6

Preventing ALS

ABSTRACT

This chapter describes the challenge of identifying individuals at risk of developing amyotrophic lateral sclerosis (ALS) given the many genetic and environmental factors suspected of causing it. It discusses approaches for identifying at-risk individuals who harbor genes associated with the development of ALS and the research opportunities that arise from having larger numbers of such individuals, including the important role those individuals will play in identifying potential avenues to prevent ALS from developing. This chapter also addresses ethical and health communication challenges to conducting expanded carrier screening to identify asymptomatic carriers of ALS-associated gene mutations. These factors help explain how difficult preventing ALS is now and will continue to be for the near future. However, specific research approaches can help to mitigate these problems.

The key to preventing, halting, or reversing the characteristic nerve cell damage of ALS is identifying individuals at risk of developing the disease and then characterizing the genetic, biochemical, and environmental factors that trigger familial ALS and sporadic ALS (Benatar et al., 2023a). To achieve such a goal, the committee believes that focusing research on individuals at risk of developing ALS could provide important insights to enable halting or significantly slowing the development of ALS.

IDENTIFYING AT-RISK GENETIC CARRIERS

There are several possible approaches for identifying at-risk, presymptomatic individuals. For individuals who have a family history of the disease, genetic testing can identify those with mutations known to increase the risk of developing ALS. The Pre-symptomatic Familial ALS study (Pre-fALS) and PREVENT ALS study are examples of studies that build on this concept.¹ Both studies follow presymptomatic individuals with a family history of ALS to learn more about genetic and environmental factors that increase the risk of developing ALS (Benatar and Wuu, 2012; Benatar et al., 2023a; MGH, 2023).

While studying at-risk genetic carriers offers a critical opportunity to gain new insights into how, when, and why ALS develops, the challenge is to identify individuals with disease-causing or disease-moderating genes without a family history of ALS or who show no signs of developing ALS. Perhaps the only way to accomplish that on a scale large enough to be informative would be to conduct population-wide genetic screening, an approach that researchers have taken to identify asymptomatic genetic carriers for other diseases, including cancer, Lynch syndrome, and familial hypercholesterolemia (Grzymski et al., 2020; Nazareth et al., 2015). However, while rapidly falling costs of whole genome sequencing are making population-based screening more feasible logistically, there are several ethical and health communication challenges to conducting expanded carrier screening to identify asymptomatic carriers of ALS-associated gene mutations (ACOG Committee on Genetics, 2017; Evans et al., 2001; Oliveri et al., 2018; Roberts et al., 2020). These challenges include:

• The high emotional cost of genetic testing. There is a significant emotional burden for individuals who discover they harbor a genetic variation that could cause ALS in themselves as well as their children and grandchildren. There is also limited access to genetic counselors or mental health supports to help an individual cope with a genetic test result and interpret whether the genetic information is actionable.
• Complex family relationships when individuals within families have different perspectives on genetic testing. Some individuals will prefer to not know if they have a genetic mutation even if they had a family member with ALS. Individuals identified as genetic carriers may not know how to convey that information to

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¹ Additional information is available at https://neals.org/als-trials/NCT00317616 (accessed June 10, 2024).

family members or may choose to not disclose that information to family members.

• Navigating the medical system with a confirmed genetic carrier status can be challenging since many clinicians are unsure of how to deal with an individual with a confirmed genetic risk for ALS. In addition, there are few guidelines for what to do after an individual has been identified as a genetic carrier (ACOG Committee on Genetics, 2017; AMA, n.d.).
• There is legitimate fear that an individual’s genetic status could be used to deny insurance, services, or employment. While the Genetic Information Nondiscrimination Act (GINA) prohibits health insurers from discrimination based on genetic information, GINA’s protections do not apply to life, disability, or long-term care insurance or to businesses with fewer than 15 employees (ASHG, 2008).

For the Pre-fALS study, the research team developed a set of principles and practices for ALS presymptomatic genetic testing. These include offering voluntary and informed consent, evaluating participants for psychosocial readiness, providing genetic counseling and information on testing logistics, providing predecision counseling to explore motivations for testing, and providing pretest and posttest counseling (Benatar et al., 2016).

One recent study using functional genomics combined with machine learning claims to have discovered 690 genes potentially associated with ALS (Zhang et al., 2022). Given these numbers, it is likely there are more individuals at risk of developing ALS who never develop the disease than there are people diagnosed with ALS. Several population-based modeling studies using methodology originally developed for cancer epidemiology suggest the development of ALS is a multistep process, which would mean that having an ALS-associated gene would not be sufficient by itself to cause ALS (Al-Chalabi et al., 2014; Chia et al., 2018; Vucic et al., 2019, 2020).

