Leukodystrofia metachromatyczna – Rokowania, prognozy i postęp choroby

Leukodystrofia metachromatyczna
Rokowania, prognozy i postęp choroby

Leukodystrofia metachromatyczna (MLD) to postępująca choroba spichrzeniowa lizosomów, prowadząca do demielinizacji ośrodkowego i obwodowego układu nerwowego. Rokowanie jest niekorzystne i zależy od wieku wystąpienia objawów oraz stopnia niedoboru enzymu arylosulfatazy A (ARSA). Postać późnoniemowlęca, stanowiąca 50-60% przypadków, manifestuje się do 30. miesiąca życia i charakteryzuje się szybkim przebiegiem, z medianą przeżycia 5-6 lat od diagnozy. Postać młodzieńcza rozwija się między 3. a 16. rokiem życia, z wolniejszą progresją i przeżyciem 10-20 lat, natomiast postać dorosła pojawia się w 4.-5. dekadzie życia, z przeżyciem 20-30 lat od wystąpienia objawów. Wszyscy pacjenci doświadczają stopniowego pogorszenia funkcji psychomotorycznych, prowadzącego do całkowitego paraliżu i śmierci, najczęściej z powodu infekcji, takich jak zapalenie płuc.

Prognozy w Leukodystrofii Metachromatycznej

Oczekiwana długość życia w różnych postaciach MLD
Przebieg naturalny choroby
Wpływ metod terapeutycznych na rokowanie
Znaczenie wczesnej diagnostyki
Perspektywy na przyszłość
Kolejne rozdziały

Prognozy w Leukodystrofii Metachromatycznej

Leukodystrofia metachromatyczna (MLD) to choroba spichrzeniowa lizosomów charakteryzująca się uszkodzeniem osłonki mielinowej otaczającej większość włókien nerwowych ośrodkowego i obwodowego układu nerwowego. Rokowanie w tej chorobie jest niekorzystne, ponieważ ma ona charakter postępujący, co oznacza, że objawy z czasem nasilają się i rozprzestrzeniają, prowadząc w końcu do całkowitej utraty funkcji mięśniowych i umysłowych, a ostatecznie do śmierci.¹²

Oczekiwana długość życia w różnych postaciach MLD

Oczekiwana długość życia w MLD zależy głównie od wieku, w którym pojawiają się pierwsze objawy choroby, oraz od typu mutacji i stopnia niedoboru enzymu ARSA (arylosulfataza A). Istnieje hipoteza, że im niższa aktywność enzymu, tym wcześniej choroba się manifestuje, choć związek ten nie został jeszcze w pełni udowodniony.³⁴

Postać późnoniemowlęca – najczęstsza forma choroby (50-60% wszystkich przypadków), objawia się do 30. miesiąca życia. Charakteryzuje się szybką progresją, a śmierć w przypadku braku terapii następuje zwykle w ciągu kilku lat od wystąpienia objawów, typowo w ciągu 5-6 lat od diagnozy.⁵⁶
Postać młodzieńcza – rozwija się między 3. a 16. rokiem życia i charakteryzuje się mniej nasilonymi objawami klinicznymi w porównaniu z formą późnoniemowlęcą. Progresja jest wolniejsza, a śmierć zwykle następuje 10-20 lat po diagnozie.⁷⁸
Postać dorosła – objawy mogą się pojawić nawet w czwartej lub piątej dekadzie życia, a pacjenci mogą żyć 20-30 lat po wystąpieniu objawów. Śmierć zwykle następuje w ciągu 6-14 lat od diagnozy.⁹¹⁰

Przebieg naturalny choroby

Wszyscy pacjenci z MLD doświadczają stopniowego pogorszenia funkcji psychomotorycznych, ostatecznie osiągając stan całkowitego paraliżu i braku reakcji na bodźce. W przypadku leczenia podtrzymującego, obejmującego założenie sondy żołądkowej do karmienia i antybiotykoterapię podczas infekcji, pacjenci mogą przeżyć w stanie wegetatywnym przez wiele lat.¹¹¹²

