Celebrating LGMD Awareness Day: Advances and Future Directions

On September 30, 2023, those across the globe come together to celebrate the ninth annual Limb-Girdle Muscular Dystrophy (LGMD) Awareness Day, an effort to raise awareness about a group of rare and progressive neuromuscular disorders. LGMDs, estimated in about 2 in every 100,000 individuals, are a group of diseases that cause weakness and wasting of the muscles in the arms and legs.¹

LGMD Disease Differences and Influence of Genetics

In the early stages of LGMD, affected individuals may have an unusual walking gait, such as waddling or walking or walking on the balls of their feet, and may also have difficulty running. Each of these disorders share common features of proximal limb girdle weakness and hip shoulder girdle weakness but vary in the rate of progression and potential loss of ambulation later in life.

“Onset of weakness is typically after 2 years of age, which helps to distinguish it from some of the other congenital muscular dystrophies, where symptoms would precede that,” Carla Zingariello, DO, a pediatric neurologist and assistant professor at the University of Florida, told NeurologyLive^®. “Cardiac involvement, respiratory involvement are quite variable, depending on the genetic subset.”

There are 33 forms of LGMD, each classified by the genetic mutations that cause them. LGMD subtypes with a “1” in the nomenclature, such as LGMD1A, LGMD1B, and LGMD1C, have an autosomal dominant pattern where only 1 parent needs to transmit the mutated gene for the disorder to be inherited. In contrast, subtypes with a “2” in the nomenclature have an autosomal recessive inheritance pattern, in which both parents are carriers of the faulty gene.²

“Now that we’ve identified various genetic subtypes, that certainly can help us with prognosis and knowing to some degree what to expect in terms of progression of symptoms, although that can be highly variable,” Zingariello added.

The advent of next generation sequencing approaches has accelerated the pace of discovery of new LGMD genes. Nearly 20 years ago, the list included 16 loci. Research has shown that autosomal dominant forms of LGMD are more adult-onset and are milder, because affected parents are usually in good health at reproductive age. Autosomal recessive forms of LGMD are much more common, having a cumulative prevalence of 1:15,000 with some differences among countries, depending on the carrier distribution and the degree of consanguinity.³

Over the years, the detail in LGMD definitions has gotten to the point where some consider it “too complex.” In a 2014 updated paper on the genetic bases of LGMDs, coauthors Vincezo Nigro, MD, and Marco Savarese, PhD, tried to reorganize the different genes by traditional nomenclature; however, noted that there were only a few letters available for the autosomal recessive forms. “The next forms will be LGMD2X, LGMD2Y, and LGMD2Z,” they wrote. “We propose, after the LGMD2Z form, the acronyms LGMD2AA, LGMD2AB, LGMD2AC, etc. to avoid renaming consolidated definitions thereby generating even higher confusion.”³

Between the different LGMD subtypes, mutations in the TTN or DYSF gene have also been associated with distal myopathic phenotypes. Several of the LGMDs are dystroglycanopathies that are also associated with a group of congenital muscular dystrophy syndromes, including Fukuyama congenital muscular dystrophy, Muscle-Eye-Brain disease, and Walker-Warburg-Syndrome. These dystroglycanopathies were grouped together due to the recognition that mutations in at least 18 different genes all interfere with the glycosylation of a-dystroglycan, and thus dystroglycan’s function as a matrix receptor.⁴

Managing LGMD

As the field continues to search for its first disease-modifying therapy, patient quality of life has been improved through a number of medical management strategies. Physical and occupational therapy programs, which have increasingly grown across the US in recent years, remain a mainstay in the LGMD treatment paradigm. Occupational therapy specifically allows for greater movement in the joints and future prevention of contractures.

For patients with LGMD, cardiac muscle may be affected, manifesting as hypertrophic/dialed cardiomyopathy and cardiac dysrhythmias. Examination, electrocardiogram, and structural heart studies with echocardiography or cardiac MRI have been used to guide clinicians when treating these complications.

