Kenneth Bender, PharmD, MA

Sonja W. Scholz, MD, PhD, an investigator in the Neurodegenerative Diseases Research Unit in the Division of Intramural Research at the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH), was the recipient of the annual Soriano Lectureship Award at the 2020 American Neurological Association (ANA) virtual meeting. The award acknowledges, according to the ANA, a “brilliant lecture delivered by an outstanding scientist.” 

Scholz was recognized for her application of advanced genetic techniques to the study of neurodegenerative disorders, including dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration. She welcomed the opportunity, utilizing the occasion to describe how advances in genetics are likely to impact daily clinical practice with patients afflicted with these types of disorders. 

While much of the recent excitement in this field has resulted from the identification of single-gene defects or deficiencies underlying rare monogenic disorders such as Batten disease and Rett syndrome, and from the emerging technologies to deliver gene replacement, Scholz emphasized the importance of also pursuing the genetic components of more common and more complex polygenic, age-related neurodegenerative disorders. 

“A lot of the work in genetics has traditionally been done in the pediatric population, where you have the single-gene disorders. But increasingly in our adult population, we are recognizing that genetics also play a role,” Scholz told 

®. “It shouldn’t really surprise us; our genes don‘t stop working just because we’re growing up. But it becomes more complicated. There are more risk factors rather than causative genetic factors, and it’s usually a combination of many.” 

“While I think that most of the immediate translations are going to happen in the Mendelian diseases, the monogenic diseases, I think there’s also a lot of hope that this knowledge can be leveraged for the more complex genetic disorders,” Scholz commented. 

After presenting her Soriano Award lecture, “Genomic Approaches Paving the Way for Precision Neurology,” Scholz spoke with 

® regarding her work and the opportunity to pursue it in collaboration with scientists both in and outside of the NIH. That discussion has been edited and abridged, and the lecture excerpted for this profile.

Pursuing Research to Improve Clinical Outcomes 

Scholz obtained her medical degree from the Medical University of Innsbruck, Austria, in 2004, after which she completed a fellowship at the Laboratory of Neurogenetics in the NIH National Institute of Aging. In 2010, she earned her PhD in neurogenomics from University College London in the United Kingdom. Before returning to the NIH, Scholz added to the clinician component of her physician-scientist background by completing her neurology residency at Johns Hopkins University School of Medicine in Baltimore, Maryland. 

In 2015, Scholz received the McFarland Transition to Independence Award for Neurologist-Scientists and rejoined the NIH to lead a team of researchers in applying advanced genetic techniques to the study of neurodegenerative disorders. She established the Atypical Parkinsonism Clinic at the NIH Clinical Center to study the natural history and molecular characteristics of patients suffering from these conditions. 

Scholz described the decision to complete her neurology residency even as she had established her path in research directly from medical school. 

“I think the ideal scenario is to combine the clinical work with research. They’re 2 worlds that sometimes live by themselves, and I think I see myself as kind of a bridge-builder between those worlds,” she recounted. 

“I really enjoy the basic sciences side, asking questions and learning more about very complicated diseases, but also kind of crystallizing out the important, translatable parts of the knowledge that we’re generating, and communicating that to the clinicians who are working with these patients. And, hopefully, contributing to the new therapies that we’re hoping to develop for patients with very complex, neurodegenerative conditions,” Scholz said.

After completing her neurology residency and receiving the McFarland Award, Scholz proposed that the NINDS establish a genetics research unit dedicated to neurodegenerative diseases. Scholz found the leadership at NINDS to be “very open to the idea” and to have already recognized the need for additional physician-scientists to work in that area. 

“With the population aged more than 65 years growing quite rapidly, we’re seeing an increase in patients with neurodegenerative diseases, and that puts a huge socioeconomic burden on the society. There is a need to come up with better insights into what is actually causing these very challenging diseases, and [into] treatments,” Scholz pointed out. 

Scholz integrated the Neurodegenerative Diseases Research Unit into the Laboratory of Neurogenetics, and established genetics research laboratory within the Intramural Research Program. The stated primary mission of the laboratory is to unravel the molecular genetic mechanisms that underlie these devastating diseases and identify targets for drug development. 

Scholz’s efforts to focus the direction of genetic research and accelerate the attainment of meaningful findings were aided by the emphasis on collaboration in the Laboratory of Neurogenetics and at the Intramural Research Program, and her research has proceeded with national and international partners. 

“Everything that we do is part of team science and team research. Nobody can do any of this by themselves,” Scholz declared. “It has to be an effort that involves the entire research community: patients, caregivers, researchers, and clinicians.”

Scholz encourages clinicians to tell patients of diverse backgrounds and ethnicity about openings in clinical trials, as well as opportunities to provide biosamples for genomic studies. 

“We have great opportunities to use genomics, [and] not just for identifying underlying genetic defects that may help with the diagnosis,” Scholz explained. “By enrolling many individuals from varied backgrounds into the research studies, we can learn more about them and build a health care system that becomes more open and more equitable, as well as more precise and more personalized.”

What I want to docus on today is [discussing] how we can use modern genomic advances for gaining insights into the molecular characteristics underlying neurodegeneration. But I also want to highlight how we can leverage this type of knowledge to gain insight into how we can use genetic markers for predictive diagnostic, prognostic, and therapeutic approaches in the near future. 

Previous speakers have mainly focused on specific Mendelian forms of disease, and I want to highlight how we can leverage genetic knowledge for the broader disease population that is suffering from more complex genetic syndromes. 

Specifically, we have learned from genome-wide association studies and other genetic approaches that most diseases are, from a genetic point of view, complex. There are multiple genetic factors that are playing a role, not all of which might be disease-causing, but many of them are playing a major role in the pathogenesis. 