U pacjentów z późnoniemowlęcą postacią MLD objawy ze strony ośrodkowego układu nerwowego są często poprzedzone szybko postępującą neuropatią obwodową, charakteryzującą się niezgrabnością, osłabieniem mięśni, deficytami czuciowymi i arefleksją. Najczęstszą przyczyną śmierci jest zapalenie płuc lub inne infekcje.¹³¹⁴

Wpływ metod terapeutycznych na rokowanie

Aktualnie nie istnieje w pełni skuteczne leczenie MLD, jednak prowadzone są różne podejścia terapeutyczne, które mogą wpływać na przebieg choroby:¹⁵

Przeszczepienie krwiotwórczych komórek macierzystych (HSCT)

U pacjentów, którzy poddani zostali HSCT przed lub natychmiast po wystąpieniu objawów, choroba może się stabilizować, a tempo utraty funkcji motorycznych i poznawczych ulega spowolnieniu. Efektywność tej metody jest jednak ograniczona:¹⁶¹⁷

U pacjentów z postacią późnoniemowlęcą nie zaobserwowano korzyści dotyczących przeżycia, funkcji motorycznych czy poznawczych – choroba postępuje podobnie jak w naturalnym przebiegu.
U pacjentów z postacią młodzieńczą (szczególnie bezobjawowych lub z minimalnymi objawami) może nastąpić stabilizacja funkcji poznawczych i motorycznych, choć u innych obserwuje się dalszą progresję choroby.
HSCT wiąże się z poważnymi powikłaniami, takimi jak śmiertelność związana z leczeniem, choroba przeszczep przeciwko gospodarzowi (GVHD) oraz konieczność ponownej transplantacji.
Stabilizacja ciężkości choroby obserwowana w badaniu MRI (zmniejszenie demielinizacji OUN) nie oznacza stabilizacji choroby nerwów obwodowych, a wpływ HSCT na rozwój neuropatii obwodowej pozostaje kontrowersyjny.

Terapia genowa i kombinowana terapia genowo-komórkowa

Obiecujące wyniki uzyskano dzięki terapii genowej wykorzystującej wektory oparte na różnych serotypach wirusów związanych z adenowirusami, a także przy użyciu mezenchymalnych komórek macierzystych i kombinowanej terapii genowo-komórkowej.¹⁸

Szczególnie obiecujące są wstępne wyniki dotyczące leczenia atidarsagenem autotemcelem (arsa-cel):¹⁹²⁰²¹

Większość pacjentów z postacią późnoniemowlęcą i wczesną młodzieńczą leczonych arsa-cel wykazuje prawidłowy rozwój, zachowanie lub wolniejszą progresję funkcji motorycznych i poznawczych, w przeciwieństwie do szybkiego spadku obserwowanego u nieleczonych pacjentów.
Zaobserwowano korzyść w zakresie przeżycia dla arsa-cel w porównaniu z naturalnym przebiegiem choroby i HSCT u pacjentów z postacią późnoniemowlęcą.
Pacjenci z postacią późnoniemowlęcą i wczesną młodzieńczą leczeni arsa-cel mieli lepsze funkcje motoryczne i poznawcze w porównaniu z HSCT, które ma ograniczony wpływ na spowolnienie spadku funkcji motorycznych i poznawczych.
W okresie około 3 lat obserwacji nie odnotowano zgonów z powodu progresji choroby u pacjentów z postacią późnoniemowlęcą i tylko u 15% pacjentów z wczesną postacią młodzieńczą leczonych arsa-cel, w porównaniu do 50% pacjentów z postacią późnoniemowlęcą i 20% pacjentów z postacią młodzieńczą leczonych HSCT, którzy zmarli w ciągu roku.