Despite patients’ respiratory function decline, the introduction of noninvasive ventilation and other devices has helped patients in this area. In addition, to address issues with inadequate intake and swallowing problems, clinicians have reverted to altering food consistency or using a chin tuck maneuver, or placement of a feeding tube. Weight-reduction or weight-stabilization diets may be recommended for some patients as being markedly overweight puts increased stress on already-weakened muscles.⁵

Due to the heterogeneity of these disorders, developing effective therapeutics remains a significant challenge. Inheritance, clinical epidemiology, gene defects, protein expression, and pathogenesis account for the relative paucity of targeted therapies. For LGMD, most treatment now is supportive and multidisciplinary, thus requiring a team of specialists in pulmonology, cardiology, rehabilitative services, and nutrition, among others. Thus far, pharmacologic approaches to improve LGMDs, including corticosteroids have been scanty and unsubstantiated; growth hormone, myoblast transfer, and myostatin inhibition have not been found to be effective.⁶

Advancing Therapeutic Options for LGMD

In recent years, the interest from research and industry leaders has brought a new hope to the community, Zingariello told NeurologyLive. While we’re not at the point of newborn screening for these disorders, Zingariello noted that the most recent approval of SRP-9001 (Elevidys; Sarepta Therapeutics), the first gene therapy for Duchenne muscular dystrophy, may open the door for potential screening of creatine kinase (CK) levels, which could incidentally discover cases of LGMD.

“Should those therapies become available, we’d want the option to treat at a younger age, and thus limit risk of developing further symptoms,” she added. “In the next 5 to 10 years, I could see some of these therapies coming to commercialization. Perhaps ribitol, perhaps gene therapy. I certainly anticipate additional gene therapy trials for other subtypes of limb girdle muscular dystrophy, so there’s a lot to be excited about in this population.”

Ribitol, or adonitol, is a crystalline pentose alcohol formed by the reduction of ribose. Previous preclinical research demonstrated that the agent increases levels of α-dystroglycan, or matriglycan, in cells in vitro and in Fukutin-related protein (FKRP)-P448LL mutant mouse model through drinking water administration.⁷

BBP-418, BridgeBio Pharma’s formulation of ribitol, demonstrated an ability to address the root cause of LGMD type 2i (LGMD2i) in a phase 2 study. The data, published in March 2022, showed that treatment with the agent resulted in a statistically significant decline of 70% in CK, a widely used biomarker of muscle injury, and an average increase of 0.21 (43%) in the ratio of glycosylated alpha-dystroglycan. Only 1 of the 12 participants included did not achieve at least a 50% reduction in CK, and 75% of the cohort reached at least twice the normal range. The company has already announced dosing in a phase 3 study, FORTIFY (NCT05775848), that will continue to assess the effects of BBP-418 as a potential treatment for LGMD2i.⁸

“With any rare disorder, there are small numbers, although some of these subtypes are more common than others,” Zingariello noted. “We hope that this leads to more phase 3 trials and commercial product being available.”

Potential of Gene Therapy

Once considered a phenomenon, advances in preclinical research and genetic testing have opened the door for gene therapy as a potential option to treat certain rare neurological disorders with mutated genes. Much of this momentum was carried by the approval of onasemnogene abeparvovec (Zolgensma; Novartis) in 2019, the first gene therapy for children with spinal muscular atrophy, a rare but fatal neuromuscular disorder.⁹

As more LGMD subtypes are discovered, the potential for gene therapy only grows. Industry leaders have already started to take notice. Sarepta Therapeutics, drug makers of SRP-9001, have several ongoing trials assessing gene therapy candidates in LGMD disorders. One study (NCT05906251) assesses the impact of SRP-6004 in ambulatory patients with LGMD Type 2B/R2 while another will look at the first-in-human application of autologous gene-edited muscle stem cells (GenPHSats-bASKet; NCT05588401) in orphan disease LGMD.^10,11