For example, Alzheimer disease, Lewy body dementia, [and] Parkinson’s disease are common, age-related neurodegenerative diseases that in most instances occur apparently sporadically in the community. Yet all of these conditions have high heritable contributions to their etiopathogenesis. 

There are an increasing number of risk genes that we’re able to decipher. GWAS (genome-wide association studies) have identified about 30 risk loci for Alzheimer disease, about 5 loci for Lewy body dementia, and approximately 90 for Parkinson disease [

]. 

So, we have to move away from our traditional thinking where we look for 1 specific molecular defect that results in 1 clear phenotype—the Mendelian diseases. But in the complex disease context, we’re mainly talking about polygenic disease factors, where multiple lower risk variants are playing a role, and in aggregate, probably together with aging and environmental factors, are enough to push your patient into disease.

Scholz emphasized the utility of the polygenic risk score (PRS) to distill genome-wide association study (GWAS) locations of loci with possible links to pathogenesis into a cumulative risk metric. In her area of research, the PRS is used to sum up the identified loci from the GWAS and weigh them by their relative effect sizes to estimate an individual’s risk for complex, polygenic degenerative neurologic disorders. 

Clinical correlations of PRS for some disorders have included estimated age at onset and the rapidity of the degenerative course. In Alzheimer disease (AD), for example, Scholz has noted that individuals in the highest decile of PRS have onset more than a decade earlier than those in the lowest decile. In the genetic assessment of age-associated AD risk cited in her lecture, the investigators demonstrate that polygenic factors beyond APOE contribute to modifying AD risk.

Scholz pointed to similar associations established for patients with Parkinson disease (PD), with patients in the highest polygenic risk category presenting with earlier disease onset. Those investigators underscore the evidence that early-onset forms of PD cannot be exclusively attributed to highly penetrant Mendelian mutation, but to an accumulation of common polygenic alleles with relatively low effect size.

Scholz is also interested in applying PRS to better differentiate patient groups from controls to increase the precision of clinical trials. She pointed to a successful example of case-control status prediction in PD that was accomplished by combining PRS with smell test data and demographics.

 She said she anticipates that the approach can help not only to distinguish participants with PD from controls, but that it will also progress to aid early diagnosis in individuals with prodromal features. 

“There’s a lot of variability in the symptoms and signs that the patients present because they’re all individuals, and that can make the diagnosis very challenging,” Scholz commented. “I think anything that can help with identifying the underlying disease mechanism will also help with instituting appropriate treatments.”

 We can use that [PRS] to predict various outcome measures, such as phenotypes. You can stratify patients based on their severity. We can study the underlying genetic architecture and draw conclusions about how related one disease is to another on a genetic basis. But we can also be smarter about predicting which treatment responses might be useful for a given patient population [

 Path From Genetic Signals to Targeted Therapeutics

Finding Interrelationship of Complex Neurodegenerative Disorders 

Scholz is a principal investigator of new research that applied genetic risk scores established for AD and PD to a large cohort of patients with Lewy body dementia.4 She and her colleagues showed that patients with Lewy body dementia have a higher risk for both AD and PD. She pointed out that the interrelationship was present even after analysis corrected for the most common high-risk alleles (

Scholz and colleagues used GWAS analysis to identify 5 independent risk loci, with genome-wide gene-aggregation tests implicating mutations in the gene 

. Scholz suggested that the shared risk profiles and pathways of these conditions, previously considered disparate, provide a deeper molecular understanding of the complex genetic architecture of the age-related neurodegenerative conditions. 

Scholz also considered these findings as immediately clinically relevant, since a therapeutic agent that targets mechanisms for PD or AD could be a candidate for Lewy body dementia as well. Trials that provide evidence for “repurposing” a therapeutic agent could hasten the possibility of effective intervention, she suggested. 

“Imagine, for example, that there is a drug that targets this specific pathway, and it shows a promising result in AD. The very obvious next thought should be, ‘Well, we’ve shown that pathway also has a defect in Lewy body dementia, so we should really try that disease population next,’” Scholz explained. “So, in a way, that can also help to accelerate the field, because we already know that these molecular overlaps exist.” Scholz also anticipated that her team’s work in demonstrating overlapping pathways in the conditions, previously considered distinct, will help prioritize the pathway targets for intervention. For example, Scholz and colleagues suspected from their mapping that SNCA-AS1 may prove to be “a more amenable therapeutic target” than SNCA itself due to its neuronal specificity.

 In a study that we recently performed, we applied Alzheimer disease and Parkinson disease genetic risk scores to a large cohort of patients with Lewy body dementia. And what we were able to show is that patients with Lewy body dementia have a higher risk for Alzheimer disease and for Parkinson disease, and that was present even after correcting for the most common high-risk alleles. This suggests that Lewy body dementia, on a molecular basis, intersects with the pathogenesis of Parkinson disease and Alzheimer disease. And that is immediately clinically relevant because any drug that works for Parkinson disease or Alzheimer disease should be tried in the Lewy body dementia population as well. So, for drug repurposing, this knowledge is really very valuable.

As part of their study on overlapping risk factors in patients with AD and PD and Lewy body dementia, Scholz and colleagues created a foundational resource, the largest whole-genome sequence repository in Lewy body dementia to date, which they anticipate will facilitate the study of molecular mechanisms across a broad spectrum of neurodegenerative diseases. This resource includes approximately 2000 elderly individuals who are neurologically healthy who could serve as control subjects for the study of other neurological diseases. 

“Determining shared molecular genetic relationships among complex neurodegenerative diseases paves the way for precision medicine and has implications for prioritizing targets for therapeutic development,” Scholz and colleagues observed.