Znaczenie wczesnej diagnostyki

Wprowadzenie diagnostyki prenatalnej i badań przesiewowych noworodków może zwiększyć skuteczność terapii, ponieważ efektywność leczenia znacząco spada po wystąpieniu objawów. Szczególnie korzystne wyniki obserwuje się u pacjentów leczonych przed pojawieniem się objawów (w stanie przedobjawowym).²²²³

Perspektywy na przyszłość

Pomimo obiecujących wyników terapii genowej, konieczne są dalsze badania, aby potwierdzić jej długoterminową skuteczność. Obecne dane opierają się na wynikach badań nierandomizowanych, a dalsze obserwacje pacjentów leczonych atidarsagenem autotemcelem są w toku. Terapia ta wydaje się być dobrze tolerowana, przy czym obserwowane działania niepożądane wynikają głównie z procedur przedleczniczych (leczenia kondycjonującego) i samej progresji choroby MLD.²⁴

Podsumowując, rokowanie w leukodystrofii metachromatycznej pozostaje poważne, szczególnie w przypadku postaci późnoniemowlęcej, ale nowe metody terapeutyczne, zwłaszcza terapia genowa, dają nadzieję na poprawę jakości i długości życia pacjentów, szczególnie gdy są zastosowane na wczesnym etapie choroby lub przed wystąpieniem objawów.²⁵²⁶