Identifying Factors Beyond Genetics

For the 90 percent of individuals who develop ALS without a family history of disease (Fang et al., 2022), and for individuals with genes known to be involved in familial ALS but do not develop the disease, research will need to identify other risk factors beyond inherited gene mutations, particularly environmental exposures, that elevate the risk of becoming symptomatic. For example, biological relatives of people with ALS without a known genetic basis have an eightfold increased risk of developing ALS (Hanby et al., 2011), and approximately 5 to 10 percent of individuals with frontotemporal dementia also develop ALS signs (Ferrari et al., 2011).

Studying those who do not develop ALS might provide insights into protective mechanisms.² Other populations with elevated risk of developing ALS include people with mild motor impairment (Benatar et al., 2022a); veterans, who have twice the risk of the general population of developing ALS (Beard et al., 2017); and those exposed to various yet-to-be-identified environmental risk factors, a presumed trigger implicated in most individuals with nongenetic ALS (Goutman and Feldman, 2020). Population-based studies have found that genetic factors account for only half of the variation in the risk of developing ALS (Ryan et al., 2019).

Another strategy for teasing out the mechanisms that cause ALS is to identify and study individuals at reduced risk for ALS. Research has shown, for example, that certain drugs used to treat hypertension, diabetes, and cardiovascular disease appear to reduce the risk of developing ALS by an unknown protective mechanism of action (Cui et al., 2022; Pfeiffer et al., 2020). Studies of individuals who experience a plateau in disease symptoms or whose symptoms improve or even resolve and those with mutations in genes associated with ALS who live to old age without developing ALS symptoms might also provide insights that could advance efforts to prevent the disease (Bedlack et al., 2016; Harrison et al., 2018).

Access to Genetic Testing and Counseling

It is important that people with ALS and at-risk genetic carriers for ALS be able to access genetic testing and counseling. For them, genetic testing could reveal useful information for navigating their ALS journey and for making important family and health care decisions. In addition, more people having access to their genetic information would provide more data for researchers seeking to answer the questions posed in earlier sections of this chapter.

Access to genetic testing and counseling for individuals living with ALS and their families varies widely. As discussed in Chapter 4, the level of services an ALS clinic can provide varies significantly across the country. Some clinics provide genetic testing and others do not. One study found that only 34.7 percent of people with ALS responding to an online survey were offered genetic testing during care (Wagner et al., 2017), while only 67.3 percent of those to whom genetic testing was offered undertook it. Almost 80 percent of respondents to the survey reported receiving care at a Muscular Dystrophy Association– and/or ALS Association (ALSA)-certified ALS clinic (Wagner et al., 2017). As a result, many individuals living with ALS have uncertain

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² This sentence was changed after release of the report to correct the description of genetic factors and the risk of developing ALS.

or limited access to genetic testing and counseling. Even when genetic testing is available, people with ALS may not be able to afford it given that the cost of such testing for all currently known genes associated with ALS is an estimated $6,000 (Vajda et al., 2017).

There are several methods by which people with ALS or at-risk genetic carriers might obtain genetic testing. Individuals living with ALS or at genetic risk of developing it who participate in clinical research will often receive free genetic testing as part of their participation in research. However, this only guarantees access to genetic testing for the approximately 10 percent of individuals living with ALS who participate in research and is not a sustainable solution (Mehta et al., 2021). ALSA has identified an opportunity for individuals living with ALS and their families to receive free genetic testing, sponsored by the biotechnology company, Biogen, and offered by Invitae, a genetic testing company.³ The genetic testing panel looks for mutations in over 20 genes associated with ALS, including C9orf72. The duration of this program is unknown. The patient-led organization, Genetic ALS & FTD: End the Legacy, also includes information on genetic testing availability and guidance for accessing genetic counseling (End the Legacy, 2024).

Guidelines from professional associations and advisory boards has helped make genetic testing for other diseases more accessible. For example, the Affordable Care Act requires insurers to cover preventive services for which the U.S. Preventive Services Task Force (USPSTF) has issued an A or B rating, based on the evidence for its usefulness.⁴ Both USPSTF and the National Cancer Center Network have recommended BRCA genetic testing for all women with certain family histories of cancer or BRCA inheritance.⁵ In a 2018 survey, clinicians participating in the Northeast ALS Consortium reported they would offer genetic testing for individuals with ALS if guidelines for ALS existed (Klepek, 2018).