REFERENCES
1. Desikan RS, Fan CC, Wang Y, et al. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 2017;14(3):e1002258. doi:10.1371/journal.pmed.1002258
2. Escott-Price V, International Parkinson’s Disease Genomics Consortium, Nalls MA, et al; IPDGC Consortium Members. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann Neurol. 2015;77(4):582-591. doi:10.1002/ana.24335
3. Nalls MA, McLean CY, Rick J, et al. Diagnosis of Parkinson’s disease on the basis of clinical and genetic classification: a population-based modeling study. Lancet Neurol. 2015;14(10):1002-1009. doi:10.1016/S1474-4422(15)00178-7
4. Chia R, Sabir MS, Bandres-Ciga S, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture. bioRxiv. Preprint posted online July 6, 2020. doi:10.1101/2020.07.06.185066

Articles

Scholz was recognized for her application of advanced genetic techniques to the study of neurodegenerative disorders, including dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.

Sonja W. Scholz, MD, PhD, on Advancing Genomics Against Complex, Polygenic Neurodegenerative Disorders

Three disease-modifying treatments for spinal muscular atrophy (SMA) that have been approved all have different mechanisms of action but at least 1 shared property: They work best when early detection of SMA enables affected patients to receive them sooner rather than later.

Prior to the approval of the first gene-modifying therapies for SMA—nusinersen (Spinraza; Biogen) in 2016,

 onasemnogene abeparvovec (Zolgensma; AveXis) in 2019,

 and risdiplam (Evrysdi; Genentech) most recently in August 2020,

 only supportive therapy was available and its timing did not alter the progressive loss of motor neurons in this autosomal recessive neuro-degenerative disorder.

“Time is neurons,” commented Mary Schroth, MD, chief medical officer at Cure SMA, a national patient advocacy and educa-tion organization. “Both the treatments that are available are disease-modifying treatments. Neither of them are cures, but they are life-changing.”

Although SMA is the leading genetic cause of infant mortality,

little progress had been made toward widespread newborn screening for early detection before the advent of gene therapies. The incorporation of SMA into newborn screening quickened with the evident success and FDA approval of nusinersen.

In response to encouraging data, the Maternal and Child Health Bureau of the Health Resources and Service Administration (HRSA) advised in 2018 that SMA be added to the Recommended Uniform Screening Panel (RUSP) in the United States.

“Based on what is known about screening and the risk of being born with SMA, experts think that screening all newborns in the United States for SMA would find about 36 babies with the disorder each year,” the HRSA report stated.

 “Each year, screening could prevent about 50 infants from needing a ventilator and about 30 deaths due to SMA Type 1.”

Inclusion in the RUSP does not mandate nationwide implementation, however, as implementation of the screen for newborns is determined by each state. According to tracking by Cure SMA, newborn screening for SMA has currently been adopted and implemented in 23 states, adopted but not yet implemented in 14 states, and undertaken as a pilot project in 3 states (

“Each state is independent in their identification of a specific SMA screening test, and the way that they go about launching it,” Schroth told NeurologyLive®. “In some states, it’s mandated by their state law that implementation occurs within a certain period of time after inclusion in RUSP.

“It is a state-by-state process,” she said, “which makes it challenging for patient advocacy organizations such as Cure SMA, and also for families because it may depend on which side of a state line you’re on as to whether the infant born today is screened or not for SMA.”

Initiatives from Cure SMA to promote newborn screening and early diagnosis include outreach to state legislators and public health laboratories, as well as maintaining an online newborn screening registry

 for data that could help support new therapy development and improve clinical care. One of its education programs, SMArt Moves, provides separate materials for families and for health care providers to increase knowledge about SMA and recognition of the disorder’s signs and symptoms.

With the increased emphasis on newborn screening for SMA that followed the advent of gene therapies, there has also been increased consideration of testing for carriers. Carrier testing for SMA had previously been recommended for all pregnant women by the American College of Medical Genetics and Genomics

 and the American College of Obstetricians and Gynecologists.

In a recent article, bioethicists argued for increasing the availability of carrier screening to identify potential risk and inform family planning.

“The dual developments of increased treatment options for SMA, Zolgensma and Spinraza, and the increased sophistication of genetic screening technologies prompted us to look at this topic,” Christopher Gyngell, PhD, of the Department of Pediatrics at the University of Melbourne and the Murdoch Children’s Research Institute in Australia, told NeurologyLive

“These developments are leading to novel ethical challenges from both a clinical and policy standpoint,” Gyngell said.

In their analysis, Gyngell and colleagues argued that a moral imperative exists to pursue ex-ante interventions, such as carrier screening, in combination with prenatal testing and preimplantation genetic diagnosis or gene editing to reduce the incidence of SMA. They argue further that such ex-ante methods should be prioritized over ex-post methods for reasons related to autonomy, beneficence, and justice. 

“One thing we touch on,” Gyngell commented, “is that carrier screening can lead to cost savings for health systems, which can be reinvested into other programs. Screening programs can therefore help build more sustainable health systems.”

Treatment Recommendations Follow New Evidence

The genetic screen for SMA is based on the determination that 95% of cases result from a homozygous deletion in the SMN1 gene that encodes the survival motor neuron (SMN) protein. In the other 5% is a mutation rather than an SMN1 deletion, which is not detected in screening.

The loss of SMN protein results in degeneration of anterior horn cells in the spinal cord, with resulting fatigue, paralysis, and atrophy of the proximal muscles.

 There is, however, an inherent mitigation, in that most individuals retain function of 1 or more copies of the paralogous SMN2 gene.

SMN2 also encodes the SMN protein, albeit in a lower amount.