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Materiały źródłowe

#1 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. […] The severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. […] Currently, there is no effective treatment for this disease. […] Clinical cases of bone marrow or cord blood transplantation have been reported, however the therapeutic effectiveness of these methods remains insufficient to prevent aggravation of neurological disorders. […] Encouraging results have been obtained using gene therapy for delivering the wild-type ARSA gene using vectors based on various serotypes of adeno-associated viruses, as well as using mesenchymal stem cells and combined gene-cell therapy.
#2 Metachromatic Leukodystrophy: What It Is, Causes & Symptoms
https://my.clevelandclinic.org/health/diseases/6067-metachromatic-leukodystrophy
The prognosis (outlook) for metachromatic leukodystrophy is poor. Its a progressive disease, which means the symptoms spread and/or get worse over time. People with MLD eventually lose all muscle and mental functions, which results in death. […] The life expectancy of metachromatic leukodystrophy depends on the age at which a person is first diagnosed. […] Late infantile form: Death typically happens within five to six years of diagnosis. […] Juvenile form: Progression is slower in this form of the disease. It typically results in death 10 to 20 years following diagnosis. […] Adult form: Death typically happens within six to 14 years after diagnosis.
#3 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
The clinical manifestations and a degree of neurodegeneration in MLD are diverse and depend on the type of mutation and the level of enzyme deficiency. […] It is hypothesized that the lower the enzyme activity the earlier the disease manifests itself, however such association has yet to be fully demonstrated. […] The most common form is the late infantile, which is found in 50-60% of all patients. […] Clinical manifestation of late infantile MLD begins up to 30 months of age. […] The juvenile form develops between the ages of 3 and 16 and is characterized by a less pronounced clinical manifestation in comparison with the late infantile form. […] In late infantile and early juvenile forms, a rapid disease progression is observed and in the absence of therapy death occurs within a few years since the disease onset.
#4 Metachromatic Leukodystrophy: What It Is, Causes & Symptoms
https://my.clevelandclinic.org/health/diseases/6067-metachromatic-leukodystrophy
The prognosis (outlook) for metachromatic leukodystrophy is poor. Its a progressive disease, which means the symptoms spread and/or get worse over time. People with MLD eventually lose all muscle and mental functions, which results in death. […] The life expectancy of metachromatic leukodystrophy depends on the age at which a person is first diagnosed. […] Late infantile form: Death typically happens within five to six years of diagnosis. […] Juvenile form: Progression is slower in this form of the disease. It typically results in death 10 to 20 years following diagnosis. […] Adult form: Death typically happens within six to 14 years after diagnosis.
#5 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
The clinical manifestations and a degree of neurodegeneration in MLD are diverse and depend on the type of mutation and the level of enzyme deficiency. […] It is hypothesized that the lower the enzyme activity the earlier the disease manifests itself, however such association has yet to be fully demonstrated. […] The most common form is the late infantile, which is found in 50-60% of all patients. […] Clinical manifestation of late infantile MLD begins up to 30 months of age. […] The juvenile form develops between the ages of 3 and 16 and is characterized by a less pronounced clinical manifestation in comparison with the late infantile form. […] In late infantile and early juvenile forms, a rapid disease progression is observed and in the absence of therapy death occurs within a few years since the disease onset.
#6 Metachromatic Leukodystrophy: What It Is, Causes & Symptoms
https://my.clevelandclinic.org/health/diseases/6067-metachromatic-leukodystrophy
The prognosis (outlook) for metachromatic leukodystrophy is poor. Its a progressive disease, which means the symptoms spread and/or get worse over time. People with MLD eventually lose all muscle and mental functions, which results in death. […] The life expectancy of metachromatic leukodystrophy depends on the age at which a person is first diagnosed. […] Late infantile form: Death typically happens within five to six years of diagnosis. […] Juvenile form: Progression is slower in this form of the disease. It typically results in death 10 to 20 years following diagnosis. […] Adult form: Death typically happens within six to 14 years after diagnosis.
#7 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
The clinical manifestations and a degree of neurodegeneration in MLD are diverse and depend on the type of mutation and the level of enzyme deficiency. […] It is hypothesized that the lower the enzyme activity the earlier the disease manifests itself, however such association has yet to be fully demonstrated. […] The most common form is the late infantile, which is found in 50-60% of all patients. […] Clinical manifestation of late infantile MLD begins up to 30 months of age. […] The juvenile form develops between the ages of 3 and 16 and is characterized by a less pronounced clinical manifestation in comparison with the late infantile form. […] In late infantile and early juvenile forms, a rapid disease progression is observed and in the absence of therapy death occurs within a few years since the disease onset.
#8 Metachromatic Leukodystrophy: What It Is, Causes & Symptoms