In September 2023, a group of ALS researchers and clinicians published a set of evidence-based consensus guidelines for the genetic testing and counseling of people with ALS (Roggenbuck et al., 2023). These guidelines call for testing every person with ALS for genes such as C9orf82, SOD1, FUS, and TARDBP; the publication also discussed genetic counseling guidelines. Groups such as ALSA have celebrated this development (ALSA, 2021). However, based on experiences in other disease spaces, such recommendations would be more powerful if they were included in ALS clinical practice guidelines, or if they were recommended by USPSTF.

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³ Additional information is available at https://ptcg.insideals.com/en-us/home/no-charge-genetic-testing.html (accessed June 10, 2024).

⁴ See 29 CFR § 2590.715-2713 - Coverage of preventive health services.

⁵ BReast CAncer gene.

Genetic Discrimination as a Barrier to Access

As noted above, at-risk genetic carriers for ALS may feel discouraged from pursuing genetic testing given the possibility of facing genetic discrimination when applying for insurance or a job. There are several protections in place for at-risk genetic carriers, but none are universal. For example, genetic information may be protected via standard research confidentiality processes. When an individual with a family history of ALS presents at an ALS clinic and requests genetic testing, it is not unusual for the clinic to refer the person to participate in a research study that includes provisions to safeguard the confidentiality of genetic test results, which includes keeping that information out of the individual’s electronic health record.

There are also legal protections against genetic discrimination, the most notable of which is GINA.⁶ GINA prohibits health insurers from asking about genetic information in many circumstances and from using genetic information to determine coverage eligibility or premiums. Employers with 15 or more employees have similar restrictions under GINA in that they may not use genetic information to make employment-related decisions. However, GINA does not prohibit genetic discrimination in life insurance, long-term care insurance, or disability insurance. These types of insurance are typically regulated by state legislatures, and there are a variety of factors to consider unique to each state’s insurance market.

In light of the gaps and uncertainties around access to genetic testing and counseling, as well as the unresolved threat of genetic discrimination, the committee offers the following recommendation:

Recommendation 6-1: Increase access to genetic testing and counseling for people with ALS and their families.

Genetic testing and counseling should be made substantially more easily and consistently available for people with ALS and their families. The Centers for Medicare & Medicaid Services and private insurers should pay for genetic testing and counseling for all people living with ALS and their families. State legislatures should examine possible measures to prohibit genetic discrimination in life insurance, long-term care insurance, and disability insurance based on genetic risk for ALS.

Preventing ALS in At-Risk Genetic Carriers

There then is the case of individuals known to be at risk of developing ALS by virtue of their genetic makeup. Studying unaffected carriers of

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⁶ See Genetic Information Nondiscrimination Act of 2008, Public Law 110-233, 110th Congress (May 21, 2008).

pathogenic ALS variants has contributed to the development of a framework and initial lexicon for further study of the presymptomatic phase of ALS (Benatar et al., 2023b). The number of cohort studies comprising at-risk genetic carriers is growing, and the results may provide opportunities to investigate potential ALS prevention strategies and stimulate more natural history studies. This includes studies of biomarkers for developing ALS, such as neurofilament light chain protein (NfL). Some at-risk genetic carriers provide biological samples for ALS research multiple times, often gathered through invasive spinal fluid procedures, at different research sites across the country. The travel costs, lost wages, and emotional toll of this participation can be considerable. If an individual wishes to track their NfL levels as a potential marker of imminent phenoconversion, they must pay for it out of pocket.

There are also clinical trials evaluating the potential for preventing ALS. Tofersen, which the U.S. Food and Drug Administration (FDA) has approved as a treatment of ALS patients with SOD1 gene mutations, is the subject of the ATLAS trial, the first-ever ALS prevention trial.⁷ The ATLAS study will monitor asymptomatic individuals with SOD1 mutations for increased blood levels of NfL. When levels of NfL rise above a predefined threshold, trial participants will be randomized to receive tofersen or placebo, to delay or even prevent the emergence of ALS symptoms (Benatar et al., 2022b). This type of clinical trial is complex and costly but will provide important data on the emergence of ALS.