 As the severity of the condition is related to the amount of available SMN, the severity is less in individuals with more copies of SMN2 (

An SMA treatment algorithm based on early detection was developed through expert consensus by a working group convened in 2018 by Cure SMA.

 The group considered preclinical and clinical data (notably from presymptomatic infants in the ongoing NURTURE trial)

 to confirm that the best outcomes occur when disease-modifying therapy agents are given as early as possible.

They found strong evidence, however, that irreversible loss of motor neurons with SMA type 1 begins early in the perinatal period, “with severe denervation in the first 3 months and loss of more than 90% of motor units within 6 months of age.”

The working group recognized that the majority of infants with SMA who have 1 copy of SMN2 would be symptomatic at birth, and they would be likely to have sustained loss that would not be remediated with disease-modifying therapy.

“In this case, the consensus is to defer to the attending physician to determine if the infant and family would benefit from treatment given his or her current disease state,” they indicated. “In the rare event that an infant with SMA with 1 copy of SMN2 is truly presymptomatic, the strong consensus is that the infant should be treated immediately.”

The 2018 working group was unanimous in recommending that immediate, presymptomatic treatment should be provided for all infants with 2 or 3 copies of SMN2. The group was split, however, on whether to extend that recommendation to infants with 4 or more copies.

They reached a consensus that infants with 4 or more copies of SMN2 should be “screened carefully for the first presentation of symptoms” rather than receive gene-modifying therapy immedi- ately after the condition is detected.

The working group was reconvened in 2019 to consider newly emerging data, including additional findings in the NURTURE trial that nusinersen treatment, when given to infants with 2 or 3 copies of SMN2 who were aged under 6 weeks, was associated with significantly better outcomes than treatment given after the age of 6 weeks.

“Patients enrolled in this trial with 2 copies of SMN2 have a dramatically altered disease course with 100% alive, 100% sitting, 88% walking with assistance, 77% walking independently, and none needing the use of permanent ventilation assistance,” the 2019 working group recounted.

From these results, the group extrapolated that such outcomes were as likely to be attained in infants with 4 copies of SMN2 as in those with 3 copies. The working group now recommends that these infants also receive disease-modifying therapy while presymptomatic, immediately after detection in newborn screening.

“With early treatment, disease should be mostly eradicated in presymptomatic patients with 4 copies of SMN2,” they concluded. Schroth emphasized that the rapid progress in treatment and notable clinical trial data that emerged after the first meeting had compelled the working group to reconvene.

“As a result of these therapies being available and clinical trials with additional treatments, clinicians have had more experience utilizing these treatments and understanding the risks and benefits,” she said. “There was a clear majority when they reconvened.”

Addressing, Averting a Devastating Course

SMA phenotypes have traditionally been categorized by the severity of symptoms and the age at onset, in the natural course without disease-modifying therapy, as well as by life expectancy and the motor function milestones that are attained.

In a 2020 journal article, Janbernd Kirschner, MD, of the Department of Neuropediatric and Muscle Disorders at the Medical Center—University of Freiburg in Germany, and colleagues described the presentations associated with the traditional phenotypes, noting that the most severe, type 1, affects more than half of patients with SMA and manifests within the first 6 months of life.

“A ‘floppy infant’ presentation, [with] reduced spontaneous movements, and a paradoxical breathing pattern are characteristic; these infants fail to achieve the free sitting milestone,” Kirschner and colleagues wrote. “SMA type 2 is characterized by a milder course,” they continued, “with onset of symptoms between the ages of 6 and 18 months. Per definition, these patients do manage free sitting, but not independent walking. The latter is achieved, at least temporarily in patients with SMA type 3, whose symptoms’ onset is during infancy or adolescence.

“In addition, some classifications define SMA type 0 and SMA type 4 with prenatal onset or a very mild phenotype entailing an adult onset of symptoms, respectively,” Kirschner and colleagues added.

They point out that disease-modifying drugs, age of onset, number of SMN2 copies, and the age at start of drug treatment will better define a clinical phenotype of SMA going forward than the traditional subtypes.

“These new disease trajectories also mean [that] we must modify and adapt the clinical approach taken,” they wrote.

This is especially relevant with the longer survival that is achieved without ventilation support following initiation of drug treatment. This “needs to be considered when counseling the parents of patients with early-onset types of SMA,” they suggested.

Kirschner and colleagues also pointed out that, despite the improved survival and motor development of symptomatic patients with early-onset SMA, these children also exhibit a higher rate of scoliosis during the first years of life.

“Greater awareness of this risk, and close monitoring of spinal deformities, [appears] crucial to react early and enable the spine to be stabilized via medial orthosis,” they wrote.

Optimal long-term outcomes will require multidisciplinary care, according to Jule Parsons, MD, professor of clinical pediatrics and neurology and codirector of the Neuromuscular Clinic at the University of Colorado Anschutz Medical Campus/Children’s Hospital Colorado in Aurora.

“We are following them to see what that actually is going to mean and look like,” Parsons told 

. “So, it is important to have assess- ments by expert clinicians, in terms of looking at motor outcomes, pulmonary outcomes, growth and weight gain, bone health—we look at and monitor a number of different issues.

“We also have to remember the current population of patients— children and adults with SMA&mdash;and [they] can be extremely complex patients who may also benefit from some of the new therapies that are coming,” Parsons said, referring mainly to risdiplam, Roche/ Genentech’s recently-approved therapy

 that has proved safe and effective in a wide range of patients with SMA, from infants to adults. The therapy, which was approved for use in adults and children with SMA types 1, 2, or 3 age 2 months and older,

 is an orally adminis- tered SMN2 splicing modifier associated with a range of benefits, including significant change in total Motor Function Measure 32 in younger patients and disease stabilization in older ones.

