clinical information improved diagnostic accuracy of the etiology of cardiomyopathy and interobserver variability in diagnosis, as compared to the addition of either modality alone. Advances in cardiac PET have also led to enhanced diagnosis of rare infiltrative diseases, particularly fluorodeoxyglucose-PET in the case of cardiac sarcoidosis, and technitium-99m pyrophosphate (PYP) scanning for the diagnosis of ATTR cardiomyopathy (which is now understood to be far more common than initially estimated). The progress made in ATTR cardiomyopathy exemplifies a self-perpetuating, virtuous cycle of diagnostic and therapeutic progress. ( Figure 3 ) As diagnostic techniques improved (particularly the move from biopsy-based, invasive testing to noninvasive PYP scanning), the natural history of ATTR cardiomyopathy became better understood, and the size of identifiable ATTR cohorts increased. This led to increased investment in ATTR drug discovery. The success of tafamadis incentivized more diagnostic testing, and fostered further diagnostic and therapeutic innovation, including novel TTR stabilizers (acoramadis), TTR silencing/knockdown therapies (patisiran, vutrisiran, and eplontersen), gene therapy (NTLA-2001), and TTR depleters (ALXN2220, NNC6019-0001, AT-02). ^,,,

The virtuous cycle of diagnostic and therapeutic progress. There is a virtuous, and self-propagating cycle of diagnostic and therapeutic progress in rare CVD. As diagnostic techniques improve, the natural history of rare CVD is better understood and rare CVD cohorts are more easily identified. This generates investment in discovery science and therapy development, leading to effective drug discovery. The availability of effective treatments leads to increased use of diagnostic testing, which then generates competition for the creation of further enhanced diagnostics, further propagating the cycle.

Genetic therapies have the potential to dramatically alter the natural history of many rare, cardiovascular diseases. As traditional medical treatments are largely ineffective in many such illnesses, genetic therapies could provide a dramatic change in disease course for rare cardiovascular disease patients. While a complete review of genetic therapies is outside the scope of this paper, certain aspects are worthy of elaboration.

Genetic therapies, broadly comprise treatments that reverse the effects of a causal genetic mutation in a genetic disorder. Such treatments include gene replacement therapy, genome editing, RNA therapeutics (including small interfering RNAs (siRNA), antisense oligonucleotides (ASO), and microRNAs (miRNA)), and enzyme replacement therapy (ERT).

Several gene replacement therapies, which involve introducing a normal functional copy of a gene into host cells to replace a defective or missing gene, have received marketing approval. Multiple other clinical studies of gene replacement therapy in rare cardiovascular diseases, including in arrhythmogenic cardiomyopathy (NCT05885412), HCM (NCT05836259), Duchenne’s muscular dystrophy (NCT03769116), Danon disease (NCT03882437), Friedreich’s ataxia (NCT05302271), Fabry’s disease (NCT04046224), and several other conditions are ongoing or soon to commence. Vectors for gene therapy include modified viruses (including adeno-viruses and adeno-associated viruses), as well as nonviral vectors including plasmids, which transport a genetic construct to the intended target. The selection of vector is determined by the size of the genetic construct it needs to carry, tissue tropism, the nature of the genetic target (gain of function versus loss of function), direct toxicity of the vector, as well as the immunogencity of the vector and the existence of antibodies against the vector in the potential recipient. The efficiency of vector delivery to the target tissue is an important determinant of the likelihood of success of a gene therapy. Targets within tissues such as liver or bone marrow have proved to be more accessible than targets within cardiomyocytes. As transthyretin protein is synthesized predominantly in the liver, TTR variants may prove easier to target for in vivo gene editing, then, for example, pathogenic variants in myosin heavy chain 7 within cardiomyocytes. Finally, consideration must be given to the route of administration of the therapy, which can include systemic intravenous infusion, intramyocardial or pericardial injection (which can be performed via a surgical or percutaneous approach), and intracoronary injection (both antegrade and retrograde, with or without coronary balloon occlusion). The increased efficiency in myocardial uptake of the therapy that can be achieved with direct myocardial delivery must be weighed against the potential risks of such invasive approaches.