https://my.clevelandclinic.org/health/diseases/6067-metachromatic-leukodystrophy
The prognosis (outlook) for metachromatic leukodystrophy is poor. Its a progressive disease, which means the symptoms spread and/or get worse over time. People with MLD eventually lose all muscle and mental functions, which results in death. […] The life expectancy of metachromatic leukodystrophy depends on the age at which a person is first diagnosed. […] Late infantile form: Death typically happens within five to six years of diagnosis. […] Juvenile form: Progression is slower in this form of the disease. It typically results in death 10 to 20 years following diagnosis. […] Adult form: Death typically happens within six to 14 years after diagnosis.
#9 Metachromatic leukodystrophy | Myriad ForesightÂ® Carrier Screen
https://myriad.com/womens-health/diseases/metachromatic-leukodystrophy/
All individuals with MLD will experience mental and motor deterioration, eventually reaching a state of paralysis and unresponsiveness. […] Most children with the infantile form of MLD die by the age of 10. Those with the juvenile form typically develop symptoms between the ages of 3 and 14 and can live 10 to 20 years after the onset of symptoms. The adult form of the disease is more variable, but affected adults may not develop symptoms until their forties or fifties and can live 20 to 30 years after symptoms begin. Death most commonly occurs from pneumonia or other infections.
#10 Metachromatic Leukodystrophy: What It Is, Causes & Symptoms
https://my.clevelandclinic.org/health/diseases/6067-metachromatic-leukodystrophy
The prognosis (outlook) for metachromatic leukodystrophy is poor. Its a progressive disease, which means the symptoms spread and/or get worse over time. People with MLD eventually lose all muscle and mental functions, which results in death. […] The life expectancy of metachromatic leukodystrophy depends on the age at which a person is first diagnosed. […] Late infantile form: Death typically happens within five to six years of diagnosis. […] Juvenile form: Progression is slower in this form of the disease. It typically results in death 10 to 20 years following diagnosis. […] Adult form: Death typically happens within six to 14 years after diagnosis.
#11 Metachromatic leukodystrophy | Myriad ForesightÂ® Carrier Screen
https://myriad.com/womens-health/diseases/metachromatic-leukodystrophy/
All individuals with MLD will experience mental and motor deterioration, eventually reaching a state of paralysis and unresponsiveness. […] Most children with the infantile form of MLD die by the age of 10. Those with the juvenile form typically develop symptoms between the ages of 3 and 14 and can live 10 to 20 years after the onset of symptoms. The adult form of the disease is more variable, but affected adults may not develop symptoms until their forties or fifties and can live 20 to 30 years after symptoms begin. Death most commonly occurs from pneumonia or other infections.
#12 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
However, with supportive treatment, including a gastric tube insertion for feeding and antibiotic therapy during infections, patients could survive in a vegetative state for years. […] In patients with a late infantile MLD form CNS symptoms are often preceded by rapidly progressive peripheral neuropathy, which is characterized by clumsiness, muscle weakness, sensory deficits and areflexia. […] In patients who received HSCT before or immediately after the symptom onset, the disease stabilizes and the rate of loss of gross motor and cognitive functions decreases. […] However, stabilization of disease severity observed on MRI (reduction of CNS demyelination) does not mean stabilization of peripheral nerve disease and the effect of HSCT on the development of peripheral neuropathy remains controversial. […] The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Thus, gene and gene-cell therapy have so far shown safety and efficacy in clinical trials.
#13 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
However, with supportive treatment, including a gastric tube insertion for feeding and antibiotic therapy during infections, patients could survive in a vegetative state for years. […] In patients with a late infantile MLD form CNS symptoms are often preceded by rapidly progressive peripheral neuropathy, which is characterized by clumsiness, muscle weakness, sensory deficits and areflexia. […] In patients who received HSCT before or immediately after the symptom onset, the disease stabilizes and the rate of loss of gross motor and cognitive functions decreases. […] However, stabilization of disease severity observed on MRI (reduction of CNS demyelination) does not mean stabilization of peripheral nerve disease and the effect of HSCT on the development of peripheral neuropathy remains controversial. […] The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Thus, gene and gene-cell therapy have so far shown safety and efficacy in clinical trials.
#14 Metachromatic leukodystrophy | Myriad ForesightÂ® Carrier Screen
https://myriad.com/womens-health/diseases/metachromatic-leukodystrophy/
All individuals with MLD will experience mental and motor deterioration, eventually reaching a state of paralysis and unresponsiveness. […] Most children with the infantile form of MLD die by the age of 10. Those with the juvenile form typically develop symptoms between the ages of 3 and 14 and can live 10 to 20 years after the onset of symptoms. The adult form of the disease is more variable, but affected adults may not develop symptoms until their forties or fifties and can live 20 to 30 years after symptoms begin. Death most commonly occurs from pneumonia or other infections.