 Parsons and colleagues noted that updated standards of care

 offer 3 general phenotype categories that are determined by motor function class: nonsitters, sitters, and ambulant. Each, they explained, has particular considerations and care needs.

“What I’m seeing is that these patients benefit from the new therapies. They continue to have enhanced motor skills,” Parsons said, “and, frankly, some of the children that we’ve followed have actu- ally met normal motor milestones, the same as for a child who doesn’t have SMA.

“With early [disease-modifying] treatment, we don’t necessarily need to use nonoral therapy, such as feeding tubes, and the respiratory support may be less than what we would have needed in the previous standard of care,” Parsons said.

Schroth agreed that the treatment landscape has changed with the advent of new, effective therapies, and that this has posed both opportunities and challenges to realize them.

“There’s less confidence about what sort of intervention the baby will require,” she acknowledged. “And so now we’re in the stage of trying to better understand the impact of these treatments across the disease spectrum, and what things need to be carefully monitored and acted upon.”

1. FDA approves first drug for spinal muscular atrophy. News release. FDA; December 23, 2016. Updated March 28, 2018. Accessed June 12, 2020. https://www.fda.gov/news-events/press-announcements/ fda-approves-first-drug-spinal-muscular-atrophy

2. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. News release. FDA; May 24, 2019. Accessed June 12, 2020. https://www.fda.gov/news-events/press-announcements/ fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease

3. PTC Therapeutics announces FDA approval of Evrysdi (risdiplam) for the treatment of spinal muscular atrophy in adults and children 2 months and older. News release. PTC Therapeutics; August 7, 2020. Accessed August 7, 2020. https://www.finance.yahoo.com/news/ptc-therapeutics-announces-fda-ap- proval-175400735.html

4. Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. 2010;12(3):145-152. doi:10.1097/GIM.0b013e3181c5e713

5. Newborn screening for spinal muscular atrophy. a summary of the evidence and advisory committee decision. Health and Resources and Services Administration. March 13, 2018. Accessed June 12, 2020. https://www.hrsa.gov/sites/default/files/hrsa/advisorycommittees/heritable-disorders/rusp/previ- ous-nominations/sma-consumer-summary.pdf

6. Newborn screening for SMA. Cure SMA. Updated July 1, 2020. Accessed July 6, 2020. https://www. curesma.org/newborn-screening-for-sma/

7. Cure SMA newborn screening registry (NBSR). Cure SMA. Accessed June 15, 2020. https://www. curesma.org/nbsr-sep2019/

8. SMArt Moves. Cure SMA. Accessed June 15, 2020. https://www.curesma.org/smartmoves/

9. Prior TW; Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med. 2008;10(11):840-842. doi:10.1097/GIM.0b013e318188d069

10. Committee Opinion No. 691 summary: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):597-599. doi:10.1097/AOG.0000000000001948

11. Gyngell C, Stark Z, Savulescu J. Drugs, genes and screens: the ethics of preventing and treating spinal muscular atrophy. Bioethics. 2020;34(5):493-501. doi:10.1111/bioe.12695

12. Schorling DC, Pechmann A, Kirschner J. Advances in treatment of spinal muscular atrophy—new phenotypes, new challenges, new implications for care. J Neuromusc Dis. 2020;7(1):1-13. doi:10.3233/JND-190424

13. Glascock J, Sampson J, Haiet-Phillips A, et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromusc Dis. 2018;5(2):145-158. doi:10.3233/JND-180304

14. De Vivo DC, Hwu W-L, Reyna SP, et al. Interim efficacy and safety results from the phase 2 NURTURE study evaluating nusinersen in pre-symptomatic infants with spinal muscular atrophy. Neurology.2017;88(16 Supplement):S46.003.

15. Biogen announces new data further establishing Spinraza (nusinersen) as a foundation of care in spinal muscular atrophy for a broad range of patients. News release. Biogen; July 1, 2019. Accessed June 16, 2020. https://investors.biogen.com/news-releases/news-release-details/ biogen-announces-new-data-further-establishing-spinrazar

16. Glascock J, Sampson J, Connolly AM, et al. Revised recommendations for the treatment of infants diag- nosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromusc Dis. 2020;7(2):97-100. doi:10.3233/JND-190468

17. Genentech’s risdiplam showed significant improvement in motor function in people aged 2-25 with type 2 or 3 spinal muscular atrophy. News release. Genentech; February 6, 2020. Accessed April 7, 2020. https//www.gene.com/media/press-releases/14836/2020-02-06/ genentechs-risdiplam-showed-significant-

18. Gibbons M, Stratton A, Parsons J. Spinal muscular atrophy (SMA) in the therapeutic era. Curr Genet Med Rep. 2019;7:162-167. doi:10.1007/s40142-019-00172-9

19. Mercuri E, Finkel RS, Muntoni F, et al; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115. doi:10.1016/j.nmd.2017.11.005 

Efforts to cut through regulatory red tape will help ensure earlier access to potentially lifesaving treatments.

Early Intervention in SMA: How Access to Therapy Will Alter Disease Management As We Know It

Despite the medical breakthrough of an orally available precursor compound that is converted after crossing the blood- brain barrier to replenish a diminished dopamine neurotransmitter in the brain, the initial consistent therapeutic response to levodopa in patients with Parkinson disease (PD) will eventually wane into “off” periods.

“After several years, sometimes as early as 1 or 2 years, sometimes in 4 or 5 years, but usually in the first couple of years, this so-called honeymoon period begins to end, and many patients begin to notice that 3 or 4 hours after taking a dose of carbidopa/levodopa, their symptoms return and break through,” Stuart Isaacson, MD, director and founder of the Parkinson’s Disease and Movement Disorders Center of Boca Raton in Florida, told NeurologyLive®. “These symptoms can be motor or nonmotor, but when these symptoms come out at the end of a dose, we call it the beginning of an off period.”

