News

SODIUM PHENYLBUTYRATE-TAURUSODIOL TRIAL SHOWS BENEFIT IN ALS

The Centaur phase II/III trial funded by Amylyx Pharmaceuticals and others showed that the oral drug combination of sodium phenylbutyrate and the supplement taurusodiol (TUDCA) slowed functional decline in patients with ALS compared to placebo. The difference was around 30% over 6 months. (Paganoni S et al. N Engl J Med 2020;383:919-930.) Following an extension phase, it was found that participants who received the study drug lived a median of 6.5 months longer over 3 years. (https://news.harvard.edu/gazette/story/2020/10/new-drug-prolongs-als-patient-survival-in-trial/).

So far, the FDA has not approved the drug for use.  It is undergoing additional study and review.

CLINICAL RESEARCH IN OUR CENTER

Clinical Drug Trials

Healey Platform Studies

Our Center is now participating in these studies. See

The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS. This trial is designed as a perpetual platform trial. This means that there is a single Master Protocol dictating the conduct of the trial. The HEALEY ALS Platform Trial Master Protocol is registered as NCT04297683.

Once a participant enrolls into the Master Protocol and meets all eligibility criteria, the participant will be eligible to be randomized into any currently enrolling regimen. All participants will have an equal chance of being randomized to any currently enrolling regimen.

If a participant is randomized to Regimen E SLS-005 - Trehalose, the participant will complete a screening visit to assess additional Regimen E eligibility criteria. Once Regimen E eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active SLS-005 or matching placebo.

Regimen E will enroll by invitation, as participants may not choose to enroll in Regimen E. Participants must first enroll into the Master Protocol and be eligible to participate in the Master Protocol before being able to be randomly assigned to Regimen E.

For a list of enrolling sites, please see the HEALEY ALS Platform Trial Master Protocol under NCT04297683.

Studies to Advance Understanding of ALS with the goal of developing better treatment: Genetics, other biomarkers, and tissue banking

Making Stem Cells from Skin

In a select number of patients, skin biopsies are taken to induce formation of stem cells (IPS), and these cells are made into motor neurons by Drs. Gleixner and Donnelly or Carlisle in the Live Like Lou Center for ALS Research. The cell lines can be studied for disease features and potentially future drug screening

Live Like Lou Center for ALS Research at the University of Pittsburgh Brain Institute.  The Live-Like-Lou Center for ALS Research was created in February 2015 following a $2.5 million dollar pledge by LiveLikeLou.org via the Pittsburgh Foundation. Live Like Lou was founded by Neil and Suzanne Alexander.  The University of Pittsburgh matched the contribution as part of an effort to raise $10 million dollars for this new research center.  The former University of Pittsburgh Center for ALS Research has been folded into the Live Like Lou Center for ALS Research, and the MDA/ALS Center is a clinical arm of this extensive research effort. 

In particular, we work closely with Christopher Donnelly, PhD and Amanda Gleixner, PhD whose laboratory https://www.isb.pitt.edu/people/faculty/christopher-donnelly-phd is focused on RNA metabolism, protein trafficking in motor neurons, and abnormal protein collections in ALS, and Dr. Gleixner directs the Stem Cell Core for the Brain Institute.

New Gene Discoveries.  Mutations in at least 33 genes are known to cause ALS.  The most important remains the one due to a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on chromosome 9p. This mutation is associated with up to 40% of cases of familial ALS (fALS). In some families, children developed onset of symptoms 7 years earlier than their parents. Either frontotemporal dementia (FTD) or motor neuron disease (MND) occurs in affected families. Some patients had psychosis with prominent delusions and hallucinations. It is still not certain as to how the C9ORF72 mutation causes motor neuron degeneration. There have been numerous reports of this gene and its presence in various populations. In the US, it is seen in about 10% of patients with "sporadic" ALS. 

C9ORF72 and SOD1 mutations account for about half of all cases of familial ALS.

The genetic causes of ALS are shown in the table below:

ALS Type
Chromosome Location
Gene
% of familial ALS
ALS 1
21q
SOD1
20%
ALS 2 (AR) juvenile
2q33.1
Alsin
 Rare
ALS 3
18q21
Unknown
Rare
ALS 4 juvenile
9q
SETX
Rare (motor neuropathy +)
ALS 5 (AR)
15q15.1-q21.1
SPG11
Rare
ALS 6
16q
FUS
4%
ALS 7
20p13
Unknown
Rare
ALS 8
20q
VAPB
Rare
ALS 9
14q
ANG
Rare
ALS 10
1p
TDP43
1-4%
ALS 11
6q
FIG4
Rare
ALS 12 (AR)
10p
OPTN
Rare
ALS 13
12q
ATXN2
Rare
ALS 14
9p
VCP
Unknown
ALS 15 (X)
Xp11.21
UBQLN2
Rare
ALS 16
9p13
SIGMAR1
Rare
ALS 17
3p12.1
CHMP2B
Rare
ALS 18
17p
PFN1
Rare
ALS 19
2q33.3-q34
ERBB4
Rare
ALS 20
12q13.1
HNRNPA 1
Rare
ALS 21
5q31.2
MATR3
Rare
ALS 22
2q35
TUBA4A
Rare
ALS 23
10q22.3
ANXA11
Rare
ALS 24
4q33
NEK1
Susceptibility?
ALS 25
12q13.3
KIF5A
Susceptibility?
ALS 26
2p13.3
TIA1
Rare
ALS FTD1
9p21.2
C9orf72
23-30%
ALS FTD2
22q11.23
CHCHD10
Rare

See http://alsod.iop.kcl.ac.uk/ for details.

Mutations in genes like NEK1, C21ORF72, TBK1, and SCFD appear to either cause or increase the risk of getting ALS. (N Engl J Med 2017;377:162-172).  Last, we were part of a team that discovered a mutation in TIA1 as a cause of ALS26. (Neuron. 2017 Aug 16;95(4):808-816. e9. doi: 10.1016/j.neuron.2017.07.025)

What else is new in ALS? 

ALS can be diagnosed earlier using the newer GOLD COAST CRITERIA. The Gold Coast criteria require (1) progressive motor impairment documented by history or repeated clinical assessment, preceded by normal motor function; (2) presence of upper motor neuron (UMN) and lower motor signs (LMN) in at least 1 body region (with UMN and LMN dysfunction noted in the same body region if only one body region is involved) OR LMN dysfunction alone in at least 2 body regions; and (3) investigations excluding other disease processes.   Link to
https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-021-002532#:~:text=The%20Gold%20Coast%20criteria%20for,if%20only%20one%20body%20region

Elevated neurofilament levels can be supportive evidence, though the current diagnosis does not require these studies, and neurofilament has not yet been accepted as a diagnostic feature of ALS.

It is increasingly recognized that cognitive problems are much more common in ALS than was known previously. Although only 10% have full-blown dementia, many patients have milder cognitive problems. In advanced ALS, the vast majority of patients will have cognitive changes (Neurology 2018). Caregivers need to be aware that these changes can affect decision-making and patient-caregiver interactions.

There is also a higher (3-10X) incidence of psychiatric disorders in families of ALS patients. The disorders include schizophrenia, obsessive compulsive disorder, and autism. (JAMA Neurol Dec 2017).

In one genetic form of ALS (C9ORF72), it was shown that a blood and spinal fluid biomarker, neurofilament light, starts to rise 1-3 years before patients become symptomatic. (Ann Neurol 2018;84:130-139)

We also now know that about 13% of patients with ALS have other “atypical features” suggesting involvement of other parts of the nervous system and explaining some of these unusual occurrences.  These abnormalities could include problems with eye movement, coordination, tremor, slow limb movement, rigidity, excessive sweating, loss of taste and/or smell.  Emotional lability (pseudobulbar affect) is more common in this group of patients as well.  (McCluskey L et al.  ALS-Plus syndrome: non-pyramidal features in a large ALS cohort.  J Neurol Sci 2014;345:118-124). 

Urinary disturbances may be more common than previously thought in patients with ALS.  In one study, up to 40% of patients with ALS had symptomatic urinary disorders.  Although some of these problems may be related to ALS, the use of medications could also predispose patients.  Medications such as those used to treat spasticity or depression can lead to urinary symptoms.  (Lopes de Carvalho ML et al.  Urinary disorders in amyotrophic lateral sclerosis.  Amyotroph Lateral Scler 2011;12:352-355.  Nübling GS et al.  Increased prevalence of bladder and intestinal dysfunction in amyotrophic lateral sclerosis.  Amyotroph Lateral Scler Frontotemporal Degener 2014;15:174-179). 

Deep venous thrombosis (blood clots) in the legs leading to pulmonary embolism or clots in the lungs has been a concern in patients with ALS.  In one study, 4 of 50 patients developed blood clots in the legs over a year.  One of these developed pulmonary emboli.  Patients at the greatest risk appear to have onset of disease in the legs and being wheelchair bound.  Unfortunately, we do not know how to prevent blood clots safely in ALS patients and whether or not patients should be routinely screened for blood clots.  (Glad M et al.  Venous thromboembolism in amyotrophic lateral sclerosis.  Neurology 2014;82:1674-1677).