#15 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. […] The severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. […] Currently, there is no effective treatment for this disease. […] Clinical cases of bone marrow or cord blood transplantation have been reported, however the therapeutic effectiveness of these methods remains insufficient to prevent aggravation of neurological disorders. […] Encouraging results have been obtained using gene therapy for delivering the wild-type ARSA gene using vectors based on various serotypes of adeno-associated viruses, as well as using mesenchymal stem cells and combined gene-cell therapy.
#16 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
However, with supportive treatment, including a gastric tube insertion for feeding and antibiotic therapy during infections, patients could survive in a vegetative state for years. […] In patients with a late infantile MLD form CNS symptoms are often preceded by rapidly progressive peripheral neuropathy, which is characterized by clumsiness, muscle weakness, sensory deficits and areflexia. […] In patients who received HSCT before or immediately after the symptom onset, the disease stabilizes and the rate of loss of gross motor and cognitive functions decreases. […] However, stabilization of disease severity observed on MRI (reduction of CNS demyelination) does not mean stabilization of peripheral nerve disease and the effect of HSCT on the development of peripheral neuropathy remains controversial. […] The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Thus, gene and gene-cell therapy have so far shown safety and efficacy in clinical trials.
#17 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
A total of 6940 titles and abstracts were retrieved from the literature searches and 26 from other sources. From these, 35 manuscripts reporting on a total of 12 studies were selected for inclusion in the review. There were no controlled multi-armed trials. However, we provide observations comparing two interventional therapies (alloHSCT and arsa-cel) and each of these to standard/supportive care (natural history). There were no benefits for survival, gross motor function and cognitive function for LI patients receiving alloHSCT, as patients experienced disease progression similar to LI natural history. For juvenile patients receiving alloHSCT, no differences in survival were observed versus natural history, however stabilisation of cognitive and motor function were reported for some patients (particularly for pre- or minimally-symptomatic LJ patients), while others experienced disease progression. Furthermore, alloHSCT was associated with severe complications such as treatment-related mortality, graft versus host disease, and re-transplantation in both LI and EJ treated patients. Most LI and EJ patients treated with arsa-cel appeared to have normal development, preservation, or slower progression of gross motor function and cognitive function, in contrast to the rapid decline observed in natural history patients. A survival benefit for arsa-cel versus natural history and versus alloHSCT was observed in LI patients. LI and EJ patients treated with arsa-cel had better gross motor function and cognitive function compared to alloHSCT, which had limited effect on motor and cognitive decline. No data has been reported for arsa-cel treatment of LJ patients.
#18 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. […] The severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. […] Currently, there is no effective treatment for this disease. […] Clinical cases of bone marrow or cord blood transplantation have been reported, however the therapeutic effectiveness of these methods remains insufficient to prevent aggravation of neurological disorders. […] Encouraging results have been obtained using gene therapy for delivering the wild-type ARSA gene using vectors based on various serotypes of adeno-associated viruses, as well as using mesenchymal stem cells and combined gene-cell therapy.
#19 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
A total of 6940 titles and abstracts were retrieved from the literature searches and 26 from other sources. From these, 35 manuscripts reporting on a total of 12 studies were selected for inclusion in the review. There were no controlled multi-armed trials. However, we provide observations comparing two interventional therapies (alloHSCT and arsa-cel) and each of these to standard/supportive care (natural history). There were no benefits for survival, gross motor function and cognitive function for LI patients receiving alloHSCT, as patients experienced disease progression similar to LI natural history. For juvenile patients receiving alloHSCT, no differences in survival were observed versus natural history, however stabilisation of cognitive and motor function were reported for some patients (particularly for pre- or minimally-symptomatic LJ patients), while others experienced disease progression. Furthermore, alloHSCT was associated with severe complications such as treatment-related mortality, graft versus host disease, and re-transplantation in both LI and EJ treated patients. Most LI and EJ patients treated with arsa-cel appeared to have normal development, preservation, or slower progression of gross motor function and cognitive function, in contrast to the rapid decline observed in natural history patients. A survival benefit for arsa-cel versus natural history and versus alloHSCT was observed in LI patients. LI and EJ patients treated with arsa-cel had better gross motor function and cognitive function compared to alloHSCT, which had limited effect on motor and cognitive decline. No data has been reported for arsa-cel treatment of LJ patients.
#20 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