Practitioners can address the emergence of PD symptoms in off periods of response to the treatment mainstay levodopa by ensuring therapeutic levels, as well as with adjunctive treatment or alternative dopaminergic agents. Yet even with optimizing therapeutic interventions, symptoms can worsen with the degeneration of dopaminergic neurons as the disease progresses. The challenge of maintaining optimal levodopa therapy also increases over years of treatment and with disease progression. Paolo Calabresi, MD, of the Clinica Neurologica at the Universita&#768; degli Studi di Perugia in Italy, and colleagues described a narrowing window for therapeutic effect and a widening likelihood of either peak-dose dyskinesias or subtherapeutic off dystonia (

The manifestations of oscillation between on and off response to treatment include wearing off, delayed on, no on, and akinesia, typically in the early morning. “These are generally considered to be among the most troublesome symptoms by [patients with] advanced PD,” observed Werner Poewe, MD, and Philipp Mahlknecht, MD, PhD, of the Department of Neurology at the Medical University of Innsbruck in Austria.

Poewe and Mahlknecht related the dyskinesias to an on-off cycle with on-period chorea, biphasic dyskinesias, and off-period dystonias that are often painful. Although severe, disabling dyskinesias are less frequent, but they do require medical attention. Milder forms of dyskinesia are more frequent but generally do not require changes in treatment, Poewe and Mahlknecht suggested, “if other components of motor function are adequately maintained.”

The risk of levodopa-induced motor complications has previ- ously given rise to debate about withholding levodopa therapy until required in later PD, particularly in patients younger than 70 years, Poewe and Mahlknecht noted, with the hope that these adverse effects might also be delayed. That position is supported by the association of levodopa-induced motor complications with a cumulative amount of levodopa, as well as higher daily doses (≥400 mg and/or >4 mg/kg). However, an association exists with longer duration of PD at the initiation of levodopa and with early-onset PD.

In a recent Viewpoint column in JAMA Neurology, Jorik Nonnekes, MD, PhD, of the Radboud University Medical Centre; Donders Institute for Brain, Cognition and Behaviour; Department of Rehabilitation, in Nijmegen, the Netherlands, and colleagues suggested that freezing of gait (FOG) might also be a manifestation of levodopa treatment and a reflection of the peak and valley levels from traditional levodopa regimens.

“It is accepted that long-term levodopa treatment, possibly because of its pulsatile administration, results in loss of compensatory postsynaptic dopaminergic receptor upregulation and maladaptive plasticity of the striatum via influence on physiological forms of synaptic plasticity,” Nonnekes and colleagues wrote.

They posited that FOG may reflect levodopa-induced aberrant plasticity, with increased thresholds of postsynaptic receptors within the motor circuitry connecting the striatum, premotor area, and supplementary motor area, necessitating higher dopamine concentrations for activation. “In the off-medication state, it is more difficult to overcome the higher-than-normal stimulation thresholds within the motor circuitry, so FOG is typically more severe in this state than the on-state,” Nonnekes and colleagues wrote.

 Although increasing levodopa dosage would initially meet the higher threshold, they suggested, over the long term, the higher dosage will further stimulate maladaptive plasticity, producing higher thresholds and greater FOG severity.

Arguing against delaying levodopa until later stages of PD to avoid motor complications, however, Poewe and Mahlknecht pointed out that delaying the treatment, particularly with the need to start with

a higher dosage for more severe symptoms, is generally associated with a shortened period of therapeutic effect before motor complications begin.

 “Therefore, the current common approach is to introduce levodopa as soon as needed to maintain good symptom control

At the onset of response oscillations and levodopa-induced motor complications, practitioners must manage the pharmacological regimen to provide more continuous and reliable dopaminergic drug delivery.2 This is typically accomplished by increasing the dosage, dividing the levodopa dosage into smaller but more frequent doses, or by modifying the pharmacokinetics of the levodopa administration.

“We believe that levodopa continues to work throughout the decades-upon-decades—long course that some patients have Parkinson disease,” Isaacson said. “That is, you do not become ‘resistant’ to levodopa. The need for taking higher doses of levodopa or doses closer together or both reflects, we think, both problems that occur in changes in the brain itself and problems that occur in its absorption through the [gastrointestinal] system,” he added.

The factors that can affect the pharmaco- kinetics and contribute to loss of levodopa effect include changes in the absorption and assimilation of the medication, according to Harsh V. Gupta, MD, of the Department of Neurology at The University of Kansas Medical Center in Kansas City, Kansas, and colleagues.

 “As the disease progresses, variations in plasma levodopa levels lead to motor fluctuations,” they wrote.

 “The common reasons behind variations in the plasma levels include delayed gastric emptying, small intestinal overgrowth, protein interaction with levodopa absorption, and limited oral bioavailability of levodopa.”

Isaacson elaborated on these pharmacokinetic and pharmaco-dynamic challenges. “This really reflects the combination of trying to replace an essential neurotransmitter like dopamine by swallowing its precursor, the circuitous route it takes and the short half-life in the bloodstream, and the difficulty with storage in the brain,” he said. “So we always look for ways of trying to adjust the timing of taking the oral [dose]. We try to use extended deliveries of levodopa, either in oral or nonoral formulations, or we look at ways of trying to make a dose begin to work quicker.”

Gupta and colleagues described a variety of formulations of levodopa or levodopa-carbidopa that circumvent or mitigate these potential barriers to maintaining optimal levels. The products—now available, in development, or currently used outside the United States&mdash;include controlled or extended-release oral formulations, orally disintegrating and inhaled formulations, and frequently dosed microtablets, as well as more invasive formulations such as intrajejunal infusion and subcutaneous injection and infusion.