The discovery and advancement of clustered regularly interspaced short palindromic repeats–associated nuclease Cas9 (CRISPR-Cas9) gene editing technologies, has led to several rare disease therapies currently in clinical study, including in ATTR cardiac amyloidosis. CRISPR-Cas9 utilizes guide RNA to identify and bind to a specific genetic sequence in the recipient’s DNA. The Cas9 enzyme can then cleave the target sequence at a precise location, introducing a double-stranded break, which can be used for genetic knock-out or allow for introduction of new genetic material (in the form of a donor DNA template), with high precision. Base editing is an alternative gene editing technology that enables the conversion of 1 base pair to another, without inducing double-stranded breaks in recipient DNA (which are felt to associate with more significant off-target effects). Base-editing has recently demonstrated potential utility in preclinical models of long QT syndrome 3, HCM, Duchenne’s muscular dystrophy, and several other rare cardiovascular diseases. ^,, Additional work has been done to utilize these techniques to correct pathologic variants in human and mouse embryos (including successful elimination of pathologic MYBPC3 , and MYH6 , mutations associated with hypertrophic cardiomyopathy); however, such work has not been translated to clinical practice. ^,

Beyond the challenges of selecting the appropriate genetic construct and viral delivery system, other hurdles in gene therapy development and administration include the need to limit off-target effects (ie, alteration of the genome at unintended places and in unintended tissues), ensuring durability of the desired change in the genome, and, given current viral vectors, the management of immunosuppression at the time of therapy administration, and managing post-treatment toxicities. Post-treatment, patients are vulnerable to both adaptive and innate-immune related inflammatory responses to viral vector administration, as well as to the immunologic toxicity of the therapy itself. This can manifest in a variety of ways including hepatotoxicity, thrombotic microangiopathy, and myocarditis. Immunosuppression is the backbone of treatment of such complications. The ideal regimen for immunosuppression has not yet been identified and it is likely that different approaches will be required depending on the disease and specific viral vector that will be used for delivery.

Despite the exciting opportunities to impact rare cardiovascular diseases with viral gene therapy, there are also limitations and challenges to this approach, and some rare cardiovascular diseases may be served by nonviral delivery methods. RNA therapeutics have demonstrated significant potential for the treatment of rare cardiovascular diseases. ASOs, siRNAs, and miRNA can all be utilized to inhibit the translation of endogenous messenger RNA into proteins. Like DNA-based therapies, the success of RNA-based therapies also relies on the effective, targeted delivery of the RNA construct, without off-target effects. This can be done using viral or nanoparticle vectors. Several RNA-based treatments are already in use, or in late-stage clinical testing in rare forms of CVD. This includes patisiran, an siRNA targeting TTR protein translation in hepatocytes, which was shown to improve 6-minute walk distance, and quality of life measures in a randomized trial of 360 patients with ATTR cardiac amyloidosis (and is FDA approved for treatment of ATTR polyneuropathy). Vutrisiran, an siRNA, and Eplontersen, an ASO, are both being assessed in phase 3 randomized control trials in patients with ATTR cardiomyopathy (NCT04153149, NCT04136171). Inclisiran, an siRNA which inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) translation in hepatocytes has also been shown to reduce LDL cholesterol by > 50% in patients with resistant hyperlipidemia. Additional RNA therapeutics are being explored in multiple other rare CVD states including rare forms of hypertriglyceridemia, rare metabolic disorders, as well as Duchenne muscular dystrophy (and its associated dilated cardiomyopathy). ^,,

ERT involves periodic infusions of a therapeutic enzyme, which in rare genetic disease corrects an underlying enzyme deficiency. While ERT requires ongoing treatment, it can effective treat genetic disease by replacing a deficient protein. ERT for lysosomal storage disorders has successfully reversed cardiovascular involvement, extending survival in infantile-onset Pompe disease, and improving cardiomyopathy in Fabry disease. ^,

Before the testing and administration of genetic therapies, multiple ethical issues must be considered. To begin, there is often significant uncertainty regarding the likelihood of benefit from participation in such trials. This uncertainty must be evaluated in the context of an individual patient’s current disease state, the likelihood of disease progression, and the availability of alternative treatments. Additionally, a treatment recipient who develops antibodies to the initial dose of an adeno or adeno-associated viral vector may be unable to receive subsequent doses. This issue is particularly problematic for early trial participants who may receive lower doses than those ultimately determined to be effective. Furthermore, unlike traditional cardiovascular medication trials, participants in genetic therapy trials have limited ability to “withdraw” from therapy once it is administered. These treatments often have potentially life-long effects and lack reversal agents, which is particularly consequential if the therapy exhibits unwanted off-target effects.