Overall, this systematic review indicates that compared to NHx and HSCT, treatment with arsa-cel results in clinically relevant benefits in LI and EJ MLD patients by preserving cognitive function and motor development in most patients, and increased survival for LI patients. Nevertheless, further research is required to confirm these findings, given they are based on results from non-RCT studies. […] In LI patients, survival for atidarsagene autotemcel appeared longer than for NHx and HSCT as observed in other studies. Survival for EJ patients appeared to be similar between atidarsagene autotemcel treated, HSCT recipients and the NHx cohort. However, no LI and only 15% of EJ patients treated with atidarsagene autotemcel were observed to have died due to disease progression over about 3 years, in contrast to 50% of LI and 20% of J patients treated with HSCT within 1 year.
#21 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
Initial data on patients treated with atidarsagene autotemcel, albeit in only one trial plus EAF, showed promising results particularly when used in patients treated before symptoms appear (pre-symptomatic). This included apparent improvements in survival, as well as reduced rate of decline in cognitive function, and gross motor function. The treatment also appeared well tolerated with no serious or treatment related effects; adverse effects observed appeared mainly due to pre-treatment procedures (conditioning treatment) and MLD disease progression. However, further data is required to confirm these findings and further follow-up of existing studies is ongoing.
#22 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches
https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/
However, with supportive treatment, including a gastric tube insertion for feeding and antibiotic therapy during infections, patients could survive in a vegetative state for years. […] In patients with a late infantile MLD form CNS symptoms are often preceded by rapidly progressive peripheral neuropathy, which is characterized by clumsiness, muscle weakness, sensory deficits and areflexia. […] In patients who received HSCT before or immediately after the symptom onset, the disease stabilizes and the rate of loss of gross motor and cognitive functions decreases. […] However, stabilization of disease severity observed on MRI (reduction of CNS demyelination) does not mean stabilization of peripheral nerve disease and the effect of HSCT on the development of peripheral neuropathy remains controversial. […] The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Thus, gene and gene-cell therapy have so far shown safety and efficacy in clinical trials.
#23 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
Initial data on patients treated with atidarsagene autotemcel, albeit in only one trial plus EAF, showed promising results particularly when used in patients treated before symptoms appear (pre-symptomatic). This included apparent improvements in survival, as well as reduced rate of decline in cognitive function, and gross motor function. The treatment also appeared well tolerated with no serious or treatment related effects; adverse effects observed appeared mainly due to pre-treatment procedures (conditioning treatment) and MLD disease progression. However, further data is required to confirm these findings and further follow-up of existing studies is ongoing.
#24 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
Initial data on patients treated with atidarsagene autotemcel, albeit in only one trial plus EAF, showed promising results particularly when used in patients treated before symptoms appear (pre-symptomatic). This included apparent improvements in survival, as well as reduced rate of decline in cognitive function, and gross motor function. The treatment also appeared well tolerated with no serious or treatment related effects; adverse effects observed appeared mainly due to pre-treatment procedures (conditioning treatment) and MLD disease progression. However, further data is required to confirm these findings and further follow-up of existing studies is ongoing.
#25 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
Overall, this systematic review indicates that compared to NHx and HSCT, treatment with arsa-cel results in clinically relevant benefits in LI and EJ MLD patients by preserving cognitive function and motor development in most patients, and increased survival for LI patients. Nevertheless, further research is required to confirm these findings, given they are based on results from non-RCT studies. […] In LI patients, survival for atidarsagene autotemcel appeared longer than for NHx and HSCT as observed in other studies. Survival for EJ patients appeared to be similar between atidarsagene autotemcel treated, HSCT recipients and the NHx cohort. However, no LI and only 15% of EJ patients treated with atidarsagene autotemcel were observed to have died due to disease progression over about 3 years, in contrast to 50% of LI and 20% of J patients treated with HSCT within 1 year.
#26 A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02814-2
Initial data on patients treated with atidarsagene autotemcel, albeit in only one trial plus EAF, showed promising results particularly when used in patients treated before symptoms appear (pre-symptomatic). This included apparent improvements in survival, as well as reduced rate of decline in cognitive function, and gross motor function. The treatment also appeared well tolerated with no serious or treatment related effects; adverse effects observed appeared mainly due to pre-treatment procedures (conditioning treatment) and MLD disease progression. However, further data is required to confirm these findings and further follow-up of existing studies is ongoing.