Although involvement of the at-risk genetic carrier community in research is growing, many questions remain regarding how ALS develops in this population and whether it can be prevented with available or new drugs. It is unknown, for example, whether current FDA-approved therapeutics to treat ALS would be effective in delaying or preventing the onset of disease in at-risk genetic carriers. A September 2023 workshop involving clinicians, scientists, genetic counselors, and individuals with a genetic risk of developing ALS and frontotemporal dementia (FTD) explored the clinical science of treating and preventing ALS and FTD. Workshop participants are planning to draft recommendations and guidance for clinicians providing care for those at elevated risk of ALS and FTD (University of Miami, 2024).

Riluzole is currently being evaluated in at-risk genetic carriers who are willing to pay out of pocket both for clinic visits and for the drug (Abrevaya, 2023). The project seeks to determine if the onset of ALS symptoms can be delayed or prevented through early initiation of riluzole. The advocacy community points out the need for research on how ALS therapeutics work in genetic carriers before they develop ALS symptoms (End the

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⁷ Additional information is available at https://www.alsatlasstudy.com/en-us/home.html (accessed May 10, 2024).

Legacy, 2023). At-risk genetic carriers might be understandably interested in taking every possible step that might avoid the onset of ALS, including accessing ALS therapeutics before symptoms develop. The risk-benefit calculation is uncertain when considering dosing a healthy individual who may not develop ALS with therapeutics that include adverse side effects, such as elevated liver enzymes and interstitial pneumonia. In addition, a health insurer would likely object to paying for prescription ALS therapeutics in a healthy at-risk genetic carrier, leaving wealthier individuals with an advantage in trying these drugs if they can identify a clinician willing to prescribe.

Potential Preventive Therapies for Familial ALS

The most obvious kind of preventive intervention for familial ALS would be to delay or prevent disease gene expression, and some work has been done along these lines. Mutations in SOD1, C9orf72, TARDBP, and FUS genes are most associated with familial ALS. Mutations in the C9orf72 gene account for up to 40 percent of familial ALS in the United States and Europe (Nguyen et al., 2018). Worldwide, SOD1 gene mutations cause 12 to 20 percent of familial ALS and 1 to 2 percent of sporadic ALS (Amado and Davidson, 2021).

An antisense oligonucleotide targeting ATNX2 overproduction is in a Phase 1/2 trial, and jacifusen, an antisense oligonucleotide targeting the FUS mutation, has been investigated based on the drug’s ability to virtually eliminate the toxic mutant FUS protein in the central nervous system (Korobeynikov et al., 2022). In 2021, the drug’s developer started a Phase 3 trial that will enroll up to 64 people (Ray, 2021). Another antisense oligonucleotide, QRL-201, has begun Phase 1 trials; this agent restores function of stathmin-2, a protein required for nerve cell stability, the levels of which are affected by TDP-43 mutations. Two antisense oligonucleotides targeting C9orf72 overexpression completed Phase 1 clinical trials, but the trials’ sponsors discontinued development of both of these agents when they demonstrated no clinical benefit despite reducing levels of toxic protein in cerebrospinal fluid (Biogen, 2022; Wave Life Sciences USA, 2023).

One approach that might delay or prevent the development of ALS would involve transplanting human neural progenitor cells into the spinal cord of people with or at risk of developing ALS. One Phase 1/2a study has shown that a single dose of human neural progenitor cells engineered to produce glial cell line-derived neurotrophic factor (GDNF) delivered into the lumbar spinal cord of 18 people with ALS had no negative effects at 1 year after injection (Baloh et al., 2022). Further study found that transplanted cells remained viable and continued to produce GDNF, which other research has shown can protect spinal motor neurons (Klein et al., 2005; Suzuki et al., 2007). Another Phase 1/2a proof-of-concept study is assessing

the safety of injecting human neural progenitor cells engineered to produce GDNF into the motor cortex of people with ALS (Svendsen, 2023).

NONGENETIC FACTORS AND PREVENTION

Estimates of heritability, the extent of a disease attributable to genetics, in sporadic ALS vary from approximately 8.5 percent (van Rheenen et al., 2016) to approximately 61 percent (Al-Chalabi et al., 2010), suggesting contributions to ALS risk that go beyond genetics. Even for carriers of highly penetrant ALS mutations—those that result in ALS in most individuals with that mutation—onset occurs following a series of steps that may involve mutations in other genes or environmental exposures (Chiò et al., 2018). However, the emphasis of environmental studies in ALS have focused on the sporadic form, given the proportionately larger contribution of environmental exposures to disease risk in this category, and more prevention research focused on environmental exposures is needed in at-risk genetic carriers.