Among the novel formulations is the inhaled form of levodopa, Inbrija (Acorda), approved by the FDA in 2018 for treatment of off episodes.5 Gupta and colleagues noted that in the pivotal randomized trials, self-administration during off periods led to a rapid improvement in symptoms.

Another distinctive formulation of carbidopa-levodopa is a pellet-like microtablet, currently available in Sweden. The microtablets are taken from an automatic dose dispenser, programmed with an alarm to remind patients. “The concept behind using a microtablet is to give a more frequent but decreased individual dose of levodopa, which leads to a reduction in fluctuations,” Gupta and colleagues said.

Adjuncts and Alternatives to Reduce Off Periods

In addition to modifying carbidopa-levodopa formulations to optimize drug levels, enzyme inhibition strategies are used to increase drug effect by prolonging synaptic availability of dopamine. Monoamine oxidase B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors have been used as add-on treatments to reduce off periods, as well as in levodopa-carbidopa “sparing” regimens.

Since the introduction of MAO-B and COMT inhibitors, novel formulations have also been developed to facilitate the administration and enhance the bioavailability of these products. The MAO-B inhibitor selegiline, for example, received initial FDA approval as a 10-mg oral tablet in 1989, and in 2006, the FDA approved a 1.25-mg orally disintegrating tablet, Zelapar (Valeant Pharmaceuticals), based on data demonstrating it provided similar plasma levels.

 In April 2020, the agency also approved the first once-daily dosage form of the COMT inhibitor opicapone (Ongentys; Neurocrine Biosciences) as add-on treatment to decrease off periods and increase on time without dyskinesia.

An additional approach to reduce off periods with a recently approved adjunct targets the adenosine A2a receptors, which are localized on cell bodies and terminals in the indirect striatal output pathway and are involved in development of motor fluctuations. Intermittent, pulsatile levodopa therapy leads to upregulation of A2a receptors, increasing stimulatory output and reduced motor activa- tion and contributing to the off periods in treatment response.

 receptor antagonist istradefylline (Nourianz; Kyowa Kirin) received approval

 in August 2019 as an adjunct to treat off episodes in patients with PD receiving levodopa. The FDA initially turned it away in 2008, requesting more data.

"I think we have to have more treatment strategies where we try to educate our patients to recognize the symptoms, motor and nonmotor, that they experience and to recognize fluctuations that can occur... and the types of off episodes and when they can occur," stated Stuart Isaacson, MD. 

The subsequent application to the FDA was supported by four 12-week, placebo-controlled trials that included a total of 1143 participants (NCT00456586, NCT00199407, NCT00455507, NCT00955526). “In all 4 studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time compared to patients receiving a placebo,” the FDA indicated in announcing the approval.

In their review of the clinical trials with istradefylline, Alok Singh, MD, of the Department of Pharmacology, All India Institute of Medical Sciences, Raipur in Chhattisgarh, India, and colleagues found a comparable efficacy with the COMT and MAO-B inhibitors in reducing daily off periods.

 One advantage of istradefylline over these agents, they pointed out, is that it lacks the potential drug interactions with antidepressants and many other drugs acting on the central nervous system.

If these measures fail to substantially reduce off periods, alternative dopaminergics may be useful. Apomorphine has been particularly valuable as a rescue measure. Gupta and colleagues attributed this to apomorphine acting on all dopamine receptor subtypes as well as on serotonergic and adrenergic receptors, in contrast with other dopamine agonists such as pramipexole and ropinirole, which have relatively selective affinity for the dopamine D2 receptor.

In addition to the currently available intermittent subcutaneous injection (Apokyn; US WorldMeds), the FDA recently approved 2 new acute options. In May, the agency granted approval to Sunovion Pharmaceuticals’ apomorphine sublingual film (Kynmobi), the first sublingual therapy for this indication.

 The novel delivery route is meant to avoid gastrointestinal absorption issues commonly observed in patients with PD, allowing for improvement in motor symptoms in as little as 15 minutes post dose. The new drug application was supported by data from the phase 3 CTH-300 trial (NCT02469090), in which apomorphine sublingual film demonstrated significant improvements in motor function compared with placebo. The mean change in Unified Parkinson’s Disease Rating Scale (UPDRS) part III at 30 minutes post treatment at week 12 was —11.1 points with apomorphine sublingual film compared with –3.5 points with placebo, representing a 7.6-point difference between the 2 groups (

 = .0002).12 During the maintenance phase, more patients treated with the study drug reported being fully on at 30 minutes post dose compared with those receiving placebo (

Late in 2018, the FDA approved Acorda Therapeutics’ inhaled levodopa powder, Inbrija.

 The application was supported by findings from the pivotal phase 3 SPAN-PD trial (NCT02240030), a 12-week, randomized, double-blind, placebo-controlled study in patients with mild to moderate PD experiencing off periods. The trial met its primary end point, with patients on the study drug experiencing a 9.83-point reduction on the UPDRS part III 30 minutes post dose compared with a 5.91-point reduction in the placebo group (

 = .009). Notably, onset of action was observed as early as 10 minutes post dose.

Such new delivery systems and formulations not only provide additional treatment options, Gupta and colleagues wrote, “but, in many cases, have also allowed for improved symptom control and improved quality of life for those living with PD.”

The array of therapeutic agents and formulations and the number in clinical testing are a welcome but challenging development, Isaacson indicated. “It’s both challenging [and exciting], and we’re quite lucky to have so many treatment options for people who live with Parkinson disease. I think we have to have more treatment strategies where we try to educate our patients to recognize the symptoms, motor and nonmotor, that they experience,” he said, “and to recognize fluctuations that can occur, resulting in off episodes, and the types of off episodes and when they can occur.”