Over the years, the use of viral vector gene therapy approaches have become more popular as well, with potential benefits in LGMD. In a 2022 mouse model study of LGMD2B, the use of low dose, lived-targeted, human acid sphingomyelinase gene therapy vector restored ability of injured muscle fibers and thus resulted in reduced muscle degeneration and enhanced functioning of the diseased muscle. The study, published in the Journal of Clinical Investigation, described a new approach that avoids the need for packaging a large gene, like dysferlin, or giving a large vector dose to target the muscles, which are bottlenecks faced in ongoing gene therapy efforts aimed at muscular dystrophies.¹²

A promising phase 1/2 trial (NCT0523049) assessing AskBio’s AB-1003, a novel investigational FKRP gene replacement therapy, was initiated in Q2 2023 with the first patient dosing. Otherwise known as the LION-CS101 trial, the double-blind, placebo-controlled study featured individuals with a genetic confirmation of LGMD2I/R9 who will be given a single intravenous infusion of AB-1003 or placebo. Recruitment for the trial remains ongoing, with an expected cohort of 14 individuals.¹³

For more information on the current ongoing trials in LGMD, including those assessing gene-based approaches, visit TREAT-NMD’s website: https://treat-nmd.org/resources-support/research-overview/about-clinical-research/current-trials-in-lgmd/

REFERENCES
1. Limb Girdle Muscular Dystrophy. Medline Plus. Updated September 9, 2019. Accessed September 29, 2023. https://medlineplus.gov/genetics/condition/limb-girdle-muscular-dystrophy/
2. LGMD facts. LGMD Awareness Foundation. Updated May 5, 2023. Accessed September 29, 2023. https://www.lgmd-info.org/wp-content/uploads/2021/05/List-of-LGMD-Facts.pdf
3. Nigro V, Savarese M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014;33(1):1-12. PMID: 24843229
4. Angelini C. LGMD: Identification, description and classification. Acta Myol. 2020;39(4):207-217. doi:10.36185/2532-1900-024
5. Limb-Girdle Muscular Dystrophy: Medical Management. Muscular Dystrophy Association. Accessed September 29, 2023. https://www.mda.org/disease/limb-girdle-muscular-dystrophy/medical-management
6. Pozsgai E, Griffin D, Potter R, et al. Unmet needs and evolving treatment for limb girdle muscular dystrophies. Future Medicine. 2021;11(5). Doi:10.2217/nmt-2020-0066
7. Wu B, Drains M, Shah SN, et al. Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model. ProS One. 2022;17(12):e0278482
8. BridgeBio announces positive phase 2 data for Limb-girdle muscular dystrophy type 2i (LGMD2i). News release. BridgeBio Pharma. March 14, 2022. Accessed September 29, 2022. https://www.globenewswire.com/en/news-release/2022/03/14/2402463/0/en/BridgeBio-Pharma-Announces-Positive-Phase-2-Data-for-Limb-girdle-Muscular-Dystrophy-Type-2i-LGMD2i.html
9. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. May 24, 2019. Accessed September 29, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease
10. A Gene Transfer Study to Evaluate the Safety, Tolerability and Efficacy of SRP-6004 in Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2B/R2 (LGMD2B/R2, Dysferlin [DYSF] Related). Clinicaltrials.gov. Updated June 15, 2023. Accessed September 29, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05906251
11. Evaluating Safety and Efficacy of Autologous Gene-edited Muscle Stem Cells (GenPHSats-bASKet). clinicaltrials.gov. Updated August 3, 2023. Accessed September 29, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05588401
12. Bittel DC, Sreetama SC, Chandra G, et al. Screted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy. J Clin Invest. 2022;132(1):e141295. Doi:10.1172/JCI141295
13. AskBio Announces First Patient Dosed in Phase 1 / Phase 2 Trial of AB-1003 Gene Therapy for Limb-Girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9). News release. AskBio. August 3, 2023. Accessed September 29, 2023. https://www.prnewswire.com/news-releases/askbio-announces-first-patient-dosed-in-phase-1–phase-2-trial-of-ab-1003-gene-therapy-for-limb-girdle-muscular-dystrophy-type-2ir9-lgmd2ir9-301892324.html