Investigation of environmental risk factors in ALS has given rise to the concept of the ALS exposome, the sum of environmental exposures over a lifetime that trigger disease onset (Goutman et al., 2023). Studies have aimed to characterize the ALS exposome and define the exposures that increase ALS risk. These efforts have identified a variety of potential exposures, including exposures to organic pollutants such as pesticides in the environment, metals, and air pollution; brain and spinal cord trauma; sports and intense physical activity; and possibly electromagnetic field exposure. The strength of the available evidence is well established for some of these exposures, such as certain pesticides (Goutman et al., 2023; Newell et al., 2022; Vasta et al., 2022).

Additional ALS risks may arise from occupational settings, such as manufacturing, construction, agriculture, and the military. For example, manufacturing and construction workers may be exposed to metal-containing welding fumes, volatile organic solvents, and particulate matter in exhaust fumes, whereas agricultural workers may be exposed to pesticides. Several recent studies demonstrate a connection between production occupations to ALS risk, as well as when and in what part of the body the disease first appears (Goutman et al., 2022a,b). Workers handling agriculture chemicals are also at elevated risk of developing ALS (Mitsumoto et al., 2022). In addition, exposure to toxins at home—if an individual’s residence is next to agricultural fields or manufacturing plants that apply certain chemical pesticides with neurotoxic effects, for example—can also affect chances of developing the disease (Andrew et al., 2021).

Military personnel may be exposed to toxins while deployed in conflict zones or to trauma from mechanical injury to the brain or spinal cord that

might lead to symptoms of ALS. In fact, strong evidence for a link between military service and ALS has existed for nearly 2 decades (IOM, 2006; McKay et al., 2021). However, basic research into the connection between military service and ALS has stalled in recent years. Improved researcher access to U.S. Department of Defense and U.S. Department of Veterans Affairs databases, along with longitudinal studies of these populations, would improve understanding of this connection.

Research on protective factors that could prevent the development of ALS has been limited. In the majority of instances, the mechanisms underlying ALS exposome-mediated neurodegeneration and triggering of ALS remain incompletely understood. A more comprehensive research program to fully delineate the ALS exposome and other risk factors could unlock the path to ALS prevention by removing or mitigating exposures.

The Need for Prospective ALS Studies

Many studies of the ALS exposome to date have been limited to retrospective studies using questionnaires to query past exposures. These research instruments are subject to recall bias, and, therefore, could limit study findings. Better characterization of the ALS exposome will require a prospective study design and querying exposures in real time, which is less subject to recall bias and generates more accurate information. Demographics, lifestyle, and clinical data can be collected in tandem, as can biospecimens for quantifying environmental exposures and biomarkers of neuronal damage. Populations at risk of ALS can be selected for these studies, because they are more likely to develop ALS, providing sufficient phenoconversion of individuals from health to disease to power prospective observations. Prospective, longitudinal studies of environmental risks should also include healthy individuals given that the causative factors for ALS are still unclear.

As the discussion in this chapter shows, involving at-risk genetic carriers in research would provide multiple avenues for investigating the causes of ALS and generating insights that could power the development of therapeutic or preventive agents. Other populations at risk of developing ALS also provide a valuable source of learning more about the environmental risks and deserve focused future study.

With the first prevention trial underway in an at-risk genetic carrier population (Biogen trial of tofersen) there is reason to believe additional research studies in genetic carriers will be possible in the future. To get to this point, the challenge is to develop evidence for clinical benefit and a biomarker signal in a symptomatic population before launching a study to evaluate disease progression or conversion to disease in an at-risk asymptomatic population. These studies can be long and challenging and will

require increased collaboration and partnership among research funders, drug developers, and ALS nonprofit organizations and the affected communities to realize progress.

It is also the case that interventions are needed to prevent ALS not just for at-risk genetic carriers but also in sporadic ALS populations that may be at risk of developing ALS (e.g., veterans, football players). Risk identification is the first step, but risk mitigation approaches will need to be tested as interventions in clinical trials for at-risk individuals.

Therefore, the committee makes the following recommendation:

Recommendation 6-2: Advance research focused on populations at risk of developing ALS.

Research funders should partner with drug developers and the ALS community to advance research focused on populations at risk of developing ALS, including at-risk genetic carriers. Research funders should partner with drug developers and the ALS community to develop specific research programs focused on the unique unmet needs of at-risk genetic carriers. Research funders should support large-scale, prospective natural history studies of populations at risk of ALS.

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