To facilitate patient education and elicit details about the patient’s experience that could help to inform treatment choice, Isaacson recommended that patients keep a diary of symptoms for 2 or 3 days prior to a visit, addressing the following questions:

How long does it take for the first oral levodopa dose to begin to work?

What symptoms improve when it begins to work?

How long does the improvement last during that on period?

What symptoms begin to return at the end of a dose interval?

At what time (interval) do they take each subsequent dose?

How long does it take for each dose to work, before the symptoms improve again and the off episode ends?

“It’s a combination of educating ourselves and our patients and their caregivers about all the different treatment options,” Isaacson explained. “We have a number that are approved and a couple dozen medicines in research programs that give us great hope in trying to treat the motor and nonmotor symptoms and the fluctuations even better over time. Through shared clinical decision-making with our patients and their families and caregivers, [we can] find which option is best.”

1. Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B. Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol. 2010;9(11):1106- 1117. doi:10.1016/S1474-4422(10)70218-0 

2. Poewe W, Mahlknecht P. Pharmacologic treatment of motor symptoms associated with Parkinson disease. Neurol Clin. 2020;38(2):255-267. doi:10.1016/j.ncl.2019.12.002 

3. Nonnekes J, Bereau M, Bloem B. Freezing of gait and its levodopa paradox. JAMA Neurol. 2020;77(3):287-288. doi:10.1001/jamaneurol.2019.4006 

4. Gupta HV, Lyons KE, Pahwa R. Old drugs, new delivery systems in Parkinson’s disease. Drugs Aging. 2019;36(9):807-821. doi:10.1007/s40266-019-00682-9 

5. Drug approval package: Inbrija. FDA. Updated May 28, 2019. Accessed May 5, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209184Orig1s000TOC.cfm 

6. Valeant Pharmaceuticals receives FDA approval of Zelapar for patients with Parkinson’s disease; Zelapar significantly reduces “off” time through unique delivery mechanism. News release. Valeant Pharmaceuticals. June 15, 2006. Accessed May 5, 2020. https://www.businesswire.com/news/home/20060615005238/en/Valeant-Pharmaceuticals-Receives-FDA-Approval-Zelapar-Patients 

7. Neurocrine Biosciences announces FDA approval of once-daily Ongentys (opicapone) as an add-on treatment for patients with Parkinson’s disease experiencing “off” episodes,. News release. Neurocrine Biosciences. April 27, 2020. Accessed May 5, 2020. http://www.multivu.com/players/English/8719751-neurocrine-biosciences-ongentys/ 

8. Sahoo AK, Gupta D, Singh A. Istradefylline: a novel drug for ‘off’ episodes in Parkinson’s disease. Drug Ther Perspect. 2020;36:208-212. doi:10.1007/s40267-020-00718-w 

9. FDA approves new add-on drug to treat off episodes in adults with Parkinson’s disease. News release. FDA. August 27, 2019. Accessed May 5, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-add-drug-treat-episodes-adults-parkinsons-disease 

10. Kyowa Hakko receives not approvable letter from FDA for Istradefylline (KW-6002). News release. Kyowa Hakko Kogyo. February 28, 2008. Accessed May 5, 2020. https://www.fiercebiotech.com/biotech/kyowa-hakko-receives-not-approvable-letter-from-fda-for-istradefylline-kw-6002 

New drug classes and formulations may help hold off breakthrough activity as the research community works to optimize levodopa delivery and absorption.

Keeping Treatment Response "On" in Parkinson Disease

A platform clinical trial, an innovative design with a single master protocol and placebo control arm for multiple candidate treatments that has been used to efficiently test and successfully launch new drugs for cancer, is now being applied by the Healey Center for ALS (amyotrophic lateral sclerosis) at Massachusetts General Hospital (MGH) to expedite clinical assessment of investigational agents for the terminal neuromuscular disease.

In contrast to the more lengthy and costly process of conducting controlled clinical trials of 1 candidate drug at a time—which has yielded only 1 FDA-approved compound for ALS (edaravone) since the first (riluzole) was approved in 1995&mdash;the Healey Center announced in September 2019 that it will launch a 

 in 2020 with initially as many as 5 candidate drugs.

“As the field develops more understanding of disease pathophysiology and targets, and has a larger pipeline of treatments, the platform trial approach is a much more efficient, patient-supportive way to develop treatments,” Merit Cudkowicz, MD, MSc, director of the Healey Center, chief of neurology at MGH, and principal investigator of the platform trial, told 

The Sean M. Healey & AMG Center for ALS is named for its benefactor, then chairman and chief executive officer of the international asset management firm, Affiliated Managers Group, Inc. Within 6 months of being diagnosed with ALS in May 2018, Healey had raised approximately $40 million for the center to launch the platform trial initiative.

The Healey Center is collaborating with the network of clinical research and treatment sites in the Northeast ALS Consortium (NEALS) and working with each of the selected biotechnology firms to tailor platform trial study arms to the respective investigational products.

Bayesian statistical tools and a common control arm will facilitate the testing of multiple investigational drugs at the same time.

“We calculate that this approach cuts in half the time to finding effective treatments, lowers the number of people needed in trials by one-third, and increases participants receiving active treatment by two-thirds,” Cudkowicz said.

Cudkowicz and colleagues designed the platform trial and selected the most promising candidate products from proposals received from biotechnology innovators whom, Cudkowicz relayed in a previous interview, “have great ideas but not deep pockets.”

The Healey ALS Platform Trial learns from successful cancer drug studies to identify and accelerate new treatments for the devastating disease.

Kenneth Bender, PharmD, MA

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